Selective toxicity of anticancer drugs: Presidential Address.

In the chemotherapy of infectious diseases, selective toxicity has been achieved by designing curative regimens based on pharmacokinetic data. Selective toxicity of antitumor drugs has been demonstrated for rapidly growing large growth fraction tumors occurring in patients under age 30. In these tumors curative schedules have been achieved by application of animal data relating to cellular and drug kinetics. The attempts to improve chemotherapy of large and small growth fraction tumors by kinetic observations in vivo in humans have been disappointing. Recent evidence suggests that the heterogeneity of cells within tumors has prevented precise observations on the relation of cellular and drug kinetics to improved selective toxicity. The availability of xenografts, flow cytometry, and tumor markers presents an opportunity to isolate subpopulations of tumor cells; to characterize their cellular and drug kinetics; and to correlate these with values obtained in vivo in humans. It should then be possible at long last to examine the potential role of cellular and drug kinetics in devising drug schedules with greater selective toxicity for human cancer.