Hyperthermia Can Reduce Cytotoxicity from Etoposide without a Corresponding Reduction in the Number of Topoisomerase II-DNA Cleavable Complexes

Joseph R. Dynlacht, Rosemary S.L. Wong, Norman Albright, William C. Dewey

Research output: Contribution to journalArticle

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Abstract

The chemotherapeutic drug etoposide (VP-16) causes the equilibrium reaction between noncleavaMe and cleavable topoisomerase II-DNA complexes to shift in favor of the cleavable complex [H. Zang, P. D'Arpa, and L. F. Liu, Cancer Cells (Cold Spring Harbor), 2:23-27,1990]. Pulsed-field gel electrophoresis was used to study induction and removal of cleavable complexes in cells heated before, during, or after VP-16 treatment Pulsed-field gel electrophoresis results were evaluated both as the fraction of activity (DNA) released from the plug and as the number of double-strand breaks (DSBs) calculated from molecular weight distributions; both end points led to the same conclusions. When cells were heated at 42C during treatment with VP-16 (12 μg/ml up to 60 min), a slight decrease in cleavable complexes (from 30 to 20 DSBs/100 megabase pairs) was detected immediately after treatment when compared with cells treated with the drug at 37C. Furthermore, heating at 42C caused a slight decrease in drug cytotoxicity as measured by less than a 2-fold increase in clono-genic survival. When cells were heated for 10 min at 45.5C prior to or after treatment with the drug, there was a reduction (50%) immediately after treatment in the number of DSBs/100 megabase pairs compared with unheated cells. The rate of removal of cleavable complexes was decreased slightly by heat After 120 min at 37C, the number of DSBs/100 megabase pairs decreased to 6 for both unheated cells and those heated prior to drug treatment and to ~8 for cells heated after drug treatment In agreement with a low effect of heat on the number of cleavable complexes after drug treatment, there was no significant effect of this heating protocol on drug cytotoxicity. However, heating at 45.5C prior to drug treatment at 37C protected cells from drug cytotoxicity (e.g., increased survival after 12 μg/ml for 60 min by ‘100-fold) despite the similarity in the induction and rate of removal of cleavable complexes when compared with nonheated cells. Thus, when cells are heated prior to administration of VP-16, drug cytotoxicity does not correlate with the number of cleavable complexes measured either immediately after treatment or 180 min later when ~75% of the initial number have been removed. Finally, since hyperthermia can actually decrease drug cytotoxicity, the use of hyperthermia as an adjuvant to chemotherapy involving topoisomerase II poisons, such as VP-16, should be approached with caution.

Original languageEnglish (US)
Pages (from-to)4129-4137
Number of pages9
JournalCancer Research
Volume54
Issue number15
StatePublished - Aug 1994

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Type II DNA Topoisomerase
Etoposide
Fever
Pharmaceutical Preparations
Heating
Pulsed Field Gel Electrophoresis
Therapeutics
Hot Temperature
Poisons
Adjuvant Chemotherapy
Molecular Weight

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Hyperthermia Can Reduce Cytotoxicity from Etoposide without a Corresponding Reduction in the Number of Topoisomerase II-DNA Cleavable Complexes. / Dynlacht, Joseph R.; Wong, Rosemary S.L.; Albright, Norman; Dewey, William C.

In: Cancer Research, Vol. 54, No. 15, 08.1994, p. 4129-4137.

Research output: Contribution to journalArticle

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title = "Hyperthermia Can Reduce Cytotoxicity from Etoposide without a Corresponding Reduction in the Number of Topoisomerase II-DNA Cleavable Complexes",
abstract = "The chemotherapeutic drug etoposide (VP-16) causes the equilibrium reaction between noncleavaMe and cleavable topoisomerase II-DNA complexes to shift in favor of the cleavable complex [H. Zang, P. D'Arpa, and L. F. Liu, Cancer Cells (Cold Spring Harbor), 2:23-27,1990]. Pulsed-field gel electrophoresis was used to study induction and removal of cleavable complexes in cells heated before, during, or after VP-16 treatment Pulsed-field gel electrophoresis results were evaluated both as the fraction of activity (DNA) released from the plug and as the number of double-strand breaks (DSBs) calculated from molecular weight distributions; both end points led to the same conclusions. When cells were heated at 42C during treatment with VP-16 (12 μg/ml up to 60 min), a slight decrease in cleavable complexes (from 30 to 20 DSBs/100 megabase pairs) was detected immediately after treatment when compared with cells treated with the drug at 37C. Furthermore, heating at 42C caused a slight decrease in drug cytotoxicity as measured by less than a 2-fold increase in clono-genic survival. When cells were heated for 10 min at 45.5C prior to or after treatment with the drug, there was a reduction (50{\%}) immediately after treatment in the number of DSBs/100 megabase pairs compared with unheated cells. The rate of removal of cleavable complexes was decreased slightly by heat After 120 min at 37C, the number of DSBs/100 megabase pairs decreased to 6 for both unheated cells and those heated prior to drug treatment and to ~8 for cells heated after drug treatment In agreement with a low effect of heat on the number of cleavable complexes after drug treatment, there was no significant effect of this heating protocol on drug cytotoxicity. However, heating at 45.5C prior to drug treatment at 37C protected cells from drug cytotoxicity (e.g., increased survival after 12 μg/ml for 60 min by ‘100-fold) despite the similarity in the induction and rate of removal of cleavable complexes when compared with nonheated cells. Thus, when cells are heated prior to administration of VP-16, drug cytotoxicity does not correlate with the number of cleavable complexes measured either immediately after treatment or 180 min later when ~75{\%} of the initial number have been removed. Finally, since hyperthermia can actually decrease drug cytotoxicity, the use of hyperthermia as an adjuvant to chemotherapy involving topoisomerase II poisons, such as VP-16, should be approached with caution.",
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