Expression of drug resistance-associated mdr-1, GST π, and topoisomerase II genes during cell cycle traverse

Cheppail Ramachandran, Dana Mead, Larry L. Wellham, Antonieta Sauerteig, Awtar Krishan

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

The expression of drug resistance-associated mdr-1, GST π, and topoisomerase II genes was analyzed in cell cycle phase enriched populations of doxorubicin-resistant murine leukemic P388/R-84 cells. Flow cytometric analysis of bromodeoxyuridine (BrdU) incorporation and staining with anti-BrdU antibodies was used to confirm the purity of cell cycle phase enriched populations obtained by centrifugal elutriation. Doxorubicin (DOX) and daunorubicin (DNR) accumulation was significantly lower in S-phase cells, and coincubation with verapamil (VPL) or chlorpromazine (CPZ) enhanced DOX and DNR accumulation more in S-phase than in G1- and G2 M-phase cells. While the cellular content of mdr-1 and topoisomerase II mRNAs changed, GST π mRNA content remained constant during the cell cycle. S-phase cells had about 3-fold higher mdr-1 mRNA content than G1- and G2 M-phase cells. In G1 cells, P-glycoprotein expression, as determined by C219 monoclonal antibody, was 12% less than that of S and G2 M cells. Topoisomerase II mRNA content increased with the progression of cell cycle and peaked in G2 M cells. These observations suggest that cell cycle stage related changes in expression of drug resistance markers may have a major bearing on chemosensitivity of drug-resistant cells.

Original languageEnglish (US)
Pages (from-to)545-552
Number of pages8
JournalBiochemical Pharmacology
Volume49
Issue number4
DOIs
StatePublished - Feb 14 1995

Keywords

  • cell cycle
  • doxorubicin
  • glutathione S-transferase
  • multidrug resistance
  • P-glycoprotein
  • topoisomerase II

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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