Collateral sensitivity to nitrosoureas in multidrug-resistant cells selected with verapamil

Bernard W Futscher, Kimberley Campbell, William S. Dalton

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

We have examined the effects of the nitrosoureas, streptozotocin (STZ) and 1,3-bis(chloroethyl)-1-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, O6-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 reflects 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 15 1992

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Methyltransferases
Verapamil
Cell Line
Streptozocin
Doxorubicin
DNA
Multiple Drug Resistance
P-Glycoprotein
Gene Expression
Gene Rearrangement
Multiple Myeloma
DNA Repair
Pharmaceutical Preparations
Clinical Trials
Phenotype
Pressure

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Collateral sensitivity to nitrosoureas in multidrug-resistant cells selected with verapamil. / Futscher, Bernard W; Campbell, Kimberley; Dalton, William S.

In: Cancer Research, Vol. 52, No. 18, 15.09.1992, p. 5013-5017.

Research output: Contribution to journalArticle

Futscher, Bernard W ; Campbell, Kimberley ; Dalton, William S. / Collateral sensitivity to nitrosoureas in multidrug-resistant cells selected with verapamil. In: Cancer Research. 1992 ; Vol. 52, No. 18. pp. 5013-5017.
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