Pharma Tips

Anti Cancer Drug

By: Pharma Tips | Views: 2532 | Date: 18-Jun-2010

Anticancer, or antineoplastic, drugs are used to treat malignancies, or cancerous growths. Drug therapy may be used alone, or in combination with other treatments such as surgery or radiation therapy.

Anti Cancer Drug

Anti Cancer



Number of Drugs Under Clinical Development in Different Tumor Types
Source: Pharmaceutical Research and Manufacturers of America, 2012, Medicine in Development for Cancer




INTRODUCTION
Definition
Anticancer, or antineoplastic, drugs are used to treat malignancies, or cancerous growths. Drug therapy may be used alone, or in combination with other treatments such as surgery or radiation therapy.

Cell Cycle
Cell proliferation is involved in many physiological and pathological processes including growth, healing, repair, hypertrophy, hyperplasia and the development of tumours. Angiogenesis (the development of new blood vessels) necessarily occurs during many of these processes. 

Proliferating cells go through what is termed the cell cycle, during which the cell replicates all its components and then bisects itself into two identical daughter cells. Important components of the signalling pathways in proliferating cells are receptor tyrosine kinases or receptor-linked kinases, and the mitogen-activated kinase cascade. In all cases, the pathways eventually lead to transcription of the genes that control the cell cycle.

THE CELL CYCLE
The cell cycle is an ordered series of events consisting of several sequential phases: G1, S, G2 and M.
• M is the phase of mitosis 
• S is the phase of DNA synthesis 
• G1 is the gap between the mitosis that gave rise to the cell and the S phase; during G1, the cell is preparing for DNA synthesis 
• G2 is the gap between S phase and the mitosis that will give rise to two daughter cells; during G2, the cell is preparing for the mitotic division into two daughter cells. 

Description
Several classes of drugs may be used in cancer treatment, depending on the nature of the organ involved. For example, breast cancers are commonly stimulated by estrogens, and may be treated with drugs that inactivate the sex hormones. Similarly, prostate cancer may be treated with drugs that inactivate androgens, the male sex hormone. However, the majority of antineoplastic drugs act by interfering with cell growth. Since cancerous cells grow more rapidly than other cells, the drugs target those cells that are in the process of reproducing themselves. As a result, antineoplastic drugs will commonly affect not only the cancerous cells, but others cells that commonly reproduce quickly, including hair follicles, ovaries and testes, and the blood-forming organs.
Newer methods of antineoplastic drug therapy have taken different approaches, including angiogenesis—the inhibition of formation of blood vessels feeding the tumor and contributing to tumor growth. Although these approaches hold promise, they are not yet in common use. Developing new anticancer drugs is the work of ongoing research. In 2003, a new technique was developed to streamline the search for effective drugs. Researchers pumped more than 23,000 chemical compounds through a screening technique to identify those that help fight cancer while leaving healthy cells unharmed. The system identified nine compounds matching the profile, including one previously unidentified drug for fighting cancer. They have expanded their research to determine how the drug might be developed. This was an important step
Antineoplastic drugs may be divided into two classes: cycle specific and non-cycle specific. Cycle specific drugs act only at specific points of the cell's duplication cycle, such as anaphase or metaphase, while non-cycle specific drugs may act at any point in the cell cycle. In order to gain maximum effect, antineoplastic drugs are commonly used in combinations.

Precautions
Because antineoplastic agents do not target specific cell types, they have a number of common adverse side effects. Hair loss is common due to the effects on hair follicles, and anemia, immune system impairment, and clotting problems are caused by destruction of the blood-forming organs, leading to a reduction in the number of red cells, white cells, and platelets. Because of the frequency and severity of these side effects, it is common to administer chemotherapy in cycles, allowing time for recovery from the drug effects before administering the next dose. Doses are often calculated, not on the basis of weight, but rather based on blood counts, in order to avoid dangerous levels of anemia (red cell depletion), neutropenia (white cell deficiency), or thrombocytopenia (platelet deficiency.)
The health professional has many responsibilities in dealing with patients undergoing chemotherapy. The patient must be well informed of the risks and benefits of chemotherapy, and must be emotionally prepared for the side effects. These may be permanent, and younger patients should be aware of the high risk of sterility after chemotherapy.
The patient must also know which side effects should be reported to the practitioner, since many adverse effects do not appear until several days after a dose of chemotherapy. When chemotherapy is self-administered, the patient must be familiar with proper use of the drugs, including dose scheduling and avoidance of drug-drug and food-drug interactions.
Appropriate steps should be taken to minimize side effects. These may include administration of antinauseant medications to reduce nausea and vomiting, maintaining fluid levels to reduce drug toxicity, particularly to the kidneys, or application of a scalp tourniquet to reduce blood flow to the scalp and minimize hair loss due to drug therapy.
Patients receiving chemotherapy also are at risk of infections due to reduced white blood counts. While prophylactic antibiotics may be useful, the health care professional should also be sure to use standard precautions, including gowns and gloves when appropriate. Patients should be alerted to avoid risks of viral contamination, and live virus immunizations are contraindicated until the patient has fully recovered from the effects of chemotherapy. Similarly, the patient should avoid contact with other people who have recently had live virus immunizations.
Other precautions which should be emphasized are the risks to pregnant or nursing women. Because antineoplastic drugs are commonly harmful to the fetus, women of childbearing potential should be cautioned to use two effective methods of birth control while receiving cancer chemotherapy. This also applies if the woman's male partner is receiving chemotherapy. Breastfeeding should be avoided while the mother is being treated.

TYPES OF CANCERS
Cancer is a group of many related diseases that begin in cells, the body's basic unit of life. Normally, cells grow and divide to produce more cells only when the body needs them. Sometimes, however, cells become abnormal and keep dividing to form more cells without control or order, creating a mass of excess tissue called a tumor. Tumors can be malignant (cancerous) or benign (not cancerous).

The cells in malignant tumors can invade and damage nearby tissue and organs. Cancer cells can also break away from a malignant tumor and travel through the bloodstream or lymphatic system to form new tumors in other parts of the body.

Most cancers are named for the organ or type of cell in which they begin. For example, cancer that begins in the lung is lung cancer, and cancer that begins in cells in the skin known as melanocytes is called melanoma. 

When cancer cells spread (metastasize) from their original location to another part of the body, the new tumor has the same kind of abnormal cells and the same name as the primary tumor. For example, if lung cancer spreads to the brain, the cancer cells in the brain are actually lung cancer cells. The disease is called metastatic lung cancer (it is not brain cancer).

Use the links below to find information on specific types of cancer, including treatment options, expertise at The James, clinical trials, and frequently asked questions. 
Common Cancers
• Bone Cancer 
• Brain Cancer 
• Breast Cancer 
• Endocrine Cancer 
• Gastrointestinal Cancer 
• Gynecologic Cancer 
• Head & Neck Cancer 
• Leukemia 
• Lung Cancer 
• Lymphoma 
• Multiple Myeloma 
• Prostate Cancer 
• Skin Cancer 
• Soft Tissue Sarcoma

ETIOLOGY

What are the Causes and Risk Factors for Cancer?
• Tobacco
According to the National Cancer Institute, smoking causes 30% of all cancer deaths in the U.S. and is responsible for 87% of cases of lung cancer. Not only does it affect the lungs, it can cause kidney, pancreatic, cervical, and stomach cancers and acute myeloid leukemia. Quitting smoking immediately decreases your risk factor for cancer.
• Physical Activity
Exercising at least 30 minutes a day, 5 days a week greatly reduces your cancer risk. Exercises like yoga, aerobics, walking and running are great activities to lower your cancer risk factor. Not only is physical activity important to preventing other diseases, it reduces the chances of becoming obese. Obesity is a major cause for many cancers. Exercising on a regular basis can prevent prostate, colon, breast, endometrial and lung cancer.
• Genetics
Genetics can play a big role in cancer development. If you have a family history of cancer, such as breast cancer, taking extra precautions is vital. When cancer is genetic, a mutated gene has been passed down. Genetic tests are available for many hereditary cancers. Keep in mind that if you have a family history of cancer, it does not mean you will develop it. You only have a greater chance of developing it.
• Environmental Factors
the environment you are in, can cause cancer. Exposure to asbestos, a group of minerals found in housing and industrial building materials can cause a variety of medical problems, such as mesothelioma.
Studies have shown that people who are exposed to high amount of benzene are at risk for cancer. Benzene is a chemical found in gasoline, smoking, and pollution.
• Unsafe Sex
practicing unsafe sex can increase your risk of developing a virus called HPV. HPV is a group of over 100 viruses, medically known as human papillioma virus. HPV increases your risk factor for cervical, anal, vulvar and vaginal cancer. Further studies are being conducted in HPV's role in the development of other cancers. 

There is a test available to see if you have contracted HPV. It involves scraping of cervical cells and then the sample is sent to a lab. The lab test can even identify the strain of the virus, also.
• Sun Exposure
Skin cancer is caused by exposure to the UV rays of the sun. Sunburn or a tan is actually the result of cell damage caused by the sun. Skin cancer can be prevented in most cases. Wearing sunscreen when outdoors and staying out of the sun between the hours of 10 a.m. and 2 p.m., when the sun's rays are strongest is your best defense.
Our current strategy against cancer is to eradicate the disease after detection. The ideal strategy is prevention, but this is not possible in most cases because the exact cause or causes of most cancers are unknown. The major exception to this is lung cancer; in which there is no doubt that cigarette smoking is the major contributing factor. Thus, lung cancer is largely a preventable cancer.
More and more studies are revealing highly suggestive clues about the causes of cancer. In this section, we will briefly survey the known and suspected causes of cancer, which fall into two broad categories: environmental and hereditary.
In addition, the oncogene concept, which is the most recent theory of cancer etiology, will be reviewed. Oncology nurses must be knowledgeable about the risk factors that may predispose individuals and
Family members to certain types of cancer. This knowledge base will allow participation in screening programs and appropriate education and counseling.

Table 1

Site Predisposing Factor
Breast Age over 40; late first full-term pregnancy; early-age menarche; late
menopause; familial history of breast cancer
Cervix Women who begin sexual activity at an early age and have multiple
partners; human papilloma virus exposure
Colon And Rectum Familial polyposis; ulcerative colitis over many years; diet high in fat,
low in fiber
Lung Cigarette smoking; exposure to asbestos, uranium, and nickel
Skin Farmers and other outdoor workers; fair-skinned individuals who
sunburn easily
Mouth Alcohol plus smoking; smokeless tobacco
Thyroid X-ray therapy of neck as infants
Urinary bladder Aniline-dye exposure; exposure to parasite Schistosoma haematobium;
cigarette smoking
Leukemia Exposure to benzene; ionizing radiation

ENVIRONMENTAL FACTORS
The role of environmental factors in human cancer was demonstrated more than 200 years ago by the English physician Percival Pott. In those days, young boys hung on ropes to clean the soot from inside chimneys. In 1775, Pott recognized a relationship between prolonged exposure to the irritating effects of chimney soot and the subsequent
development of scrotal cancer in these young boys. Since then, evidence documenting environmental factors in the etiology of cancer has continued to accumulate. Today, it is estimated that environmental factors may be involved in a significant percentage of cancers.

