The targeted-therapy revolution has arrived, but the principles and limitations of chemotherapy discovered by the early researchers still apply. [5] Chemotherapy being a major treatment modality used for the control of advanced stages of malignancies and as a prophylactic against possible metastasis, exhibits severe toxicity on normal tissues. [6][7]

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. In this review we try to summarize therapeutic benefits as well as major toxicities associated with antineoplastic drugs.

2. THERAPEUTIC POTENTIAL AND TOXICITIES OF THE DRUGS:

2.1 Mercaptopurine

Therapeutic potential: - It is used to treat leukemia. It is also used for pediatric non-Hodgkin's lymphoma, and inflammatory bowel disease. [8] It has demonstrated some in vitro effectiveness against Mycobacterium paratuberculosis. [9]

Toxicity: - Some of the adverse reactions of taking mercaptopurine might include diarrhea, nausea, vomiting, loss of appetite, stomach/abdominal pain, weakness, skin rash, darkening of the skin, or hair loss. Serious adverse reactions include mouth sores, fever, sore throat, easy bruising or bleeding, pinpoint red spots on the skin, yellowing of eyes or skin, dark urine, painful or difficult urination. Unlikely but serious side effects include: black or tarry stools (melena), bloody stools, and bloody urine. Symptoms of allergic reaction to mercaptopurine include rash, itching, swelling, dizziness, trouble breathing. [10]

2.2 Fluorouracil

Therapeutic potential: - The chemotherapy agent 5-FU (fluorouracil), which has been in use against cancer for about 40 years, acts in several ways, but principally as a thymidylate synthase inhibitor. Interrupting the action of this enzyme blocks synthesis of the pyrimidine thymidine, which is a nucleotide required for DNA replication. Like many anti-cancer drugs, 5-FU's effects are felt system wide but fall most heavily upon rapidly dividing cells that make heavy use of their nucleotide synthesis machinery, such as cancer cells. Some of its principal use is in colorectal cancer and pancreatic cancer, in which it has been the established form of chemotherapy for decades.

Toxicity: - Side effects include myelosuppression, mucositis, dermatitis, diarrhea and cardiac toxicity. 5-FU also causes both acute CNS damage and progressively worsening delayed degeneration of the CNS in mice. This latter effect is caused by 5-FU-induced damage to the oligodendrocytes that produce the insulating myelin sheaths. [10]

2.3 Amifostine

Therapeutic potential: - Amifostine is a cytoprotective adjuvant used in cancer chemotherapy involving DNA-binding chemotherapeutic agents. Also commonly known as WR-1065 in its active form. It is marketed by MedImmune under the trade name Ethyol. Amifostine is used therapeutically to reduce the incidence of neutropenia-related fever and infection induced by DNA-binding chemotherapeutic agents including alkylating agents e.g. cyclophosphamide and platinum-containing agents e.g. cisplatin. It is also used to decrease the cumulative nephrotoxicity associated with platinum-containing agents. Amifostine is also indicated to reduce the incidence of xerostomia in patients undergoing radiotherapy for head and neck cancer.

Toxicity:-Common side effects of Amifostine include hypocalcaemia, diarrhea, nausea, vomiting, sneezing, somnolence, and hiccoughs. Serious side effects include, hypotension (found in 62% of patients), erythema multiform, Stevens-Johnson syndrome and toxic epidermal necrolysis, immune hypersensitivity syndrome, erythroderma, anaphylaxis, and loss of consciousness (rare) [11].

2.4 Anthracycline

Therapeutic potential: - Anthracyclines (or anthracycline antibiotics) are a class of drugs used in cancer chemotherapy derived from Streptomyces bacteria [12] more specifically, Streptomyces peucetius var. caesius. [13] These compounds are used to treat a wide range of cancers, including leukemias, lymphomas, and breast, uterine, ovarian, and lung cancers. The anthracyclines are some of the most effective anticancer treatments ever developed and are effective against more types of cancer than any other class of chemotherapy agents.[14][15][16]

Toxicity:-.Their main adverse effects are heart damage (cardiotoxicity), which considerably limits their usefulness, and vomiting. The first anthracycline discovered was daunorubicin (trade name Daunomycin), which is produced naturally by Streptomyces peucetius, a species of actinobacteria. Doxorubicin (Adriamycin) was developed shortly after, and many other related compounds have followed, although few are in clinical use. [17]

