The role of DNA topoisomerases II in drug resistance.
The essential nuclear enzyme DNA topoisomerase II is required for the action of a significant number of cytotoxic compounds. Resistance mechanisms identified in cell lines include down-regulation of protein expression, by gene methylation or down-regulation of mRNA, altered drug-DNA-protein interaction or ATP binding, post translational modification of the protein and alteration in expression of the isoenzymes. There is a lack of data relating the findings from these cell lines to observations from clinical practice and the evolution of specific drug resistance in patients. For leukaemias, several studies using different in vitro chemosensitivity assays show a correlation between the clinical response and the in vitro sensitivity (Sargent & Taylor, 1989; Pieters et al, 1989; Larsson et al, 1992; Bosanquet, 1991). From this data, outcome may be related to the mechanism of resistance and allow the development of strategies to overcome them. This includes the use of colony stimulating factors or antimetabolites or the development of new drugs to utilize topoisomerases as their target but which are not transported by P-glycoprotein. Thus an understanding of these mechanisms may help in the optimal use of the topoisomerase II inhibitors.
Alton
P A
PA
Department of Haematology, Pembury Hospital, Kent.
Harris
A L
AL
D000818:Animals; D002455:Cell Division / Q000502:physiology; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000502:physiology*; D004351:Drug Resistance / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes; D059005:Topoisomerase II Inhibitors
D006133:Growth Substances; D007527:Isoenzymes; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II