The Industrial Environment
Some occupations have been implicated in the etiology of cancer. For example, workers in the aniline dye industry have an increased risk of developing bladder cancer. Lung cancer is more prevalent among those who mine or work with asbestos and those working with chromate or uranium ores, especially if they also smoke cigarettes. Workers in nickel-refining plants are more likely to develop cancer of the nasal sinuses than are average individuals. Exposure to certain solvents, e.g., benzene, has been associated with an incidence of leukemia. Asbestos workers may develop mesotheliomas of the pleural or peritoneal cavities.

Ultraviolet Light and Irradiation
Excessive exposure to sunlight is responsible for a high incidence of skin cancer among farmers and other outdoor workers. Fair-skinned individuals who sunburn easily also are at high risk for developing skin cancer. Cancer of the thyroid is more common in individuals who received irradiation to the neck as children. The survivors of the A-bomb explosions at Hiroshima and Nagasaki are subject to an increased incidence of cancers, particularly acute myelogenous leukemia. Although not a common cause of cancer, radiation exposure does increase the risk of lung cancer in the uranium, strontium, nickel, and beryllium industries. An increased incidence of leukemia has been reported after exposure to radiation.

Cigarette Smoke
Cigarette smokers run a much greater risk of developing lung cancer than do nonsmokers.
Increasing incidence of lung cancers in women is directly linked to the increase in smoking of this population. Smoking-related illnesses cause more than 419,000 premature deaths every year. We must emphasize that lung cancer is largely a preventable disease.

Diet
Aside from prostate cancer in men and breast cancer in women, the yearly number of new cases of colorectal cancer (131,200) in the US is second only to lung cancer. It is suspected that this high incidence is due, in part, to diet. As refrigeration and processed food have led to a reduction in roughage and bulk (non-digestible complex carbohydrates)
In the typical Western diet, the incidence of colon cancer has increased and stomach cancer decreased. Populations who traditionally have a non-Western diet high in fiber have a very low incidence of colorectal cancer but a high incidence of stomach cancer. The precise reasons for these epidemiologic observations are uncertain, but clearly diet influences cancer development. Research in Africa, England, and India by Dr. Denis Burkitt and others has shown a direct relationship between the fiber content of food an intestinal bulk. Bulk fiber represents nonabsorbable sugars which increase intestinal mass and may actually change the intestinal milieu, particularly the transit time of carcinogens and the type of bacteria present. Unlike low-fiber foods, those with a high fiber content produce greater waste bulk, which moves through the intestine faster and produces large, soft stools that are easy to excrete. Low-fiber foods may produce a reverse effect, resulting in greater formation of potential carcinogens in the large bowel by the action of certain bacteria on bile salts. Burkitt postulates that bile salts in the colon may be increased by the greater consumption of fat in Western countries. It is not known whether bacteria may be affected by changes in fat, fiber, or both food constituents. In any event, a low-residue (low bulk fiber) diet produces a small stool that tends to take longer to pass
Through the intestine, allowing the bacteria more time to degrade bile salts.

Thus, any carcinogen formed has longer contact with the bowel lining and a greater opportunity to cause cancer. Diet also seems to be related to the high incidence of liver cancer among certain groups of black Africans living in Africa, compared to American blacks. The high incidence among black Africans in Africa correlates with the eating of foods (especially peanuts) contaminated with a fungus known as Aspergillus flavus. This fungus produces a highly carcinogenic substance known as aflatoxin. On the other hand, chronic hepatitis is known to predispose to the development of liver cancer, and chronic hepatitis is very common in Africa and Asia.

An association between high-fat diets and breast cancer has been suggested from several different sources of data. Epidemiologic data cannot, however, establish a firm cause-effect relationship, and the resolution of this issue must await clinical studies of the influence of a reduced-fat diet on breast cancer incidence. Lung cancer has been associated with low intake of vitamin A. Attempts to reduce the incidence of lung cancer by administration of vitamin A–like compounds (retinoids) have not been successful. The American Cancer Society has recently developed dietary guidelines, as seen in Table 2 below.


TABLE 2
Nutrition and Cancer: Dietary Recommendations
Choose most of the foods you eat from plant sources.
• Eat five or more servings of fruits and vegetables each day.
• Eat other foods from plant sources, such as breads, cereals, grain products, rice, pasta,
or beans several times each day.
Limit your intake of high-fat foods, particularly from animal sources.
• Choose foods low in fat.
• Limit consumption of meats, especially high-fat meats.
Be physically active: achieve and maintain a healthy weight.
• Be at least moderately active for 30 minutes or more on most days of the week.
• Stay within your healthy weight range.
Limit consumption of alcoholic beverages, if you drink at all.

Other Environmental Factors
The parasite Schistosoma haematobium, common in some parts of the world such as Egypt, can cause bladder cancer. The parasite enters the body through the skin as workers stand in infested waters. It then migrates to the bladder. Long-term infestation is associated with an increased incidence of bladder cancer. Smoking is also implicated in the risk of developing bladder cancer. The exact mechanism is unknown, but statistics show that there is a correlation between smoking and an increased incidence of bladder cancer. Alcohol is thought to be a carcinogen or cocarcinogen (along with cigarette smoke) for cancers of the head, neck, and esophagus. It may also play a role in the etiology of liver cancer. Women who become sexually active at an early age and who have multiple partners are at greater than normal risk of developing cervical cancer.

DRUGS AND CANCER

Immunosuppressive and Cytotoxic Induced Cancer

A number of drugs in clinical use have also been rarely associated with cancer. The majority of the highly implicated agents are immunosuppressive agents, principally the antimetabolites and glucocorticosteroids. Table 3 lists the different drugs that are associated with possible carcinogenesis in man. It should be kept in mind that the risk of developing drug-induced cancer is dependent on several nondrug factors:
1) Age at first exposure (younger age increases risk); 
2) The long latency period between exposure and cancer development (an average of 40–50 years in industrial exposures, 5–10 years for drugs); and 
3) The presence of cocarcinogens (such as cigarette smoking or ionizing radiation).
The most highly implicated carcinogenic drugs are anticancer agents, and the major cancers produced are leukemias and lymphomas. Acute myelocytic leukemia is an unfortunate and rare complication of alkylating agents such as melphalan and cyclophosphamide. The drugs most commonly associated with second neoplasms are the alkylating agents. These drugs bind to DNA and induce mutations. Radiotherapy
Potentiates the leukemogenic action of alkylating agents. Immunosuppression secondary to chemotherapy, AIDS, or immunosuppressive drugs may lead to Epstein-Barr virus (EBV)–induced non- Hodgkin’s lymphoma.

Table 3

Cancers Associated With Drugs in Common Clinical Usage
Agent Patient
Population Associated Cancers
Cyclophosphamide Cancer Bladder cancer, acute myelogenous leukemia (AML)
Melphalan Multiple myeloma AML
Azathioprine and
cyclosporine Allotransplants recipients Non-Hodgin’s lymphomas, skin cancers
Nitrogen mustard, procarbazine,
ionizing radiation Cancer AML

Synthetic 
(diethylstilbestrol) Females Vagina, cervix                 (adenocarcinoma)
Phenacetin-containing drugs Over-the-counter pain treatment Renal pelvis
carcinoma

HORMONES AND CANCER

Some hormones are thought to possess carcinogenic potential and this is important in three cancers.
1. Breast Cancer:  Large doses of estrogens, when given continuously, can cause breast cancer in susceptible strains of mice. Animal studies also show that estrogen is a cocarcinogen; e.g., it is carcinogenic when administered experimentally along with another cancer-causing agent such as x-rays or the chemical methylcholanthrene.
The animal data have raised concern that women who take birth control pills, or who receive estrogen supplements at menopause, might incur an increased risk of cancer. Most of the largescale studies suggest that exogenous estrogen probably is not a significant factor in human breast cancer, although some experts still feel that the safety of estrogen has not been proven.

2. Endometrial Cancer:  Many scientists now suspect that estrogen increases the hazard of developing cancer of the uterine endometrium. This is based upon several case-control studies reporting an increased risk of malignancy in women receiving estrogen supplements—though other studies report no such increases, and still other studies find an actual decrease in the risk. Despite the possible hazard of increased malignancy,
Many doctors now feel that low-dose estrogen supplementation is safe for menopausal
or oophorectomized women who have symptoms of estrogen deficiency. One consequence of low estrogen levels is osteoporosis, which greatly increases the risk of serious injury from bone fractures.

3. Vaginal Adenocarcinoma:  In 1947, it was thought that synthetic estrogens such as DES (diethylstilbestrol) were well tolerated in pregnancy, safe for the fetus, and effective for preventing abortion. As a result, DES and related synthetic estrogens were widely prescribed until a 1977 study showed that the daughters of DES-treated mothers had an increased incidence of vaginal dysplasia and carcinoma. Because the use of DES in pregnancy has been stopped, this complication will cease to be a problem in a few years.

4. Prostate Cancer:  The most important risk factor in prostate cancer is age, but testosterone after being metabolized to dihydrotestosterone is a potent stimulator of cell division in prostate cells. Dihydrotestosterone may be involved in malignant transformation, and studies are under way to determine whether inhibition of dihydrotestosterone production will reduce the incidence of prostate cancer.

HEREDITARY FACTORS
Evidence supporting the role of genetic factors in cancer comes primarily from animal studies. Breeding experiments with mice led to the development of mouse families with very high incidences of specific cancers, such as lung and breast cancer. Other selected mating of mice produced families that were essentially cancer-free. Statistical evidence supports the genetic etiology of cancer in humans. The best example of a hereditary cancer in man is retinoblastoma, a relatively uncommon neoplasm of children. However,
genetic factors probably play an important role in the familial tendencies toward some common cancers such as cancer of the colon (familial polyposis), hereditary nonpolyposis colorectal cancer (HNPCC), breast cancer, and stomach cancer. A genetic history is an essential part of every cancer patient’s medical history. Breast cancer is one
of the best examples of a malignancy for which a genetic predisposition influences clinical practice. The incidence of breast cancer may double or more than double when one or more female relatives of a woman have had breast cancer. Hence, knowledge
of a family’s cancer history can help in planning early detection programs for high-risk subjects. The recent identification of two genes associated with an increased risk of breast cancer, ovarian cancer, and prostate cancer (BRCA1, BRCA2) has raised the possibility of testing for genetic susceptibility. As yet, the technological advances necessary
to move this from a research to a practical clinical setting have not been made.

