Sensitization of Nitrosourea-resistant Mer+ Human Tumor Cells to N-(2-Chloroethyl)-N'-cyclohexyl-N-nitrosourea by Mild (41°C) Hyperthermia

R. Timothy Mulcahy*, Jerry Gipp, Martin A. Tanner

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Experiments were designed to determine whether heat treatment could sensitize nitrosourea-resistant human tumor cell lines expressing a repair system (Ob-alkylguanine DNA alkyltransferase; Mer+) capable of removing monoadducts from the DNA of treated cells prior to the formation of lethal interstrand cross-links. Effects of temperatures compatible with systemic hyperthermia were of particular interest, and, consequently, the effect of 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) exposure in vitro for 4 h at 37°C was compared with that for 1 h at 41°C followed by 3 h at 37°C. CCNU toxicity was significantly enhanced by heat treatment in the Mer+ HT-29 human colon carcinoma, and in HeLa-S3 and HeLa-CCL2 cell lines [thermal enhancement factor (ratio of CCNU doses required to reduce cell survival to 0.001 at 37° and 41°C) = 13-1.4). Pharmacokinetic studies indicated that the effect of heat treatment on CCNU toxicity was not attributable to exposure to increased concentrations of reactive species, nor was the enhancement due to a direct effect of heat and/or drug on alkyltransferase activity. A similar enhancement of CCNU toxicity was also observed in a Mer-line, HeLa-MR (thermal enhancement factor = 1.3). Heat-sequencing experiments clearly demonstrate that heat and CCNU must be administered concurrently. Alkaline elution experiments were designed to examine DNA-DNA cross-link formation in Mer+ and Mer-cells exposed to CCNU at 37° and 41°C, but quantitation of cross-link formation was not possible owing to the persistence of single strand breaks in the DNA of drug-treated cells. Nevertheless, collectively the data indicate that thermal enhancement of CCNU toxicity is independent of effects on alkyltrans-ferase activity and indicate that hyperthermia could provide an effective strategy for improving the nitrosourea response of resistant Mer+ tumors.

Original languageEnglish (US)
Pages (from-to)1086-1090
Number of pages5
JournalCancer Research
Volume48
Issue number5
StatePublished - 1988

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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