2.5 Carboplatin

Therapeutic potential: - Carboplatin is a chemotherapy drug used against some forms of cancer (mainly ovarian carcinoma, lung, head and neck cancers). It was introduced in the late 1980s and has since gained popularity in clinical treatment due to its vastly reduced side-effects compared to its parent compound cisplatin. Cisplatin and carboplatin, as well as oxaliplatin, interact with DNA, akin to the mechanism of alkylating agents. [18]

Toxicity: - Relative to cisplatin, the greatest benefit of carboplatin is its reduced side effects, particularly the elimination of nephrotoxic effects. Nausea and vomiting are less severe and more easily controlled. Carboplatin has also proven effective in some strains of cancer that may not be susceptible to cisplatin, including germ-line cell, small and non-small cell lung, ovary, and bladder cancers, as well as acute leukemia. [19]

2.6 Cetuximab

Therapeutic potential: - Cetuximab is used in metastatic colon cancer with irinotecan (Camptosar). Irinotecan blocks DNA topoisomerase I. Head and neck cancer: Cetuximab was approved by the FDA [20] for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck or as a single agent in patients who have had prior platinum-based therapy.

Toxicity:- A possibly severe, debilitating, acne-like rash occurs in more than 30% of patients. Several studies have reported that rash is less common with a similar monoclonal antibody, Nimotuzumab. [21]

2.7 CISPLATIN

Therapeutic potential: - Cisplatin or cisplatinum is a platinum-based chemotherapy drug used to treat various types of cancers, including sarcomas, some carcinomas, lymphomas, and germ cell tumors. It was the first member of a class of anti-cancer drugs which now also includes carboplatin and oxaliplatin. These platinum complexes react in vivo, binding to and causing cross linking of DNA which ultimately triggers apoptosis. [22]

Toxicity: - Cisplatin has a number of side-effects that can limit its use. It causes nephrotoxicity neurotoxicity,nausea and vomiting, ototoxicity and Alopecia. Cisplatin can cause hypomagnesaemia, hypokalaemia and hypocalcaemia. The hypocalcaemia seems to occur in those with low serum magnesium secondary to cisplatin, so it is not primarily due to the Cisplatin. [23]

2.8 Cladribine

Therapeutic potential: - Cladribine or Leustatin is a drug used to treat hairy cell leukemia and multiple sclerosis. There are so many treatment schedules for Cladribine. Actual doses are calculated according to the surface area of the patient's skin instead of by weight, and divided by the number of planned treatments. All schedules produce the same benefits and disadvantages. Five-day and seven-day daily schedules give the same total amount of drug and have the same outcomes, including remissions and adverse effects. [24] Daily and weekly schedules give the same total amount of drug and have the same outcomes, including similar proportions of complete responses and similar proportions of patients hospitalized for fevers and opportunistic infections. [25]

Toxicity: - Existing studies estimate that from 18% [26] to 42% [27] of patients will experience a fever after Cladribine infusion. This is usually a transient fever which can be treated with acetaminophen. [28] These fevers resolve in less than 48 hours, [29] have no evidence of being related to infection. However, some patients have fevers that last longer and may be caused by an infection. [30][31] Very few infections have actually been documented, [32] but they do happen, and these infections are largely responsible for the 3% mortality rate associated with Cladribine therapy in HCL. [33]

2.9 Cyclophosphamide

Therapeutic potential: - The main use of cyclophosphamide is together with other chemotherapy agents in the treatment of lymphomas, some forms of leukemia and some solid tumors. It is a chemotherapy drug that works by slowing or stopping cell growth. It also works by decreasing the immune system's response to various diseases. [34]

Toxicity: - Many people taking cyclophosphamide do not have serious side effects. Side-effects include chemotherapy-induced nausea and vomiting, bone marrow suppression, stomach ache, diarrhea, darkening of the skin, nails, alopecia or thinning of hair, changes in color and texture of the hair, and lethargy. Cyclophosphamide is itself carcinogenic, potentially causing transitional cell carcinoma of the bladder as a long-term complication. It can lower the body's ability to fight an infection.

2.10 Docetaxel

Therapeutic potential: - Docetaxel is a clinically well established anti-mitotic chemotherapy medication used mainly for the treatment of breast, ovarian and non-small cell lung cancer. [35][36] Docetaxel has an approved claim for treatment of patients, who have locally advanced, or metastatic breast or non small-cell lung cancer that have undergone anthracycline-based chemotherapy and failed to stop cancer progression or relapsed. Administered as a one-hour infusion every three weeks generally over a ten cycle course, Docetaxel is considered as or more effective than doxorubicin, paclitaxel and fluorouracil as a cytotoxic antimicrotubule agent.