ONCOGENES
The most enduring hypothesis concerning the origin of cancer is that some genetic alteration, induced by elements in the environment, acts on a genetically determined predisposition and results in the unregulated proliferation of cells. One very exciting new area of cancer research, which serves to combine hereditary and environmental factors, is the study of oncogenes. Oncogene is derived from two Greek words: Onkos means bulk or mass and refers to a tumor, or has some relationship to a tumor, while gene, which is
the functional unit of heredity is derived from the word genos, meaning birth. Therefore, something that causes a tumor is said to be oncogenic and a gene that when activated causes a cancer is an oncogene. Each cell contains a set of genes that are essential
for embryonic tissue development, tissue repair, and normal proliferation. The control of stem cell proliferation is exercised via these special genes. It now appears that these genes are activated by radiation, chemicals, viruses, and other as yet undefined factors. These oncogenes then act as cellular transforming genes, causing uncontrolled
proliferation of previously normal cells. Certain proteins produced by oncogenes have
been identified, and in some cases the proteins form cell surface receptors for growth factors, intracellular signals that turn on or turn off cell growth, and factors that alter the expression of DNA. Our understanding of the biochemical mechanisms involved in cancer offers the potential for improved detection, prognosis, and treatment. Table 8 lists some of the oncogenes that have been associated with specific human cancers. Many of these oncogenes are silent until the gene moves or translocates from one chromosome to
another. This chromosomal breakage and reunion is known to occur in several cancers, including chronic leukemias and lymphomas. Some genes suppress abnormal cell growth and when they are damaged or missing, cancer is more likely to develop. The best example of this type of gene is the retinoblastoma (RB) gene.

VIRUSES
Oncogenes were first identified in viruses that cause cancer in animals. Later it was learned that the viruses had captured a normal host gene that regulated stem cell proliferation. These oncogenic viruses caused cancer by activating that normal
host gene inside a host cell. It is known that members of a group of small DNA
viruses called papovaviruses cause a variety of animal tumors. Among them are the papilloma viruses, responsible for papillomas in rabbits, and the polyoma virus, which causes malignant tumors of the parotid gland, mammary gland, and kidney as well as subcutaneous fibrosarcomas when injected into mice. Also, ribonucleic acid (RNA)
viruses have been shown to cause leukemias in chickens, mice, and cats, and mammary carcinomas in mice. A human retrovirus, human T-cell lymphotropic virus (HTLV-1), has been recognized as the etiologic agent of an aggressive form of leukemia known as adult T-cell leukemia/lymphoma (ATLL). Also, in African Burkitt’s lymphoma, a viral etiology seems possible. Generally, it occurs between the ages of 2 and 14, with a peak incidence at age 7. It is a cancer of the B-cell lymphocytes, and it is common in areas of the world where malaria is endemic. Viral involvement in Burkitt’s lymphoma is difficult
to discount because cells from nearly every biopsy of African Burkitt’s lymphoma contain a herpes virus: the Epstein-Barr virus. EBV is also associated with carcinoma of the nasopharynx, a common malignancy in Southern China, Malaysia, Indonesia, and parts of Africa. EBV has also been implicated in the etiology at Hodgkin’s disease and
in non-Hodgkin’s lymphoma in patients who are immunosuppressed. Another factor implicating viruses in causing human cancers is that carcinomas of the cervix are more common after infection by the type II herpes virus. In spite of such data, however, more research is needed to prove conclusively that viruses cause human cancers. Furthermore, we need to determine whether these viruses cause human cancer directly or indirectly by activating a host oncogene. Table 4 lists the human cancers that have been associated with a specific oncogenic virus.


Table 4
Examples of Oncogenes and Cancer Suppressor Genes Associated With Human Cancers

GENE TUMORS
MYC Many solid tumors and hematologic malignancies
N-MYC Neuroblastoma and lung cancers
L-MYC Small cell lung cancer
RAS Many solid tumors
p53 Many sporadic malignancies (most commonly mutated cancer gene);
when inherited, causes the Li-Fraumeni familial cancer syndrome
BRCA1 Breast cancer, ovarian cancer, prostate cancer
BRCA2 Breast and ovarian cancer
APC Colon familial polyposis (a premalignant condition)
MSH, MLH Mismatch repair genes associated with hereditary nonpolyposis
colon cancer (HNPCC)
DCC Colon cancer
RB Retinoblastoma and some other tumors
NF1, NF2 Neurofibroma
C-ERB-β2 Breast cancer (also called HER-2/neu), other tumors
ABL Chronic myeloid leukemia
WT1 Wilms’ tumor
ATM Ataxia telangiectasia associated with multiple cancers
MEN Multiple endocrine neoplasia syndrome
HPC1 Prostate cancer
VHL Renal and some other cancers
PTCH Basal cell cancers (Gorlin syndrome)
p16 Melanoma
BCL-2 Non-Hodgkin’s lymphoma

SUMMARY
This section has dealt with the causes of cancer. Environmental factors may be important in a significant percentage of human cancers. Such factors as exposure to radiation, nickel dust, uranium dust, strontium, and cigarette smoking are all suspected causes of cancer. Dietary factors, immunosuppressive and cytotoxic drugs, and hormones also play a role. It is believed that heredity plays a role in developing cancer. Statistical evidence supports a genetic etiology of some cancers in humans. Some scientists think that cancer is not caused by a single agent or factor, but by the interplay of several factors that combine to cause the “normal” cell to change into a “malignant” cell. lt is generally
believed that transformation of the normal cell into a malignant cell occurs when one or more oncogenes are activated.

Table 5
Human Viruses Associated With Cancer

VIRUS TYPE ASSOCIATED CANCER COFACTORS
Herpes Epstein-Barr Burkitt’s lymphoma 
Lymphoma Malaria Immunodeficiency
Papillomavirus HPV-16, -18, -33,    -39
HPV-5, -18, -17 Anogenital cancers

Skin cancer Smoking (?),
other factors
Sunlight, genetic
disorders, immune
suppression
Hepatitis HBV, HCV Hepatocellular,
carcinoma Aflatoxin,  alcohol
Retrovirus HTLV-1


HTLV-2 Adult T-cell 
leukemia/lymphoma

Hairy cell leukemia Uncertain
Unknown

CLASSIFICATION OF ANTICANCER DRUGS

1. Polyfunctional alkylating agents  
o Nitrosoureas
o Mustards (Nitrogen Mustards)
o Methanesulphonates (Busulphan)
o Ethylenimines

2. Other Alkylating Drugs 
o Procarbazine (Matulane) 
o Dacarbazine (DTIC) 
o Altretamine (Hexalen) 
o Cisplatin (Platinol) 

3. Antimetabolites
o Antifolic acid compounds (Methotrexate)
o Amino acid Antagonists (Azaserine)

4. Purine antagonists 
o Mercaptopurine (6-MP)
o Thioguanine (6-TG)
o Fludarabine Phosphate 
o Cladribine (Leustatin) 
o Pentostatin (Nipent)

5. Pyrimidine antagonists 
o Fluorouracil (5-FU) 
o Cytarabine (ARA-C) 
o Azacitidine

6. Plant alkaloids 
o Vinblastine (Velban) 
o Vincristine (Oncovin) 
o Etoposide (VP-16,VePe-sid) 
o Teniposide (Vumon) 
o Topotecan (Hycamtin) 
o Irinotecan (Camptosar) 
o Paclitaxel (Taxol) 
o Docetaxel (Taxotere) 

7. Antibiotics 
o Anthracyclines 
 Doxorubicin (Adriamycin, Rubex, Doxil) 
 Daunorubicin (DaunoXome) 
o Dactinomycin (Cosmegen) 
o Idarubincin (Idamycin) 
o Plicamycin (Mithramycin) 
o Mitomycin (Mutamycin) 
o Bleomycin (Blenoxane)


8. Monoclonal Antibodies
o Introduction 
o Examples

9. Hormonal agents 
o Introduction 
o Tamoxifen (Nolvadex) 
o Flutamide (Eulexin) 
o Gonadotropin-Releasing Hormone Agonists 
 (Leuprolide and Goserelin (Zoladex)) 
o Aromatase Inhibitors 
 Aminoglutethimide 
 Anastrozole (Arimidex) 
10. Miscellaneous anticancer drugs 
o Amsacrine 
o Hydroxyurea (Hydrea) 
o Asparaginase (El-spar) 
o Mitoxantrone (Novantrone) 
o Mitotane 
o Retinoic Acid Derivatives 
o Bone Marrow Growth Factors 
o Amifostine 

Newer and experimental approaches

Hematopoietic stem cell transplant approaches
Stem cell harvesting and autologous or allogeneic stem cell transplant has been used to allow for higher doses of chemotheraputic agents where dosages are primarily limited by hematopoietic damage. Years of research in treating solid tumors, particularly breast cancer, with hematopoeitic stem cell transplants, has yielded little proof of efficacy. Hematological malignancies such as myeloma, lymphoma, and leukemia remain the main indications for stem cell transplants.
Isolated infusion approaches
Isolated limb perfusion (often used in melanoma), or isolated infusion of chemotherapy into the liver or the lung have been used to treat some tumours. The main purpose of these approaches is to deliver a very high dose of chemotherapy to tumor sites without causing overwhelming systemic damage. These approaches can help control solitary or limited metastases, but they are by definition not systemic, and, therefore, do not treat distributed metastases or micrometastases.
Targeted delivery mechanisms
Specially-targeted delivery vehicles aim to increase effective levels of chemotherapy for tumor cells while reducing effective levels for other cells. This should result in an increased tumor kill and/or reduced toxicity.
Specially-targeted delivery vehicles have a differentially higher affinity for tumor cells by interacting with tumor-specific or tumour-associated antigens.
In addition to their targeting component, they also carry a payload - whether this is a traditional chemotherapeutic agent, or a radioisotope or an immune stimulating factor. Specially-targeted delivery vehicles vary in their stability, selectivity, and choice of target, but, in essence, they all aim to increase the maximum effective dose that can be delivered to the tumor cells. Reduced systemic toxicity means that they can also be used in sicker patients, and that they can carry new chemotherapeutic agents that would have been far too toxic to deliver via traditional systemic approaches.
Nanoparticles
Nanoparticles have emerged as a useful vehicle for poorly-soluble agents such as paclitaxel. Protein-bound paclitaxel (e.g., Abraxane) or nab-paclitaxel was approved by the U.S. Food and Drug Administration (FDA) in January 2005 for the treatment of refractory breast cancer, and allows reduced use of the Cremophor vehicle usually found in paclitaxel. Nanoparticles made of magnetic material can also be used to concentrate agents at tumour sites using an externally applied magnetic field.

