Collateral Sensitivity to Nitrosoureas in Multidrug-resistant Cells Selected with Verapamil

Bernard W. Futscher, Kimberley Campbell, William S. Dalton

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

We have examined the effects of the nitrosoureas, streptozotocin (STZ) and 1,3-bis(chlor(>ethyIH nitrosourea (BCNU), on a human multiple myeloma cell line, RPMI 8226, and its drug-resistant variants. Cell lines selected for doxorubicin (DOX) resistance alone displayed a STZ and BCNU cytotoxicity profile similar to that of the parent cell line. In contrast, two of the drug-resistant variants selected with DOX plus verapamil, an agent which inhibits P-glycoprotein-mediated multidrug resistance, displayed a collateral sensitivity to STZ and BCNU. Verapamil was included in the selection protocol because it has been shown to inhibit the P-glycoprotein-mediated multidrug resistance phenotype and is now in clinical trials as a chemosensitizing agent. The collateral sensitivity to these nitrosoureas seen in the DOX plus verapamil-selected cell lines Is due to the functional loss of a DNA repair molecule, (-Methylguanine DNA methyltransferase (MGMT). The functional loss of MGMT is secondary to the loss of MGMT gene expression. The loss of MGMT gene expression is not due to loss or gross rearrangement of the MGMT-coding region. If this selection pressure applied in vitro rEffects the in vivo situation, then new chemotherapeutic strategies may be devised to exploit this phenomenon. These cell lines will serve as useful models for delineating mechanisms which govern MGMT expression.

Original languageEnglish (US)
Pages (from-to)5013-5017
Number of pages5
JournalCancer Research
Volume52
Issue number18
StatePublished - Sep 1992

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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