Cross-Resistance to Camptothecin Analogues in a Mitoxantrone-resistant Human Breast Carcinoma Cell Line Is Not Due to DNA Topoisomerase I Alterations

Chih Hsin J. Yang, Kenneth H. Cowan, Julie K. Horton, Erasmus Schneider

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

We have previously described a mitoxantrone-resistant human breast carcinoma cell line, MCF7/MX, in which resistance was associated with a defect in the energy-dependent accumulation of mitoxantrone in the absence of P-glycoprotein overexpression (M. Nakagawa et aL, Cancer Res. 52: 6175–6181, 1992). We now report that this cell line is highly cross-resistant to the camptothecin analogues topotecan (180-fold), 9-aminocamptothecin (120-fold), CPT-11 (56-fold), and SN38 (101-fold), but is only mildly cross-resistant to the parent compound camptothecin (3.2-fold) and 10,11-methylenedioxy-camptothecin (2.9-fold). Topotecan accumulation was decreased in MCF7/MX cells compared to parental MCF7/WT cells, and there was a corresponding reduction in topotecan-mediated stimulation of the enzyme/DNA complex formation in MCF7/MX cells compared to MCF7/WT cells. No overexpression of the multidrug resistance-associated protein was detected compared to parental MCF7/WT cells. Furthermore, both sensitive MCF7/WT and mitoxantrone-resistant MCF7/MX cells contain equal amounts of DNA topoisomerase I protein, and DNA relaxation activities were equal in both cell lines and inhibited to the same extent by topotecan and camptothecin. Thus, these results suggest a novel mechanism of resistance to topoisomerase I inhibitors in cancer cells.

Original languageEnglish (US)
Pages (from-to)4004-4009
Number of pages6
JournalCancer Research
Volume55
Issue number18
StatePublished - Sep 15 1995
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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