Polyfunctional alkylating agents

• Common Structural Features: 
o bis(chloroethyl)amine 
o ethylenimine 
o nitrosoureas 
• Not cell-cycle specific: Cells most susceptible in late G1 and S phase-- Blocks in G2 
Most useful agents: 
• Cyclophosphamide (Cytoxan) 
o fosfamide 
• Mechlorethamine 
• Melphalan (Alkeran) 
• Chlorambucil (Leukeran)  Secondary agents 
• Thiopeta (Thioplex) 
o Ovarian cancer 
• Busulfan (Myleran) 
o Chronic myeloid leukemia 

Major nitrosoureas:
• Carmustine (BCNU) 
• Lomustine (CCNU) 
• Semustine (methyl CCNU) 

Polyfunctional Alkylating Drugs:
Mechanism of Action:
• Alkyl group transfer 
o Major interaction: Alkylation of DNA 
 Primary DNA alkylation site: N7 position of guanine (other sites as well) 
 interaction may involve single strands or both strands (cross linking, due to bifunctional [2 reactive centers] characteristics) 
o Other interactions: these drugs react with carboxyl, sulfhydryl, amino, hydroxyl, and phosphate groups of other cellular constituents 
o These drugs usually form a reactive intermediate -- ethyleneimonium ion 
Polyfunctional Alkylating Drug Resistance
• Increased ability to repair DNA defects 
• Decreased cellular permeability to the drug 
• Increased glutathione synthesis 
o inactivates alkylating agents through conjugation reactions (catalyzed by glutathione S-transferase) 

Polyfunctional Alkylating Drugs:
S.A.R.
Genotoxic carcinogens, able to damage DNA by alkylation reactions, represent a very diverse class of agents which are capable of producing a wide range of DNA modifications. The mechanisms leading to genetic changes as a result of exposure to alkylating agents (AAs) have been studied in male germ cells of Drosophila using a structure-activity relationship approach (SAR). The analytical tools available concern both genetic and molecular assays. The genetic tests enable to quantify excision repair and clastogenic potency of the AA after treatment of post-meiotic male germ cells and to determine the degree of germ-cell specificity, i.e., the mutagenic effectiveness in post- versus premeiotic cell stages. For a selected group of alkylating agents the molecular spectra have been studied in post-meiotic cell stages. On the basis of these descriptors clear SAR's between genotoxic activity in germ cells and physico-chemical parameters (s-values and O6/N7-alkylguanine adducts) and carcinogenic potency in rodents became apparent, resulting in five distinct classes of alkylating agents so far. These classes are: 1) SN2-type monofunctional AAs, 2) SN1-type monofunctional AAs, 3) polyfunctional AAs, 4) agents able to form etheno-DNA adducts, and 5) aflatoxin B1 (AFB1) a bulky-adduct forming agent. The recent finding that the molecular data obtained with Drosophila and data of the specific locus tests in male mice show remarkable similarities for most genotoxic agents supports the view that Drosophila is a useful model system for the study of transgenerational damage.

Pharmacological Effects: Polyfunctional Alkylating Drugs
•  Injection site damage (vesicant effects) and systemic toxicity. 
• Toxicity: 
o dose related 
o primarily affecting rapidly dividing cells 
  bone marrow 
  GI tract 
 nausea and vomiting within less than an hour-- with mechlorethamine, carmustine (BCNU) or cyclophosphamide 
 Emetic effects: CNS 
 reduced by pre-treatment with phenothiazines or cannabinoids. 
 gonads 

o Cyclophosphamide cytotoxicity depends on activation by microsomal enzyme system. 
 Hepatic microsomal P450 mixed-function oxidase catalyzes conversion of cyclophosphamide to the active forms: 
 4-hydroxycyclophosphamide 
 aldophosphamide 

o  Major Toxicity: bone marrow suppression 
 dose-related suppression of myelopoiesis: primary effects on 
 megakaryocytes 
 platelets 
 granulocytes 
 Bone marrow suppression is worse when alkylating agents are combined with other myelosuppressive drugs and/or radiation (dose reduction required) 
 If bone marrow suppression is severe, treatment may have to be suspended and then re--initiated upon hematopoietic recovery. 
 Long-term consequences of alkylating agent treatment include: 
 ovarian failure (common) 
 testicular failure (common) 
 acute leukemia (rare) 
• Oral Route of Administration:
Cyclophosphamide (Cytoxan), melphalan (Alkeran), chlorambucil (Leukeran), busulfan (Myleran), lomustine (CCNU, CeeNU) 
• Cyclophosphamide (Cytoxan):   most useful alkylating agent at present. 
• Busulfan (Myleran): specificity for granulocytes -- chronic myelogenous leukemia 


• Nitrosoureas: 
o  Not cross reactive (with respect to tumor resistance) with other alkylating drugs. 
o Nonenzymatic by transformation required to activate compounds. 
o Highly lipid- soluble-- crosses the blood-brain barrier (BBB) 
 useful in treating brain tumors 
o Act by cross-linking: DNA alkylation 
o More effective against cells in plateau phase than cells in exponential growth phase 
o Major route of elimination:urinary excretion 
o Steptozocin: 
 sugar-containing nitrosourea 
 minimal bone marrow suppression 
 effective in insulin-secreting islet cell pancreatic carcinoma and sometimes in non-Hodgkin's lymphoma 
SAR
A novel series of symmetrical ureas of [(7-amino(2-naphthyl))sulfonyl]phenylamines were designed, synthesized, and tested for their ability to increase glucose transport in mouse 3T3-L1 adipocytes, a surrogate readout for activation of the insulin receptor (IR) tyrosine kinase (IRTK). A structure-activity relationship was established that indicated glucose transport activity was dependent on the presence of two acidic functionalities, two sulfonamide linkages, and a central urea or 2-imidazolidinone core. Compound 30 was identified as a potent and selective IRTK activator. At low concentrations, 30 was able to increase the tyrosine phosphorylation of the IR stimulated by submaximal insulin. At higher concentrations, 30 was able to increase tyrosine the phosphorylation levels of the IR in the absence of insulin. When administered intraperitoneally (ip) and orally (po), 30 improved glucose tolerance in hypoinsulinemic, streptozotocin-treated rats. These data provide pharmacological validation that small molecule IRTK activators represent a potential new class of antidiabetic agents.

Other Alkylating Drugs
• Procarbazine (Matulane) 
o Methylhydrazine derivative 
o Active in Hodgkin's disease (combination therapy) 
o Teratogenic, mutagenic, leukemogenic. 
o  Side effects: 
 nausea, vomiting, myelosuppression 
 hemolytic anemia 
 pulmonary effects 
• Dacarbazine (DTIC) 
o Clinical use: 
 Melanoma 
 Hodgkin's disease 
 soft tissue sarcoma 
o Synthetic drug; requires activation by liver microsomal system. 
o Parenteral administration 
o  Side effects: 
 nausea, vomiting, myelosuppression 
• Altretamine (Hexalen) 
o Clinical use: 
 alkylating agent-resistant: ovarian carcinoma 
o Activated by biotransformation (demethylation) 
o  Side effects: 
 nausea, vomiting, central and peripheral nervous system neuropathies. 
 relatively mild myelosuppressive effects. 


• Cisplatin (Platinol) 

o Clinical use: 
 Genitourinary cancers 
 testicular 
 ovarian 
 bladder 
 In combination with bleomycin and vinblastine: curative treatment for nonseminomatous testicular cancer 
 Carboplatin (less GI and renal toxicity; with myelosuppressive toxicity): alternative to cisplatin 
o Inhibits DNA synthesis; cross-linking; guanine N7 site 
o Platinum compounds: synergistic with other anticancer agents 
o Site effects: 
 major acute effect: nausea, vomiting 
 relatively little bone marrow effects 
 significant renal dysfunction (minimized by adequate hydration/diuretics) 
 acoustic nerve dysfunction 

Alkylating Agent Toxicity: Summary
• IV mechlorethamine, cyclophosphamide, carmustine: Nausea and Vomiting (common) 
• Oral cyclophosphamide: Nausea and Vomiting (less frequently) 
•  Most Important Toxic Effect:Bone marrow suppression, leukopenia, thrombocytopenia 
o secondary to myelosuppression -- 
 severe infection 
 septicemia 
o hemorrhage 
• Cyclophosphamide (Cytoxan): 
Alopecia, hemorrhagic cystitis (may be avoided by adequate hydration) 

Antimetabolites
•  Structural analogues: Neoplastic cells’ metabolic differences -- increased susceptibility to actions of antimetabolites. 
• Most antimetabolites interfere with nucleic acid synthesis or nucleotide synthesis. 

Methotrexate (MTX)
N[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid

DRUG CLASS AND MECHANISM: 
Methotrexate is classified as an antimetabolite drug which means it is capable of blocking the metabolism of cells. (Metabolism consists of the production and destruction of important components of the cell as well as the production of energy for use by the cell.) As a result of this effect, it has been found helpful in treating certain diseases associated with abnormally rapid cell growth, such as cancer of the breast and psoriasis. Recently, methotrexate has been shown to be effective in inducing miscarriage, for example in patients with ectopic pregnancy. This effect of methotrexate is attributed to its action of killing the rapidly growing cells of the placenta. It has also been found very helpful in treating rheumatoid arthritis, although its mechanism of action in this illness is not known. It seems to work, in part, by altering immunity, which may play a role in causing rheumatoid arthritis. 

PREPARATIONS: 
Injectable: 25mg/ml; powder for injection 1 g. Tablet: 2.5, 5, 7.5, 10, and 15 mg 
STORAGE: 
Store at room temperature 15° to 30°C (59° to 86°F), avoid light. 
PRESCRIBED FOR: 
Methotrexate is used for cancer treatment generally in higher doses than for other uses and is often administered intravenously or intramuscularly. Methotrexate is used to treat psoriasis, an inflammatory skin disease, as well as the arthritis that occurs in 10 percent of these patients (psoriatic arthritis). It is also used to treat active rheumatoid arthritis in adults and children and other rheumatic diseases, including polymyositis and systemic lupus erythematosus. Methotrexate has been used to induce miscarriage in patients with ectopic pregnancies. 
DOSING: 
Methotrexate may be taken with or without food. 
For rheumatoid arthritis and psoriasis, the dose of Methotrexate is given WEEKLY, by injection or orally. 
For psoriasis, the starting oral dose is a single 7.5 mg dose weekly or 2.5 mg every 12 hours for three doses, once weekly
.

DRUG INTERACTIONS: 
Using nonsteroidal anti-inflammatory drugs (NSAIDs) before or during methotrexate treatment may result in serious adverse events because NSAIDS may increase the blood concentrations of methotrexate. Combining methotrexate with drugs that adversely affect the liver or kidneys may result in additional liver or kidney toxicity. 
PREGNANCY:
Methotrexate should not be used in pregnancy, as it can be toxic to the embryo and can cause fetal defects and spontaneous abortion (miscarriage). It should be discontinued prior to conception if used in either partner. Male patients should stop taking methotrexate at least 3 months prior to a planned conception and females should discontinue use for at least one ovulatory cycle before conception. 
NURSING MOTHERS:
Methotrexate is excreted in breast milk and should not be used by nursing mothers. 
SIDE EFFECTS:
Methotrexate can be well tolerated, but also can cause severe toxicity which is usually related to the dose taken. The most frequent reactions include mouth sores, stomach upset, and low white blood counts. Methotrexate can cause severe toxicity of the liver, kidneys and bone marrow, which require regular monitoring with blood tests. It can cause headache and drowsiness which may resolve if the dose is lowered. Methotrexate can cause itching, skin rash, dizziness, and hair loss. A dry, non-productive cough can be a result of rare lung toxicity.
o Mechanism of Action: Folic acid antagonist: acts at catalytic side of dihydrofolate reductase 
o Polyglutamate: important in methotrexate action 

o Tumor resistance to methotrexate: 
 decreased drug transport into the cell 
 altered dihydrofolate reductase enzyme -- lower affinity for methotrexate 
 decreased polyglutamate formation 
 quantitative increase in dihydrofolate reductase enzyme concentration in the cell (gene amplification, increased message) 

o  Adverse effects: 
 Bone marrow suppression 
 Dermatologic 
 GI mucosa 
 Adverse effects reversed by leucovorin (citrovorum factor) 
 Leucovorin "rescue" may be used in cases of over dosage or in high-dose methotrexate protocols 
o Other uses: 
 Treatment of rheumatoid arthritis 
 In combination with a prostaglandin: induces abortion 

Purine Antagonists
o 6-Thiopurines (Mercaptopurine [6-MP]; Thioguanine [6-TG]) 


Mercaptopurine (Purinethol)

1,7-Dihydro-6H-purine-6-thione
 Mechanism of Action: Activation by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to form 6-thioinosinic acid which inhibits enzymes involved in purine metabolism. (thioguanylic acid and 6-methylmercaptopurine ribotide (MMPR) also active) 
 Clinical Use: 
 childhood acute leukemia 
 the analog, azathioprine (Imuran)-- immunosuppressive agent. 

