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Alkylating Agents

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  • Alkylating Agents (73) • Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases.

The antineoplastic agents or anticancer drugs represent a large and diverse class of medications.  They generally have limited but important uses, and often have significant hepatotoxicity.   The antineoplastic agents are not easily classified.  Historically, they are categorized as (1) alkylating agents, (2) antimetabolites, (3) natural products, (4) hormones and antagonists, and (5) miscellaneous.  In recent years, however, the miscellaneous group has come to include some of the most important agents.  anticancer agents can also be classified by indication (lymphoma, leukemia, melanoma, solid tumor), mechanism of action (such as alkylating agents, antibiotics, biological response modifiers, antiandrogens, topoisomerase inhibitors or protein kinase inhibitors), chemical structure (folic acid analog, platinum coordination complex, purine or pyrimidine analog, monoclonal antibody) or as cytotoxic or nonspecific vs noncytotoxic or targeted.  The classification used in WikiMD represents a mixture of these systems, which generally follow those given in modern pharmacology textbooks.

Liver toxicity of Alkylating Agents

Almost all antineoplastic agents have some degree of hepatotoxicity, and the liver injury is usually due to direct, intinsic toxicity.  The typical manifestation is an elevation in liver enzymes or bilirubin during therapy that reverses rapidly with stopping treatment or dose modification.  This type of hepatotoxicity is dose related and generally self-limiting, but can be severe, progressive and even fatal as can occur with sinusoidal obstruction syndrome or acute toxic hepatic injury.  The antineoplastic agents often have a narrow toxic-therapeutic ratio, although the usual dose limiting toxicity is myelosuppression.  Nevertheless, liver injury also can be dose limiting, which generally becomes clear in early dose finding studies.  For this reason, many antineoplastic agents acquire a reputation for hepatotoxicity based upon premarketing studies, but are later found to be reasonably well tolerated and only rare causes of clinically significant liver injury when given in lower doses.  antineoplastic agents that are well known to cause significant direct hepatotoxicity when given in moderate to high doses (particularly when used in myeloablation before hematopoietic cell transplantation) include busulfan, mephalan, cyclosphosphamide, dacarbazine, cytarabine, fluorouracil, carboplatinin and L-asparaginase.  At lower doses, these agents are well tolerated.

Side effects of Alkylating Agents

Some antineoplastic agents can also cause idiosyncratic liver injury due to immunologic or metabolic idiosyncrasy.  Thus, typical drug induced cholestatic liver injury can occur in rare instances after therapy with cyclosphosphamide, azathioprine, mercaptopurine, melphalan and temozolomide.  Acute hepatocellular injury can occur with flutamide, bicalutamide and thalidomide.  Steatohepatitis can occur with L-asparaginase, methotrexate and tamoxifen (although this pattern may be due to direct toxicity rather than idiosyncratic injury).  Selected anticancer agents have also been linked to immunoallergic hepatitis or to autoimmune hepatitis-like injury.  A distinctive autoimmune pattern is found in rare instances after monoclonal antibody therapies or with the protein kinase inhibitors.  The pathogenesis of these immune reactions is not always well understood.  Finally, some antineoplastic agents can cause reactivation of hepatitis B, exacerbations of chronic hepatitis C, or lead to decompensation of an preexisting cirrhosis.    A classification of the antineoplastic agents with listing of individual agents is given below.  There has been a steady increase in development of innovative antineoplastic agents in recent years and between 5 and 10 new anticancer agents are approved yearly.  The hepatotoxicity of these recently introduced agents has not always been well defined.  The following links are to individual drug records for the antineoplastic agents; those that are not underlined have yet to be added.

Several naturally occurring compounds with antibiotic activity also have potent antitumor activity and were developed as anticancer agents.  These cytotoxic antibiotics are often grouped together, even though they have diverse mechanisms of action, widely different indications, a range of efficacies and distinctive toxicities.  The cytotoxic antibiotics in current use in the United States include (with trade name and year of approval):  bleomycin (Blenoxane, 1973), dactinomycin (Cosmegen, 1964), daunorubicin (Cerubidine, 1979), doxorubicin (Adriamycin, 1974), epirubicin (Ellence, 1999), idarubicin (Idamycin, 1990), plicamycin (previously known as mithramycin, still experimental), mitomycin (Mutamycin, 2002) and mitoxantrone (Novantrone, 1987).  A discussion of the mechanism of action, current use and hepatotoxicity, along with structural information and references of these drugs, are provided for each agent individually.  The anthracycline antibiotics include daunorubicin, doxorubicin, epirubicin and idarubicin (which are discussed together) and mitoxantrone, which is an anthracycline analog and discussed separately. 

Alphabetic list of antineoplastic agents - 0-9 - A1 - A2 - A3 - A4 - A5 -A6 - B - C - D - E - F - G - H - I - JK - L - M - NO - PQ - R - S - T - UVW - XYZ

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