Toxicity antineoplastic drugs

Antineoplastic Drugs. Cyclophosphamide (193) produces antineoplastic effects (see Chemotherapeutics, anticancer) via biochemical conversion to a highly reactive phosphoramide mustard (194) it is chiral owing to the tetrahedral phosphoms atom. The therapeutic index of the (3)-(-)-cyclophosphamide [50-18-0] (193) is twice that of the (+)-enantiomer due to increased antitumor activity the enantiomers are equally toxic (139). The effectiveness of the DNA intercalator dmgs adriamycin [57-22-7] (195) and daunomycin [20830-81-3] (196) is affected by changes in stereochemistry within the aglycon portions of these compounds. Inversion of the carbohydrate C-1 stereocenter provides compounds without activity. The carbohydrate C-4 epimer of adriamycin, epimbicin [56420-45-2] is as potent as its parent molecule, but is significandy less toxic (139). 

Bendamustine is a useful antineoplastic drug for the treatment of non-Hodgkin s lymphomas, multiple myeloma and as a partner drug in the combination therapy of some solid tumors. The cross-resistance with other alkylating drugs is not complete. Myelosuppression and lymphocytopenia is its main dose-limiting toxicity. 

Antineoplastic drugs are potentially toxic and their administration is often associated with many serious adverse reactions. At times, some of these adverse effects are allowed because the only alternative is to stop treatment of the malignancy. A treatment plan is developed that will prevent, lessen, or treat most or all of the symptoms of a specific adverse reaction. An example of prevention is giving an antiemetic before administering an antineoplastic drug known to cause severe nausea and vomiting. An example of treatment of the symptoms of an adverse reaction is the administration of an antiemetic and intravenous (IV) fluids and electrolytes when severe vomiting occurs. 

Plasma digoxin levels may decrease when the drug is administered with bleomycin. When bleomycin is used witii cisplatin, there is an increased risk of bleomycin toxicity Pulmonary toxicity may occur when bleomycin is administered with other antineoplastic drugs. Plicamycin, mitomycin, mitoxantrone, and dactino-mycin have an additive bone marrow depressant effect when administered with other antineoplastic drugs. In addition, mitomycin, mitoxantrone, and dactinomycin decrease antibody response to live virus vaccines. Dactinomycin potentiates or reactivates skin or gastrointestinal reactions of radiation therapy There is an increased risk of bleeding when plicamycin is administered witii aspirin, warfarin, heparin, and the NSAIDs. 

Antineoplastic dragp are potentially toxic dragp that can cause a variety of effects during and after their administration. Display 55-2 summarizes important points to keep in mind when administering an antineoplastic drug. 

Grieshaber, C. (1991). Prediction of human toxicity of new antineoplastic drugs from studies in animals. In The Toxicity of Anticancer Drugs. Powis, G. and Hacker, M. Eds. Pergamon Press, New York, pp. 10-24. 

Originally developed for chemotherapy, azathioprine is used today mainly as an immunosuppressive agent and rarely as an antineoplastic drug. It was introduced as an immunosuppressive agent by a British pioneer of tissue transplantation, Roy Caine. Azathioprine was used to prevent rejection after tissue transplantation as a replacement for 6-mercaptopurine because it was less toxic. In addition to tissue transplantation, it is also used for rheumatoid arthritis and Crohn s disease. Azathioprine is a prodrug which in the body is converted to its active metabolites 6-mercaptopurine and 6-thioinosinic acid. Until the discovery of cyclosporine, azathioprine in combination with steroids was the standard treatment to prevent rejection after tissue transplantation. 

Consequently, antineoplastic drugs typically have a very low therapeutic index compared with drugs that are used to treat less serious disorders (see Chapter 1). Considering that cancer is usually life threatening, these toxic effects must be expected and tolerated during chemotherapeutic treatments. Some side effects, however, can be treated with other drugs. In particular, gastrointestinal disturbances (e.g., nausea,... 

Oxidative stress reduces the rate of cell proliferation, and that occurring during chemotherapy may interfere with the cytotoxic effects of antineoplastic drugs, which depend on rapid proliferation of cancer cells for optimal activity. Antioxidants detoxify ROS and may enhance the anticancer effects of chemotherapy. For some supplements, activities beyond their antioxidant properties, such as inhibition of topoisomerase II or protein tyrosine kinases, may also contribute. ROS cause or contribute to certain side effects that are common to many anticancer drugs, such as gastrointestinal toxicity and muagenesis. ROS also contribute to side effects that occur only with individual agents, such as doxorubicin-induced cardiotoxicity, cisplatin-induced nephrotoxicity, and bleomycin-induced pulmonary fibrosis. Antioxidants can reduce or prevent many of these side effects, and for some supplements the protective effect results from activities other than their antioxidant properties. Certain side effects, however, such as alopecia and myelosuppression, are not prevented... 

Foster-Nora JA, Siden R. Amifostine for protection from antineoplastic drug toxicity. Am J Health Syst Pharm 1997 54(7) 787-800. 

Berns JS, Ford PA. Renal toxicities of antineoplastic drugs and bone marrow transplantation. Semin Nephrol 1997 17 54-66. 

Because many antineoplastic drugs affect DNA synthesis, any cell with a high turnover rate will be more sensitive to the toxic effects of chemotherapy. Cancer cells do not necessarily proliferate faster than normal cells. Normal tissues that consist of rapidly proliferating cells are targets for the toxicities of many anticancer drugs.The bone marrow, intestinal mucosa, and hair follicles are such tissue sites where drug effects are manifested. 

Antineoplastic drugs such as 6-mercaptopurine, methotrexate, cyclophosphamide, and aminopterin administered in early pregnancy have produced various congenital malformations. Cy to toxic drugs also have induced fetal malformation and early abortion of malformed fetuses [4-6],... 

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