Thioguanine

 Purine nucleotide pathway enzyme-inhibitor 
 decreased intracellular concentration of guanine nucleotides 
 inhibition of glycoprotein synthesis 
 Mechanism of Action: inhibits DNA/RNA synthesis 
 Clinical Use: 
 Synergistic with cytarabine in treating adult acute leukemia. 
o Drug resistance 
 Decreased HGPRT activity 
 In acute leukemia -- increased alkaline phosphatase, which dephosphorylates thiopurines nucleotides 
o  Adverse Effects: 
 Both mercaptopurine and thioguanine, given orally, are excreted in the urine. 
 6-MP is converted to an inactive metabolite, 6-thioruric acid, by xanthine oxidase .6-TG: requires deamination before metabolism by xanthine oxidase. 
 In cancer (hematologic) chemotherapy, allopurinol is used to inhibit xanthine oxidase, to prevent hyperuricemia associated with tumor cell lysis {xanthine oxidase inhibition blocks purine degradation -- purines (more soluble) are excreted instead of uric acid (less soluble)} 
 Use of allopurinol thus blocks acute gout and nephrotoxicity. 
  However, the combination of allopurinol and 6-mercaptopurine, because of xanthine oxidase inhibition, can lead to mercaptopurine toxicity; this interaction does not occur with 6-TG. 

Fludarabine phosphate
9H-Purin-6-amine,2-fluoro-9-(5-O-phosphono--D-arabinofuranosyl)-. 
9--D-Arabinofuranosyl-2-fluoroadenine 5-(dihydrogen phosphate)

 parenteral administration; renal excretion 
 dephosphorylated to active form: 
 Mechanism of Action:DNA synthesis inhibition 
 Clinical Use: 
 lymphoproliferative disease 
 Adverse Effect: dose-limiting -- myelosuppression. 

Cladribine:  (Leustatin) 
2-chloro-6-amino-9-(2-deoxy-β-D-erythropento-furanosyl) purine
 phosphorylated by deoxycytidine kinase 
 incorporated into DNA 
 Mechanism of Action: increased strand breaks (inhibition of repair mechanisms) 
 Clinical Use: 
 Hairy cell leukemia 
 Adverse Effects: 
 Transient severe myelosuppression; possibly associated with infection. 

Pentostatin:
(8R)-3-[4-hydroxy-5-(hydroxymethyl) oxolan-2-yl]-7, 8-dihydro-4H-imidazo [4, 5-f] [1, 3] diazepin-8-ol
 irreversible inhibitor adenosine deaminase 
 results in toxic accumulation of deoxyadenosine nucleotides (especially in lymphocytes) 
 Adverse Effects: 
 immunosuppression (T cell mediated immunity) 
 myelosuppression 
 kidney function impairment 
 CNS toxicity 
 liver toxicity 

Pyrimidine Antagonists:
• Fluorouracil (5-FU)
Normally given by IV administration (oral absorption erratic) 
 Biotransformed to ribosyl- and deoxyribosyl- derivatives. 
 Mechanism of Action: 
 One derivative, 5-fluoro-2'-deoxyuridine 5'-phosphate (FdUMP), inhibits thymidylate synthase and its cofactor, a tetrahydrofolate derivative, resulting in inhibition of thymidine nucleotide synthesis. 
 Another derivative, 5-fluorouridine triphosphate is incorporated into RNA, interfering with RNA function. 
 Cytotoxicity:effects on both RNA and DNA 


 Clinical Use: Systemically -- adenocarcinomas; Topically: skin cancer 
 Floxuridine (FUDR): similar to 5-FU, used for hepatic artery infusion. 
  Major Toxicity: myelosuppression, mucositis. 


• Cytarabine (Ara-C)
IV administration 
 Mechanism of Action: S phase-specific antimetabolite 
 Biotransformed to active forms: Ara-CTP, competitive inhibitor of DNA polymerase. 
 Blocks DNA synthesis; no effect on RNA or protein synthesis 
 cytarabine incorporated into RNA and DNA -- interfering with chain elongation 
 Clearance: deamination (inactive form) 
 S phase specificity: highly schedule-dependent 
 Clinical Use: almost exclusively for acute myelogenous leukemia 
  Adverse Effects: 
 nausea 
 alopecia 
 stomatitis 
  severe myelosuppression 


o Azacitidine (IV administration):
 Mechanism of Action: active derivatives inhibit orotidylate decarboxylase -- reducing pyrimidine nucleotide synthesis; azacitidine -- incorporated into DNA and RNA; inhibits DNA, RNA, and protein synthesis. 
 Investigational drug -- second-line agent in treatment of acute leukemia 
 Adverse Effect: myelosuppression. 

Plant Alkaloids

• Vinblastine -- (Velban)
o Mechanism of action: microtubule depolymerization 
 Mitotic arrest at metaphase; interferes with chromosome segregation 
o Clinical Use:: 
 Systemic treatment of Hodgkin's disease 
 Lymphomas 
o  Adverse Effects: 
 nausea 
 vomiting 
 alopecia 
 bone marrow suppression 


• Vincristine -- (Oncovin) 
o Mechanism of action: microtubule depolymerization 
 Mitotic arrest at metaphase; interferes with chromosome segregation 
o Clinical Use:: 
 In combination with prednisone: induction of remission in children with acute leukemia 
 useful in treating some other rapidly proliferating neoplasms 
o  Adverse Effects: 
 significant frequency of neurotoxic reactions 
 occasional: bone marrow depression 


• Podophyllotoxins (etoposide {VP- 16}and teniposide {VM-26})
o  Etoposide and teniposide: structurally similar 
o Mechanism of action: Block cell cycle: in late S-G2 phase 
 inhibition of topoisomerase II -- DNA damage 
o IV administration 
o Urinary excretion; some in bile 
o Clinical Use: 
  Etoposide  (VP-16,VePe-sid): 
 monocytic leukemia 
 testicular cancer 
 oat cell lung carcinoma 
  Teniposide (Vumon): lymphomas 
o  Adverse Effects: 
 nausea 
 vomiting 
 alopecia 
 significant hematopoietic toxicity and lymphoid toxicity 


•  Camptothecins (topotecan and irinotecan ) 
o Mechanism of action: interfere with activity of topoisomerase I (cuts and religates single stranded DNA. DNA is damaged 
o Clinical Uses: 
 Topotecan: metastatic ovarian cancer -- including cisplatin-resistant forms (as effective as paclitaxel). 
  Adverse Effects: Topotecan -- 
 Primary 
 neutropenia 
 thrombocytopenia 
 anemia 
 Other 
 nausea 
 nominee 
 alopecia 
 Irinotecan: prodrug- metabolized active topoisomerase-I inhibitor 
 Used in management of colon and rectal cancer, including tumors not responding to 5-FU 
 Adverse Effects of Irinotecan -- 
 Most common: diarrhea 
 also common: nausea, vomiting 
 Dose limiting adverse effect: myelosuppression 

• Taxanes (Paclitaxel (Taxol) and Docetaxel (Taxotere)) 

o Paclitaxel (Taxol): derivative of the Western Yew 
o Mitotic spindle inhibitor: enhances tubulin polymerization 
o Clinical Uses: 
 Ovarian 
 Advanced breast cancer 
o  Dose-limiting Adverse Effects: 
 neutropenia 
 thrombocytopenia 
 peripheral neuropathy 
o Docetaxel (Taxotere):Used in advanced breast cancer 
 Adverse Effects:bone marrow suppression 


Antibiotics

• Clinically useful anticancer antibiotics: derived from Streptomyces 
• These antibiotics act by: 
o DNA intercalation, blocking synthesis of DNA and RNA 


• Anthracyclines: 
Doxorubicin (Adriamycin, Rubex, Doxil) and Daunorubicin (DaunoXome) 
Doxorubicin
o IV administration; hepatic metabolism; biliary excretion; some urinary excretion; enterohepatic recirculation. 
o Among the most useful anticancer antibiotics 
o Mechanism of action: 
 DNA intercalation -- blocking synthesis of DNA and RNA; DNA strands scission -- by affecting topoisomerase II 
 Altering membrane fluidity and ion transport 
 Semiquinone free radical an oxygen radical generation (may be responsible for myocardial damage) 
• Clinical Uses: 
o Doxorubicin (Adriamycin, Rubex, Doxil)-- very important anticancer agent – 

Carcinomas-Doxorubicin
breast carcinoma  ovarian carcinoma  thyroid carcinoma
endometrial carcinoma  testicular carcinoma  lung carcinoma

Sarcomas-Doxorubicin
Ewing's sarcoma  osteosarcoma  rhabdomyosarcomas

Hematological Cancers-Doxorubicin
acute leukemia  multiple myeloma  Hodgkin's disease  non-Hodgkin's lymphoma
• Adjuvant therapy in: osteogenic sarcoma and breast cancer 
• Generally used in combination protocols with: 
o cyclophosphamide (Cytoxan) 
o cisplatin (Platinol) 
o nitrosoureas 
• Major Use: Acute Leukemia 
• Daunorubicin: limited utility-- limited efficacy in treating solid tumors. 
• Idarubicin: approved for acute myeloid leukemia 
o Idarubicin in combination with cytarabine: more active than daunorubicin in inducing complete remission in acute myelogenous leukemia. 
•  Adverse Effects: 
o Bone marrow depression (short duration) 
o Cumulative, dose-related, possibly irreversible cardiotoxicity. 
o Total, severe alopecia 

• Dactinomycin (Cosmegen) 

o IV administration; 50 percent remains unmetabolized. 
o Mechanism of action: intercalation between guanine-cytosine base pairs 
 inhibits DNA-dependent RNA synthesis 
 blocks protein synthesis 
o Clinical Uses: 
 dactinomycin in combination with vincristine (Oncovin)and surgery (may include radiotherapy) in treatment of Wilms' tumor 
 Dactinomycin with methotrexate: maybe curative for localized or disseminated gestational choriocarcinoma. 
o  Adverse Effects: 
  Major dose limiting toxicity: bone marrow suppression (all blood elements affected -- particularly platelets and leukocytes) 
 occasional severe thrombocytopenia 
 nausea 
 vomiting 
 diarrhea 
 oral ulcers 
 Dactinomycin: immunosuppressive (patient should not receive live virus vaccines) 
 alopecia/skin abnormalities 
 interaction with radiation ("radiation recall") 
• Plicamycin (Mithramycin) 
• Mechanism of action: Binds to DNA -- interrupts DNA-directed RNA synthesis 
o Also decreases plasma calcium (independent tumor cell action; acts on osteoclasts) 
• Clinical Uses: 
o Some efficacy in testicular cancer that is unresponsive to standard treatment: 
o Especially useful in managing severe hypercalcemia associated with cancer 
•  Adverse Effects: 
o nausea 
o vomiting 
o thrombocytopenia 
o leukopenia 
o hypocalcemia 
o liver toxicity 
o bleeding disorders 

