Clinical pharmacology of systemic chemotherapeutic agents in skin neoplasms

Considerable progress recently has been made in the systemic chemotherapy of disseminated skin neoplasms. Several agents are particularly useful in this regard: the nitrosoureas, methotrexate, actinomycin D, and dacarbazine. This paper reviews their pharmacologic disposition in man. The nitrosoureas have short plasma half-lives; however, they are extensively degraded to metabolites that persist in the body, and are only slowly excreted. Highly soluble in lipids, the nitrosoureas penetrate significantly into the central nervous system. Actinomycin D is only minimally metabolized in vivo; its elimination from the plasma shows a prolonged slow phase with a half-life of 36 hours; but its excretion is even slower than expected about 30% in a week. A potent inhibitor of dihydrofolate reductase, methotrexate exhibits a multiphasic plasma disappearance, and accumulates in tissues with high dihydrofolate reductase activities. At the normal therapeutic dosages, methotrexate is eliminated by the kidneys as the unchanged drug; appropriate dosage modifications are mandatory if renal function is compromised. Dacarbazine has a relatively short plasma half-life, and is rapidly excreted partly as the unchanged drug; it undergoes extensive biotransformation in the body. Like other antitumor agents, these drugs may cause gastrointestinal toxicities and myelosuppression; in addition each drug can have its own individual organ toxicity.