Toxicity: - Docetaxel is a chemotherapeutic agent and is a cytotoxic compound and so is effectively a biologically damaging drug. [37] As with all chemotherapy, adverse effects are common and many varying side-effects have been documented. [38][39] Because Docetaxel is a cell cycle specific agent, it is cytotoxic to all dividing cells in the body. This includes tumour cells as well as hair follicles, bone marrow and other germ cells. [40]

2.11 Doxorubicin

Therapeutic potential:- Doxorubicin is commonly used to treat some leukemia’s, Hodgkin's lymphoma, as well as cancers of the bladder, breast, stomach, lung, ovaries, thyroid, soft tissue sarcoma, multiple myeloma, and others. [41]

Toxicity: - Acute side-effects of doxorubicin can include nausea, vomiting, and heart arrhythmias. It can also cause neutropenia as well as complete alopecia. Doxorubicin cardiotoxicity is characterized by a dose-dependent decline in mitochondrial oxidative phosphorylation. Reactive oxygen species, generated by the interaction of doxorubicin with iron, can then damage the myocytes causing myofibrillar loss and cytoplasm vacuolization. Due to these side effects and its red color, doxorubicin has earned the nickname Red devil [42] or Red death. [43]

2.12 Irinotecan

Therapeutic potential: - Irinotecan is a drug used for the treatment of cancer. Irinotecan is a topoisomerase 1 inhibitor, which prevents DNA from unwinding. Chemically, it is a semisynthetic analogue of the natural alkaloid camptothecin. Its main use is in colon cancer, particularly in combination with other chemotherapy agents.

Toxicity:-The most significant adverse effects of Irinotecan are severe diarrhea and extreme suppression of the immune system.

2.13 Asparaginase

Therapeutic potential: - Asparaginase is an enzyme that catalyzes the hydrolysis of asparagine to aspartic acid. It is used to treat acute lymphoblastic leukemia and is also used in some mast cell tumor protocols. Unlike other chemotherapy agents, it can be given as an intramuscular, subcutaneous, or intravenous injection without fear of tissue irritation. [44]

Toxicity: - The main side effect is an allergic or hypersensitivity reaction. Asparaginase has also been associated with pancreatitis. Additionally, it can also be associated with a coagulopathy as it decreases protein synthesis, including synthesis of coagulation factors and anticoagulant factor, leading to bleeding or thrombotic events such as stroke.

2.14 Methotrexate

Therapeutic potential: - Methotrexate was originally used as part of combination chemotherapy regimens to treat many kinds of cancers. It is still the mainstay for the treatment of many neoplastic disorders including acute lymphoblastic leukemia. It is also used in medical termination of pregnancy, [45] and autoimmune diseases. [46]

Toxicity:-Possible side effects can include anemia, neutropenia, increased risk of bruising, nausea and vomiting, dermatitis and diarrhea. A small percentage of patients develop hepatitis, and there is an increased risk of pulmonary fibrosis where dry cough can be an important sign.

2.14 Paclitaxel

Therapeutic potential: - Paclitaxel is approved in the UK for ovarian cancer, breast cancer, and lung cancer. It is also used in the treatment of Kaposi's sarcoma. [47]

Toxicity: - Common side-effects include nausea and vomiting, loss of appetite, change in taste, thinned or brittle hair and pain in the joints of the arms or legs lasting 2–3 days, changes in the color of the nails, tingling in the hands or toes. More serious side effects such as unusual bruising or bleeding, pain, redness, swelling at the injection site, change in normal bowel habits for more than 2 days, fever, chills, cough, sore throat, difficulty swallowing, dizziness, shortness of breath, severe exhaustion, skin rash, facial flushing and chest pain can also occur.

2.15 Pentostatin

Therapeutic potential: - Pentostatin is used to treat hairy cell leukemia. It is given by intravenous infusion once every two weeks for three to six months. Additionally, Pentostatin has been used to treat steroid-refractory acute and chronic graft-versus-host disease. [48]

Toxicity: - side-effects include insomnia, euphoria, and alopecia.

2.16 Rituximab

Therapeutic potential: - Rituximab destroys both normal and malignant B cells that have CD20 on their surfaces, and is therefore used to treat diseases which are characterized by having too many B cells, overactive B cells or dysfunctional B cells.