• Mitomycin: (Mutamycin):
o Mechanism of action: 
 Metabolic activation to produce a DNA alkylating agent. 
 Solid tumor hypoxic stem cells may be more sensitive to the action of mitomycin. 
 Best available drug, in combination with x-rays, to kill hypoxic tumor cells. 


o  Clinical Use: 
 in combination chemotherapy {with vincristine and bleomycin}: squamous sell carcinoma of the cervix 
 adenocarcinoma of the stomach, pancreas, and lung {along with fluorouracil and doxorubicin} 
 second-line drug: metastatic colon cancer 
 Topical intravesical treatment of small bladder papillomas. 
o  Adverse Effects: 
  Severe myelosuppression, especially after repeated doses, suggest action on hematopoietic stem cells. 
 Vomiting 
 anorexia 
 occasional nephrotoxicity 
 occasional interstitial pneumonitis 

• Bleomycin (Blenoxane) 

• Mechanism of Action: binds to DNA -- produces single- and double-strand breaks (free radical formation) 
o Cell cycle specific: arrests division in G2 
o Synergistic effects with vinblastine and cisplatin (curative protocol for testicular cancer) 
• Clinical Uses: 
o Testicular cancer 
o Squamous cell carcinoma: head, neck, cervix, skin, penis, and rectum 
o combination treatment: lymphoma 
o intracavity treatment: malignant effusions in ovarian breast cancer 

•  Adverse Effects: 
o Anaphylactoid reaction (potentially fatal) 
o Fever 
o anorexia, blistering, hyperkeratosis (palms) 
o pulmonary fibrosis (uncommon) 
o No significant myelosuppression 


Monoclonal antibodies
Monoclonal antibodies work by targeting tumour specific antigens, thus enhancing the host's immune response to tumour cells to which the agent attaches itself.
Examples are trastuzumab (Herceptin), cetuximab, and rituximab (Rituxan or Mabthera). Bevacizumab (Avastin) is a monoclonal antibody that does not directly attack tumor cells but instead blocks the formation of new tumor vessels.


Anticancer Agents: Hormones
• Breast and prostatic cancer: palliation with sex hormone therapy 

• Prostate cancer is often sensitive to finasteride, an agent that blocks the peripheral conversion of testosterone to dihydrotestosterone. 

• Breast cancer cells often highly express the estrogen and/or progesterone receptor. Inhibiting the production (with aromatase inhibitors) or action (with tamoxifen) of these hormones can often be used as an adjunct to therapy. 

• Estrogen role in cancer : About 80% of breast cancers, once established, rely on supplies of the hormone estrogen to grow: they are known as hormone-sensitive or hormone-receptor-positive cancers. Suppression of production in the body of estrogen is a treatment for these cancers. It encourages the growth of female characteristics, such as breasts and endometrium (lining for the uterus). When oestrogen is released two things begin to happen. Firstly the lining of the womb starts to shed and FSH is started to be released.
• Adrenal corticosteroid treatment-- useful in: 
o acute leukemia 
o myeloma 
o lymphomas 
o other hematologic cancers 


• Pharmacological effects: 
o Steroid hormones bind to steroid receptors: 
o Efficacy of steroid treatment depends on specific receptor presence on malignant cell surface. 
•  Clinical Use: Treatment of: 
o female and male breast cancer 
o prostatic cancer 
o endometrial cancer of uterus 
•  Adverse Effects: 
o Fluid retention (secondary to Na-retaining properties) 
o Androgens-masculinization (long-term use) 
o Estrogens-feminization (long-term use) 
o Adrenocortical steroids: 
 hypertension 
 diabetes 
 enhanced susceptibility to infection 
 cushingoid appearance 

Estrogen and Androgen Inhibitors: (Tamoxifen and Flutamide)

• Tamoxifen: Breast cancer treatment 
o Oral administration. 
o Activity against progesterone-resistant endometrial neoplasm 
o Chemopreventive: Women -- high-risk for breast cancer 


o Mechanism of Action: 
 Competitive partial agonist-inhibitor of estrogen 
 Binds to estrogen-sensitive tissues (receptors present) 
 Best antiestrogen effect requires minimal endogenous estrogen presence {estradiol has a much higher affinity for the estrogen receptor than tamoxifen's affinity for the estrogen receptor} 
 Suppresses serum levels of insulin-like growth factor-1; and up-regulates local TGF-beta production. These properties may explain tamoxifen antitumor activity in melanoma and ovarian cancer. 
o  Adverse Effects: 
 Generally mild 
 Most frequent: hot flashes 
 Occasionally: fluid retention, nausea 
o  Clinical Use: 
 Advanced breast cancer 
 Most likely to be effective if: 
 lack endogenous estrogens {oophorectomy; postmenopausal} 
 Presence of cytoplasmic estrogen receptor; presence of cytoplasmic progesterone receptor Coleman 
 Prolongs survival {surgical adjuvant therapy} in postmenopausal women with estrogen receptor-positive breast cancer. 


• Flutamide (Eulexin): 
Prostatic cancer 
o Antagonizes remaining androgenic effects after orchiectomy or leuprolide treatment 
Gonadotropin-Releasing Hormone Agonists (Leuprolide and Goserelin (Zoladex))
• Leuprolide and goserelin: synthetic peptide analogues of gonadotropin-releasing hormone (GnRH, LHRH) 
o Mechanism of Action: Analogues more potent -- behave as GnRH agonists. 
 Pituitary effects: when given continuously -- initial stimulation then inhibition of follicle-stimulating hormone and leutinizing hormone. 
 Causes reduced testicular androgen synthesis, the reason why these agents are effective in treating metastatic prostate carcinoma 
•  Clinical Use: treating metastatic prostate carcinoma 
• Comparing leuprolide with diethylstilbestrol (DES): 
o Similar suppression of androgens synthesis and serum prostatic acid phosphatase (an index of metastatic tumor load) 
o  Adverse Effects: Leuprolide less frequently causes: 
 nausea 
 vomiting 
 edema 
 thromboembolism 
 painful gynecomastia 
o Leuprolide and goserelin: medication more costly, the more cost-effective given reduced frequency of complications. 



Aromatase Inhibitors (Aminoglutethimide and Anastrozole (Arimidex))
• Aminoglutethimide:  
o Mechanisms of action: Reduction in estrogen concentration 
 Aminoglutethimide: inhibitor of adrenal steroid synthesis ( blocks conversion of cholesterol to pregnenolone {first-step}) 
 Aminoglutethimide inhibits extra-adrenal estradiol and estrone synthesis. 
 Aminoglutethimide inhibits an aromatase enzyme {catalyzes conversion of androstenedione to estrone} 
 This conversion may occur in fat. 
o Clinical Use: 
 Metastatic breast cancer (tumors contain estrogen or progesterone receptors) 
 Aminoglutethimide is administered with adrenalreplacement doses of hydrocortisone to ensure avoidance of adrenal insufficiency. 
 Hydrocortisone is used in preference to dexamethasone, because dexamethasone increases the degradation of aminoglutethimide. 
 Aminoglutethimide in combination with hydrocortisone: Second-Line Therapy for women treated with tamoxifen (aminoglutethimide causes more adverse side effects than tamoxifen) 
• Anastrozole (Arimidex): new, selective, nonsteroidal aromatase inhibitor. 
o appears to have no effect on glucocorticoid or mineralocorticoid synthesis 
o Clinical Use: 
 Treatment of advanced estrogen-or progesterone-receptor positive non--tamoxifen responsive breast cancer 

Miscellaneous Anticancer Drugs
• Amsacrine:  
o Hepatic metabolism 
o Mechanism of Action: 
 DNA intercalation: produces single-and double-strand breaks 
 interaction with topoisomerase II-DNA complexes 
o Clinical Uses: 
 Anthracyclines- and cytarabine-resistant acute myelogenous leukemia 
 Advanced ovarian cancer 
 Lymphomas 
o  Adverse Effects: 
 Does-limiting hepatic toxicity 
 Cardiac arrest has been noted with amsacrine infusion 

• Asparaginase  (El-spar): 
o Mechanism of action: depletion of serum asparagine {forming aspartic acid and ammonia} 
 Decreased blood levels of asparagine and glutamine inhibit protein synthesis in those neoplastic cells that express decreased levels of asparagine synthase. 
 Most normal cells express sufficient levels of asparagine synthase to avoid toxicity. 
• Hydroxyurea: 
o Mechanism of action: 
 Inhibits ribonucleotide reductase; depletes deoxyribonucleoside triphosphate pools 
 Acts at S phase. 

o Clinical Uses: 
 Melanoma [secondary role] 
 Chronic myelogenous leukemia [secondary role] 
o  Adverse Effects: 
 Bone marrow suppression 
 nausea 
 vomiting 
 diarrhoea 

• Mitoxantrone (Novantrone): 
o Mechanism of action: 
 Induces DNA strand breaks 
 Inhibits RNA and DNA synthesis 
o Clinical Uses: 
 Refractory acute leukemia 
 Pediatric and adult acute myelogenous leukemia 
 non-Hodgkin's lymphoma's 
 breast cancer 
o  Adverse Effects: 
 Dose-limiting: leukopenia 
 mild nausea 
 vomiting 
 stomatitis 
 alopecia 
 some cardiotoxicity {arrhythmias} 



• Mitotane  (Lysodren): 
o  Clinical Use: Single indication-- adrenal carcinoma 
 Reduces excessive steroid secretion 
o Adverse Effects: 
 diarrhoea 
 mental depression 
 skin eruption 
 anorexia 
 nausea 
 somnolence 
 dermatitis 

• Retinoic acid Derivatives: 
o Clinical Uses: 
 Remissions -- acute promyelocytic leukemia 
 13-cis-Retinoic acid: chemopreventive -- second primary tumors in patients with hand and neck squamous cell carcinoma. 
o  Adverse Effects: 
 skeletal effects 
 hepatic effects 
 teratogenic effects 
 mucocutaneous effects 

• Bone Marrow Growth Factors (sargramostim and filgrastim): 
o Reduces neutropenic sepsis and other complications of chemotherapy 
o Filgrastim shortens neutropenic state following induction chemotherapy for acute nonlymphocytic leukemia. 

• Amifostine  
o Cytoprotective from effects of chemotherapy.


