CRITICAL FACTS III: Drugs that disrupt DNA
(if med school is a Minnesota forest with millions of trees,
these are the red pines)
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From a mechanistic standpoint, drugs that disrupt DNA can be divided into several classes and subclasses, including: CROSSLINKING AGENTS (alkylating agents and miscellaneous others), INTERCALATING AGENTS (esp. anthracycline antibiotics) and DRUGS THAT CAUSE STRAND BREAKS/PREVENT REPLICATION. These drugs fall into several chemical classes, including alkylating agents, natural products (antibiotics and plant alkaloids) and miscellaneous drugs.
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Toxicities may be unique to an individual drug (such as hemorrhagic cystitis with CYCLOPHOSPHAMIDE), or common to a particular chemical class of agents (e.g., the cardiomyopathy associated with ANTHRACYCLINE ANTIBIOTICS) or mechanism of action (e.g., bone marrow suppression, gastritis and alopecia as these drugs target rapidly dividing cells).
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Although crosslinking agents are dependent upon proliferation, these drugs ARE NOT cell cycle specific (i.e., they are CCNS) because the alkylation reactions that initiate cell death can occur during any phase of the cell cycle. However, primary toxicity occurs in late G1 and S phase.
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One major distinguishing feature among alkylating agents is the rate at which the parent drug is converted to a strong electrophile. For some drugs (e.g., MECHLORETHAMINE), the reaction is virtually instantaneous --- these agents are given IV to minimize blistering and GI effects. Other agents (such as BUSULFAN, CYCLOPHOASPHAMIDE, IFOSFAMIDE and MELPHALAN) must be activated in the liver and other tissues, and they can be given orally.
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The anthracycline antibiotics (e.g. DOXORUBICIN) work by intercalating into DNA. Their major toxicity is an UNUSUAL CARDIOMYOPATHY that is often IRREVERSIBLE and related to the TOTAL DOSE of the drug.
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BLEOMYCIN has a unique mechanism of action and spectrum of toxicities, and it is therefore included in many combination therapies. BLEOMYCIN generates free radicals that cut through DNA strands. Unlike many other drugs that target rapidly growing cells, BLEOMYCIN does not cause significant myelosuppression. It does cause skin and lung damage, because those tissues do not have the enzyme (hydrolase) required to metabolize BLEOMYCIN.