TOPOISOMERASE-II IN MULTIPLE-DRUG RESISTANCE

Topoisomerase II is a target of alkaloid, anthracycline and related an titumor agents. Two types of multiple drug resistance are associated w ith these enzymes. In classical (typical) multidrug resistance, inhibi tors are actively effluxed from cells by P-glycoprotein. In atypical m ultidrug resistance, topoisomerase II is either reduced in cellular co ntent or mutated to a form that does not interact with inhibitors. Bec ause cytotoxicity of most antineoplastic topoisomerase II inhibitors i s directly related to the number of active topoisomerase II molecules, a reduction in this number leads to resistance. In the topoisomerase II mechanism, through which the DNA linking number is altered, DNA dou ble strands are cleaved, and the termini transiently bound covalently (5') or noncovalently (3') to the enzyme while a second double strand is passed through the break in the first. This transition state comple x then decays to enzyme and DNA of altered linking number. Most cytoto xic topoisomerase II inhibitors stabilize these reaction intermediates as ternary complexes, which are converted to lethal lesions when cell s attempt to utilize the damaged DNA as templates. Toxicity is related to topoisomerase II content as well as to drug concentration. Thus, m ultidrug resistance results from either 1) decreasing cellular content of the inhibitor by P-glycoprotein (typical) or 2) decreasing cellula r content and/or activity of the target, topoisomerase II, as, for exa mple, when its content or activity is modulated downward by decreased expression, deactivation, or by mutations to the TopII gene, producing an enzyme that reacts poorly with inhibitors (atypical). Mixed types, i.e., both typical and atypical, are known. Attempts to abrogate or p revent both typical and atypical multidrug resistance to topoisomerase II inhibitors have been described.