Common Side-effects of Chemotherapy

The treatment can be physically exhausting for the patient. Current chemotherapeutic techniques have a range of side effects mainly affecting the fast-dividing cells of the body. Important common side-effects include (dependent on the agent):
• Pain 
• Nausea and vomiting 
• Diarrhea or constipation 
• Anemia 
• Malnutrition 
• Hair loss 
• Memory loss 
• Depression of the immune system, hence (potentially lethal) infections and sepsis 
• Weight loss or gain 
• Hemorrhage 
• Secondary neoplasms 
• Cardiotoxicity 
• Hepatotoxicity 
• Nephrotoxicity 
• Ototoxicity 

A woman being treated with docetaxel chemotherapy for breast cancer. Cold mittens and wine coolers are placed on her hands and feet to prevent deleterious effects on the nails. Similar strategies can be used to prevent hair loss.
Immunosuppression and myelosuppression
Virtually all chemotherapeutic regimens can cause depression of the immune system, often by paralysing the bone marrow and leading to a decrease of white blood cells, red blood cells, and platelets. The latter two, when they occur, are improved with blood transfusion. Neutropenia (a decrease of the neutrophil granulocyte count below 0.5 x 109/litre) can be improved with synthetic G-CSF (granulocyte-colony stimulating factor, e.g., filgrastim, lenograstim, Neupogen, Neulasta).
In very severe myelosuppression, which occurs in some regimens, almost all the bone marrow stem cells (cells that produce white and red blood cells) are destroyed, meaning allogenic or autologous bone marrow cell transplants are necessary. (In autologous BMTs, cells are removed from the patient before the treatment, multiplied and then re-injected afterwards; in allogenic BMTs the source is a donor.) However, some patients still develop diseases because of this interference with bone marrow.

Nausea and vomiting
Nausea and vomiting caused by chemotherapy; stomach upset may trigger a strong urge to vomit, or forcefully eliminate what is in the stomach.
Stimulation of the vomiting center results in the coordination of responses from the diaphragm, salivary glands, cranial nerves, and gastrointestinal muscles to produce the interruption of respiration and forced expulsion of stomach contents known as retching and vomiting. The vomiting center is stimulated directly by afferent input from the vagal and splanchnic nerves, the pharynx, the cerebral cortex, cholinergic and histamine stimulation from the vestibular system, and efferent input from the chemoreceptor trigger zone (CTZ). The CTZ is in the area postrema, outside the blood-brain barrier, and is thus susceptible to stimulation by substances present in the blood or cerebral spinal fluid. The neurotransmitters dopamine and serotonin stimulate the vomiting center indirectly via stimulation of the CTZ.
The 5-HT3 inhibitors are the most effective antiemetics and constitute the single greatest advance in the management of nausea and vomiting in patients with cancer. These drugs are designed to block one or more of the signals that cause nausea and vomiting. The most sensitive signal during the first 24 hours after chemotherapy appears to be 5-HT3. Blocking the 5-HT3 signal is one approach to preventing acute emesis (vomiting), or emesis that is severe, but relatively short-lived. Approved 5-HT3 inhibitors include Dolasetron (Anzemet), Granisetron (Kytril, Sancuso), and Ondansetron (Zofran). The newest 5-HT3 inhibitor, palonosetron (Aloxi), also prevents delayed nausea and vomiting, which occurs during the 2-5 days after treatment. A granisetron transdermal patch (Sancuso) was approved by the FDA in September of 2008. The patch is applied before chemotherapy and can be left in place for up to 5 days.


Another drug to control nausea in cancer patients became available in 2005. The substance P inhibitor Aprepitant (marketed as Emend) has been shown to be effective in controlling the nausea of cancer chemotherapy. The results of two large controlled trials were published in 2005, describing the efficacy of this medication in over 1,000 patients. 
Some studies and patient groups claim that the use of Cannabinoids derived from marijuana during chemotherapy greatly reduces the associated nausea and vomiting, and enables the patient to eat. Some synthetic derivatives of the active substance in marijuana (Tetrahydrocannabinol or THC) such as Marinol may be practical for this application. Natural marijuana, known as medical cannabis is also used and recommended by some oncologists, though its use is regulated and not legal everywhere. 
Other side-effects
In particularly large tumors, such as large lymphomas, some patients develop tumor lysis syndrome from the rapid breakdown of malignant cells. Although prophylaxis is available and is often initiated in patients with large tumors, this is a dangerous side-effect that can lead to death if left untreated.
Some patients report fatigue or non-specific neurocognitive problems, such as an inability to concentrate; this is sometimes called post-chemotherapy cognitive impairment, referred to as "chemo brain" by patients' groups. 
Specific chemotherapeutic agents are associated with organ-specific toxicities, including cardiovascular disease (e.g., doxorubicin), interstitial lung disease (e.g., bleomycin) and occasionally secondary neoplasm (e.g., MOPP therapy for Hodgkin's disease).

Radiation Therapy

Radiation therapy (or radiotherapy) is the medical use of ionizing radiation as part of cancer treatment to control malignant cells (not to be confused with radiology, the use of radiation in medical imaging and diagnosis). Radiotherapy may be used for curative or adjuvant cancer treatment. It is used as palliative treatment (where cure is not possible and the aim is for local disease control or symptomatic relief) or as therapeutic treatment (where the therapy has survival benefit and it can be curative). Total body irradiation (TBI) is a radiotherapy technique used to prepare the body to receive a bone marrow transplant. Radiotherapy has several applications in non-malignant conditions, such as the treatment of trigeminal neuralgia, severe thyroid eye disease, pterygium, pigmented villonodular synovitis, prevention of keloid scar growth, and prevention of heterotopic ossification. The use of radiotherapy in non-malignant conditions is limited partly by worries about the risk of radiation-induced cancers.

Radiation therapy of the pelvis. Lasers and a mould under the legs are used to determine exact position

Radiotherapy is used for the treatment of malignant tumors (cancer), and may be used as the primary therapy. It is also common to combine radiotherapy with surgery, chemotherapy, hormone therapy or some mixture of the three. Most common cancer types can be treated with radiotherapy in some way.
The precise treatment intent (curative, adjuvant, neoadjuvant, therapeutic, or palliative) will depend on the tumour type, location, and stage, as well as the general health of the patient.
Radiation therapy is commonly applied to the cancerous tumour. The radiation fields may also include the draining lymph nodes if they are clinically or radiologically involved with tumour, or if there is thought to be a risk of subclinical malignant spread. It is necessary to include a margin of normal tissue around the tumour to allow for uncertainties in daily set-up and internal tumor motion. These uncertainties can be caused by internal movement (for example, respiration and bladder filling) and movement of external skin marks relative to the tumour position.
To spare normal tissues (such as skin or organs which radiation must pass through in order to treat the tumour), shaped radiation beams are aimed from several angles of exposure to intersect at the tumour, providing a much larger absorbed dose there than in the surrounding, healthy tissue.

Linear accelerator

Mechanism of action
Radiation therapy works by damaging the DNA of cells. The damage is caused by a photon, electron, proton, neutron, or ion beam directly or indirectly ionizing the atoms which make up the DNA chain. Indirect ionization happens as a result of the ionization of water, forming free radicals, notably hydroxyl radicals, which then damage the DNA. In the most common forms of radiation therapy, most of the radiation effect is through free radicals. Because cells have mechanisms for repairing DNA damage, breaking the DNA on both strands proves to be the most significant technique in modifying cell characteristics. Because cancer cells generally are undifferentiated and stem cell-like, they reproduce more, and have a diminished ability to repair sub-lethal damage compared to most healthy differentiated cells. The DNA damage is inherited through cell division, accumulating damage to the cancer cells, causing them to die or reproduce more slowly. Proton radiotherapy works by sending protons with varying kinetic energy to precisely stop at the tumor.
One of the major limitations of radiotherapy is that the cells of solid tumors become deficient in oxygen. This is because solid tumours usually outgrow their blood supply, causing a low-oxygen state known as hypoxia. The more hypoxic the tumours are the more resistant they are to the effects of radiation because oxygen makes the radiation damage to DNA permanent. Much research has been devoted to overcoming this problem including the use of high pressure oxygen tanks, blood substitutes that carry increased oxygen, hypoxic cell radiosensitizers such as misonidazole and metronidazole, and hypoxic cytotoxins, such as tirapazamine. There is also interest in the fact that high-LET (linear energy transfer) particles such as carbon or neon ions may have an antitumour effect which is independent of tumour hypoxia.

Side effects
Radiation therapy is in itself painless. Many low-dose palliative treatments (for example, radiotherapy to bony metastases) cause minimal or no side effects. Treatment to higher doses causes varying side effects during treatment (acute side effects), in the months or years following treatment (long-term side effects), or after re-treatment (cumulative side effects). The nature, severity, and longevity of side effects depends on the organs that receive the radiation, the treatment itself (type of radiation, dose, fractionation, concurrent chemotherapy), and the patient.
Most side effects are predictable and expected. Side effects from radiation are usually limited to the area of the patients body that is under treatment. One of the aims of modern radiotherapy is to reduce side effects to a minimum, and to help the patient to understand and to deal with those side effects which are unavoidable.
Acute side effects
• Damage to the epithelial surfaces. Epithelial surfaces like skin, oral, pharyngeal and bowel mucosa, urothelium, etc. may sustain damage from radiation therapy. The rates of onset of damage and recovery from it depend upon the turnover rate of epithelial cells. Typically the skin starts to become pink and sore several weeks into treatment. The reaction may become more severe during the treatment and for up to about one week following the end of radiotherapy, and the skin may break down. Although this moist desquamation is uncomfortable, recovery is usually quick. Skin reactions tend to be worse in areas where there are natural folds in the skin, such as underneath the female breast, behind the ear, and in the groin. 

Similarly, the lining of the mouth, throat, esophagus, and bowel may be damaged by radiation. If the head and neck area is treated, temporary soreness and ulceration commonly occur in the mouth and throat. If severe, this can affect swallowing, and the patient may need painkillers and nutritional support. The esophagus can also become sore if it is treated directly, or if, as commonly occurs, it receives a dose of collateral radiation during treatment of lung cancer. 
The lower bowel may be treated directly with radiation (treatment of rectal or anal cancer) or be exposed by radiotherapy to other pelvic structures (prostate, bladder, female genital tract). Typical symptoms are soreness, diarrhoea, and nausea. 
• Swelling (edema or Oedema). As part of the general inflammation that occurs, swelling of soft tissues may cause problems during radiotherapy. This is a concern during treatment of brain tumours and brain metastases, especially where there is pre-existing raised intracranial pressure or where the tumour is causing near-total obstruction of a lumen (e.g., trachea or main bronchus). Surgical intervention may be considered prior to treatment with radiation. If surgery is deemed unnecessary or inappropriate, the patient may receive steroids during radiotherapy to reduce swelling. 
• Infertility. The gonads (ovaries and testicles) are very sensitive to radiation. They may be unable to produce gametes following direct exposure to most normal treatment doses of radiation. Treatment planning for all body sites is designed to minimize, if not completely exclude dose to the gonads if they are not the primary area of treatment. 
• Generalized fatigue. 

