HYPERTHERMIA, THERMOTOLERANCE AND TOPOISOMERASE-II INHIBITORS

HH KAMPINGA*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

28 Citations (Scopus)

Abstract

The cytoxicity of both intercalating (m-AMSA) and non-intercalating (VP16, VM26) topoisomerase II-targeting drugs is thought to occur via trapping DNA topoisomerase II on DNA in the form of cleavable complexes. First, analysis of cleavable complexes (detected as DNA double-strand breaks) by pulsed-field gel electrophoresis confirmed the correlation between cleavable complex formation and cytotoxicity of three topoisomerase-targeting drugs in HeLa S3 cells (the order of effects being VM26>m-AMSA>VP16). In contrast to many antineoplastic agents, hyperthermic treatments were found to protect cells against the toxicity of all three topoisomerase II drugs. Hyperthermia treatment does not alter drug accumulation but reduces the ability of the drug-topoisomerase II complex to form the cleavable complexes. Nuclear protein aggregation induced by heat at the sites of topoisomerase II-DNA interaction may explain such an effect. In thermotolerant cells, the toxic effects of VP16 but not m-AMSA were reduced. For both drugs, however, the status of thermotolerance did not affect cleavable complex formation by the drugs. Thus, protection against VP-16 toxicity seems not to be associated with heat-induced activation of the P-gp 170 pump or altered topoisomerase II-DNA interactions. Rather, a protective (heat shock protein mediated?) mechanism against non-intercalating topoisomerase II drugs seems to occur at a stage after DNA-drug interaction. Finally, heal treatment before topoisomerase II drug treatment reduced toxicity and cleavable complex formation in thermotolerant cells to about the same extent as in non-tolerant cells, consistent with the presumption of nuclear protein aggregation being responsible for this effect.

Original languageEnglish
Pages (from-to)333-338
Number of pages6
JournalBritish Jounal of Cancer
Volume72
Issue number2
Publication statusPublished - Aug-1995

Keywords

  • HYPERTHERMIA
  • TOPOISOMERASE II DRUGS
  • THERMOTOLERANCE
  • HEAT SHOCK PROTEINS
  • PROTEIN AGGREGATION
  • HEAT-SHOCK PROTEIN
  • CHINESE-HAMSTER CELLS
  • CHEF ELECTROPHORESIS
  • CYTO-TOXICITY
  • DNA CLEAVAGE
  • DRUG-RESISTANCE
  • MAMMALIAN-CELLS
  • STRAND BREAKS
  • RADIATION
  • SITES

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