Toxicity: - Serious adverse events, which can cause death and disability that include severe infusion reactions, cardiac arrest, tumor lysis syndrome, causing acute renal failure, infections, hepatitis B reactivation and other viral infections. [49]

2.17 Tamoxifen

Therapeutic potential:-Tamoxifen is used to treat infertility in women with anovulatory disorders. A dose of 10–40 mg per day is administered in days 3–7 of a woman's cycle. [50] In addition, a rare condition occasionally treated with Tamoxifen is retroperitoneal fibrosis. [51] In men, Tamoxifen is sometimes used to treat gynecomastia that arises for example as a side effect of antiandrogen prostate cancer treatment. [52] Tamoxifen is also used by bodybuilders [53] to prevent or reduce drug-induced gynecomastia caused by the estrogenic metabolites of anabolic steroids. [54]

Toxicity: - A beneficial side effect of Tamoxifen is that it prevents bone loss by acting as an estrogen receptor agonist in this cell type. Therefore, by inhibiting osteoclasts, it prevents osteoporosis. [55] When Tamoxifen was launched as a drug, it was thought that Tamoxifen would act as an estrogen receptor antagonist in all tissue, including bone, and therefore it was feared that it would contribute to osteoporosis. It was therefore very surprising that the opposite effect was observed clinically. Hence tamoxifen's tissue selective action directly led to the formulation of the concept of selective estrogen receptor modulators. [56] In contrast Tamoxifen appears to be associated with bone loss in premenopausal women who continue to menstruate after adjuvant chemotherapy. [57]

2.18 Vincristine

Therapeutic potential: - Vincristine is delivered via intravenous infusion for use in various types of chemotherapy regimens. Vincristine is occasionally used as an immunosuppressant, for example, in treating thrombotic thrombocytopenic purpura (TTP) or chronic idiopathic thrombocytopenic purpura (ITP). It is used in combination with prednisone to treat childhood leukemia.

Toxicity:-The main side-effects of vincristine are peripheral neuropathy, hyponatriamia, constipation and hair loss. Peripheral neuropathy can be severe, and hence a reason to avoid, reduces, or stops the use of vincristine. One of the first symptoms of peripheral neuropathy is foot drop: a person with a family history of foot drop and/or Charcot-Marie-Tooth disease (CMT) may benefit from genetic testing for CMT before taking vincristine. [58] Accidental injection of vinca alkaloids into the spinal canal is highly dangerous, with a mortality rate approaching 100%. The medical literature documents cases of ascending paralysis due to massive encephalopathy and spinal nerve demyelization, accompanied by intractable pain, almost uniformly leading to death and a handful of survivors were left with devastating neurological damage with no hope of recovery. Rescue treatments consist of washout of the cerebrospinal fluid and administration of protective medications. [59]

2.19 Vinorelbine

Therapeutic potential: - Vinorelbine is an anti-mitotic chemotherapy drug that is given as a treatment for some types of cancer, including breast cancer and non-small cell lung cancer.

Toxicity: - Vinorelbine has a number of side-effects that can limit its use that include lowered resistance to infection, bruising or bleeding, anemia, constipation, diarrhoea, nausea, numbness or tingling in hands or feet, tiredness and a general feeling of weakness (asthenia), inflammation of the vein into which it was injected. Seldom severe hyponatriamia is seen. Less common effects are hair loss and allergic reaction. [60]

3. CONCLUSION:

Cancer affects people at all ages with the risk for most types increasing with age. Most commonly, chemotherapy acts by killing cells that divide rapidly, one of the main properties of most cancer cells. So it also harms cells that divide rapidly under normal circumstances e.g. cells in the bone marrow, digestive tract and hair follicles etc. This results in the most common side effects of chemotherapy that are myelosuppression, mucositis and alopecia. Other uses of cytostatic chemotherapy agents are the treatment of autoimmune diseases such as multiple sclerosis, dermatomyositis, polymyositis, lupus, rheumatoid arthritis and the suppression of transplant rejections. Newer anticancer drugs act directly against abnormal proteins in cancer cells, this is termed targeted therapy. The targeted therapy in treatment of neoplasm is a potential approach to treat cancer. Over time, cancer cells become more resistant to chemotherapy treatments. Chemotherapy techniques have a range of side effects that depend on the type of medications used. The most common medications mainly affect the fast-dividing cells of the body, such as blood cells and the cells lining the mouth, stomach, and intestines. Common side effect includes depression of the immune system, fatigue, anemia, tendency to bleed easily, hair loss. Gastrointestinal distress that includes nausea and vomiting are common side effects of chemotherapeutic medications that kill fast-dividing cells.

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Received on 19.10.2010

Accepted on 25.11.2010

Research J. Pharmacology and Pharmacodynamics. 2(6): Nov. –Dec. 2010, 370-375