Medium and long-term side effects
These depend on the tissue that received the treatment; they may be minimal.
Fibrosis 
Tissues which have been irradiated tend to become less elastic over time due to a diffuse scarring process. 
Hair loss 
This may be most pronounced in patients who have received radiotherapy to the brain. Unlike the hair loss seen with chemotherapy, radiation-induced hair loss is more likely to be permanent, but is also more likely to be limited to the area treated by the radiation. 
Dryness 
The salivary glands and tear glands have a radiation tolerance of about 30 Gy in 2 Gy fractions, a dose which is exceeded by most radical head and neck cancer treatments. Dry mouth (xerostomia) and dry eyes (xerophthalmia) can become irritating long-term problems and severely reduce the patient's quality of life. Similarly, sweat glands in treated skin (such as the armpit) tend to stop working, and the naturally moist vaginal mucosa is often dry following pelvic irradiation. 
Fatigue 
Fatigue is among the most common symptoms of Radiation therapy, and can range from a few months, a few years, depending on the quantity of the treatment and cancer type. Lack of Energy, reduced activity and overtired feelings are common symptoms 
Cancer 
Radiation is a potential cause of cancer, and secondary malignancies are seen in a very small minority of patients, generally many years after they have received a course of radiation treatment. In the vast majority of cases, this risk is greatly outweighed by the reduction in risk conferred by treating the primary cancer. 

Death 
Radiation has potentially excess risk of death from heart disease seen after some past breast cancer RT regimens.[1] 
Cumulative side effects
Cumulative effects from this process should not be confused with long-term effects—when short-term effects have disappeared and long-term effects are subclinical, reirradiation can still be problematic.[2]
Dose
The amount of radiation used in radiation therapy is measured in gray (Gy), and varies depending on the type and stage of cancer being treated. For curative cases, the typical dose for a solid epithelial tumor ranges from 60 to 80 Gy, while lymphoma tumors are treated with 20 to 40 Gy.
Preventative (adjuvant) doses are typically around 45 - 60 Gy in 1.8 - 2 Gy fractions (for Breast, Head and Neck cancers respectively.) Many other factors are considered by radiation oncologists when selecting a dose, including whether the patient is receiving chemotherapy, whether radiation therapy is being administered before or after surgery, and the degree of success of surgery.
Fractionation
The total dose is fractionated (spread out over time) for several important reasons. Fractionation allows normal cells time to recover, while tumor cells are generally less efficient in repair between fractions. Fractionation also allows tumor cells that were in a relatively radio-resistant phase of the cell cycle during one treatment to cycle into a sensitive phase of the cycle before the next fraction is given. Similarly, tumor cells that were chronically or acutely hypoxic (and therefore more radioresistant) may reoxygenate between fractions, improving the tumor cell kill. Fractionation regimes are individualized between different radiotherapy centres and even between individual doctors. In the USA, Australia, and Europe, the typical fractionation schedule for adults is 1.8 to 2 Gy per day, five days a week. In the northern United Kingdom, fractions are more commonly 2.67 to 2.75 Gy per day, which eases the burden on thinly spread resources in the National Health Service. In some cancer types, prolongation of the fraction schedule over too long can allow for the tumor to begin repopulating, and for these tumor types, including head-and-neck and cervical squamous cell cancers, radiation treatment is preferably completed within a certain amount of time. For children, a typical fraction size may be 1.5 to 1.8 Gy per day, as smaller fraction sizes are associated with reduced incidence and severity of late-onset side effects in normal tissues.
In some cases, two fractions per day are used near the end of a course of treatment. This schedule, known as a concomitant boost regimen or hyperfractionation, is used on tumors that regenerate more quickly when they are smaller. In particular, tumors in the head-and-neck demonstrate this behavior.
One of the best-known alternative fractionation schedules is Continuous Hyperfractionated Accelerated Radiotherapy (CHART). CHART, used to treat lung cancer, consists of three smaller fractions per day. Although reasonably successful, CHART can be a strain on radiation therapy departments.
Implants can be fractionated over minutes or hours, or they can be permanent seeds which slowly deliver radiation until they become inactive.


History of radiation therapy
Radiation therapy has been in use as a cancer treatment for more than 100 years, with its earliest roots traced from the discovery of x-rays in 1895.[3] The concept of therapeutic radiation was invented by German physicist Wilhelm Conrad Röntgen when he discovered that the x-ray was a powerful and effective tool with which to treat cancer.
The field of radiation therapy began to grow in the early 1900s largely due to the groundbreaking work of Nobel Prize-winning scientist Marie Curie-Sklodowska, who discovered the radioactive elements polonium and radium. This began a new era in medical treatment and research.[3] Radium was used in various forms until the mid-1900s when cobalt and caesium units came into use. Medical linear accelerators have been developed since the late 1940s.
With Godfrey Hounsfield’s invention of computed tomography (CT) in 1971, three-dimensional planning became a possibility and created a shift from 2-D to 3-D radiation delivery; physicians and physics were no longer limited because CT-based planning allowed physicians to directly measure the dose delivered to the patient's anatomy based on axial tomographical images. Orthovoltage and cobalt units have largely been replaced by megavoltage linear accelerators, useful for their penetrating energies and lack of physical radiation source.
In the last few decades, the advent of new imaging technologies, e.g., magnetic resonance imaging (MRI) in the 1970s and positron emission tomography (PET) in the 1980s, as well as new radiation delivery and visualization products, e.g., digital linear accelerator, image fusion has moved radiation therapy from 3-D conformal to intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT). These advances have resulted in better treatment outcomes and fewer side effects. Now 50-70% of cancer patients receive radiation therapy as part of their cancer treatment.
Types of radiation therapy
Historically, the three main divisions of radiotherapy are external beam radiotherapy (EBRT or XBRT) or teletherapy, brachytherapy or sealed source radiotherapy and unsealed source radiotherapy. The differences relate to the position of the radiation source; external is outside the body, while sealed and unsealed source radiotherapy has radioactive material delivered internally. Brachytherapy sealed sources are usually extracted later, while unsealed sources may be administered by injection or ingestion. Proton therapy is a special case of external beam radiotherapy where the particles are protons. Introperative radiotherapy is a special type of radiotherapy that is delivered immediately after surgical removal of the cancer. This method has been employed in breast cancer (TARGeted Introperative radioTherapy), brain tumours and rectal cancers.
Conventional external beam radiotherapy
Conventional external beam radiotherapy (2DXRT) is delivered via two-dimensional beams using linear accelerator machines. 2DXRT mainly consists of a single beam of radiation delivered to the patient from several directions: often front or back, and both sides. Conventional refers to the way the treatment is planned or simulated on a specially calibrated diagnostic x-ray machine known as a simulator because it recreates the linear accelerator actions (or sometimes by eye), and to the usually well-established arrangements of the radiation beams to achieve a desired plan. The aim of simulation is to accurately target or localize the volume which is to be treated. This technique is well established and is generally quick and reliable. The worry is that some high-dose treatments may be limited by the radiation toxicity capacity of healthy tissues which lay close to the target tumor volume. An example of this problem is seen in radiation of the prostate gland, where the sensitivity of the adjacent rectum limited the dose which could be safely prescribed using 2DXRT planning to such an extent that tumor control may not be easily achievable. Previous to the invention of the CT, physicians and physicists had limited knowledge about the true radiation dosage delivered to both cancerous and healthy tissue. For this reason, 3-dimensional conformal radiotherapy is becoming the standard treatment for a number of tumor sites.
Virtual simulation, 3-dimensional conformal radiotherapy, and intensity-modulated radiotherapy
The planning of radiotherapy treatment has been revolutionized by the ability to delineate tumors and adjacent normal structures in three dimensions using specialized CT and/or MRI scanners and planning software.[5] Virtual simulation, the most basic form of planning, allows more accurate placement of radiation beams than is possible using conventional X-rays, where soft-tissue structures are often difficult to assess and normal tissues difficult to protect.
An enhancement of virtual simulation is 3-Dimensional Conformal Radiotherapy (3DCRT), in which the profile of each radiation beam is shaped to fit the profile of the target from a beam's eye view (BEV) using a multileaf collimator (MLC) and a variable number of beams. When the treatment volume conforms to the shape of the tumour, the relative toxicity of radiation to the surrounding normal tissues is reduced, allowing a higher dose of radiation to be delivered to the tumor than conventional techniques would allow.
Intensity-Modulated Radiation Therapy (IMRT) is an advanced type of high-precision radiation that is the next generation of 3DCRT.[6]IMRT also improves the ability to conform the treatment volume to concave tumor shapes, for example when the tumor is wrapped around a vulnerable structure such as the spinal cord or a major organ or blood vessel. Computer-controlled x-ray accelerators distribute precise radiation doses to malignant tumors or specific areas within the tumor. The pattern of radiation delivery is determined using highly-tailored computing applications to perform optimization and treatment simulation (Treatment Planning). The radiation dose is consistent with the 3-D shape of the tumor by controlling, or modulating, the radiation beam’s intensity. The radiation dose intensity is elevated near the gross tumor volume while radiation among the neighboring normal tissue is decreased or avoided completely. The customized radiation dose is intended to maximize tumor dose while simultaneously protecting the surrounding normal tissue.
Because sparing healthy tissue as compared with conventional radiation therapy techniques (2DXRT and 3DCRT). This in turn results in better tumor targeting, lessened side effects, and improved treatment outcomes than even 3DCRT.
3DCRT is still used extensively for many body sites but the use of IMRT is growing in more complicated body sites such as CNS, head and neck, prostate, breast and lung. Unfortunately, IMRT is limited by its need for additional time from experienced medical personnel. This is because physicians must manually delineate the tumors one CT image at a time through the entire disease site which can take much longer than 3DCRT preparation. Then, medical physicists and dosimetrists must be engaged to create a viable treatment plan. Also, the IMRT technology has only been used commercially since the late 1990s even at the most advanced cancer centers, so radiation oncologists who did not learn it as part of their residency program must find additional sources of education before implementing IMRT.
Proof of improved survival benefit from either of these two techniques over conventional radiotherapy (2DXRT) is growing for many tumor sites, but the ability to reduce toxicity is generally accepted. Both techniques enable dose escalation, potentially increasing usefulness. There has been some concern, particularly with 3DCRT, about increased exposure of normal tissue to radiation and the consequent potential for secondary malignancy. Overconfidence in the accuracy of imaging may increase the chance of missing lesions that are invisible on the planning scans (and therefore not included in the treatment plan) or that move between or during a treatment (for example, due to respiration or inadequate patient immobilization). New techniques are being developed to better control this uncertainty—for example, real-time imaging combined with real-time adjustment of the therapeutic beams. This new technology is called image-guided radiation therapy (IGRT) or four-dimensional radiotherapy.

Radioisotope Therapy (RIT)
Radiotherapy can also be delivered through infusion (into the bloodstream) or ingestion. Examples are the infusion of metaiodobenzylguanidine (MIBG) to treat neuroblastoma, of oral iodine-131 to treat thyroid cancer or thyrotoxicosis, and of hormone-bound lutetium-177 and yttrium-90 to treat neuroendocrine tumors (peptide receptor radionuclide therapy). Another example is the injection of radioactive glass or resin microspheres into the hepatic artery to radioembolize liver tumors or liver metastases.
In 2002, the United States Food and Drug Administration (FDA) approved Ibritumomab tiuxetan (Zevalin), which is a monoclonal antibody anti-CD20 conjugated to a molecule of Yttrium-90. [7] In 2003, the FDA approved Tositumomab Iodine-131 (Bexxar), which conjugates a molecule of Iodine-131 to the monoclonal antibody anti-CD20. [8] These medications were the first agents of what is known as radioimmunotherapy, and they were approved for the treatment of refractory non-Hodgkins lymphoma.
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