Mechanism of increased sensitivity to etoposide in a mitomycin C-resistant human bladder cancer cell line

Hong Xia, Richard J. Bleicher, Vicram Gupta, Howard A. Zaren, Shivendra V. Singh

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

The mechanism of increased sensitivity to etoposide (VP-16) in a human bladder cancer cell line (J82/MMC-2), which is > 9-fold more resistant to mitomycin C (MMC) compared with parental cells (J82/WT), was investigated. Colony formation assays, following 1 hr drug exposure, revealed that about a 2.2-fold higher concentration of VP-16 was required to kill 50% of the J82/WT cell line compared with J82/MMC-2. The MTT assays, following continuous drug exposure, also showed that the J82/MMC-2 cell line was significantly more sensitive to VP-16 compared with J82/WT. Accumulation of VP-16 was significantly higher in the J82/MMC-2 cell line compared with J82/WT at every drug concentration tested. Likewise, intracellular VP-16 retention was significantly higher in the J82/MMC-2 cell line compared with J82/WT when drug uptake was measured as a function of varying incubation time and at a fixed VP-16 concentration. The efflux of VP-16 from the J82/MMC-2 cell line was equivalent to that from J82/WT. In agreement with the results of drug uptake studies, the levels of VP-16-induced protein-DNA complexes were markedly higher in the J82/MMC-2 cell line compared with J82/WT. The catalytic activity of topoisomerase II (topo II) in 0.35 M NaCl nuclear extract of J82/WT cells was equivalent to that of J82 results suggest that the mechanism responsible for the collateral sensitivity of the J82/MMC-2 cell line to VP-16 may be attributable to a relatively higher drug accumulation in this cell line compared with parental cells.

Original languageEnglish (US)
Pages (from-to)606-611
Number of pages6
JournalInternational Journal of Cancer
Volume70
Issue number5
DOIs
StatePublished - 1997

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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