Apoptosis induced by anticancer drugs.
Most of the cytotoxic anticancer drugs in current use have been shown to induce apoptosis in susceptible cells. The fact that disparate agents, which interact with different targets, induce cell death with some common features (endonucleolytic cleavage of DNA, changes in chromatin condensation) suggests that cytotoxicity is determined by the ability of the cell to engage this so-called 'programmed' cell death. The mechanism of the coupling of a stimulus (drug-target interaction) to a response (cell death) is not known, but modulation of this coupling may affect the outcome of drug treatment. This review surveys the recent evidence which supports the idea that the drug-target interaction per se is not the sole determinant of cellular sensitivity of cytotoxic drugs. Studies of the signals which might engage apoptosis, the genes which modulate it and the biochemical process of drug-induced apoptosis itself are described, where possible, for glucocorticoids, topoisomerase inhibitors, alkylating agents, antimetabolites and antihormones. It is suggested that identification of the gene products which couple the stimulus to the response, and so determine intrinsic cellular sensitivity (and resistance), will be important targets for new types of drugs. These might then allow responses to occur in the major cancers of man, which are chemoresistant.
Hickman
J A
JA
CRC Molecular and Cellular Pharmacology Group, School of Biological Sciences, University of Manchester, UK.
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis; D004247:DNA / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D010641:Phenotype; D011965:Receptors, Glucocorticoid / Q000502:physiology; D059004:Topoisomerase I Inhibitors
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D059004:Topoisomerase I Inhibitors; D004247:DNA; D002784:Cholesterol; D002118:Calcium