Modulation of melphalan and cisplatin cytotoxicity in human ovarian cancer cells resistant to alkylating drugs

Daniela Gornati, Nadia Zaffaroni, Raffaella Villa, Cinzia De Marco, Rosella Silvestrini

Research output: Contribution to journalArticle

Abstract

We investigated the effect of pharmacological modulators on the cytotoxic activity of melphalan and cisplatin in human ovarian cystadenocarcinoma cells sensitive (OAW42) or resistant (OAW42MER) to bifunctional alkylating agents. By filter elution experiments we observed a reduced accumulation and a faster repair of melphalan-induced DNA interstrand cross-links in the OAW42MER resistant cells than in the OAW42 parental, sensitive cells. Moreover, resistant cells were characterized by an increased level of mRNA encoding enzymes involved in the nucleotide excision repair pathway, such as ERCC (excision repair cross complementing)1 and ERCC2. Among the modulators used, the topolsomerase I inhibitor topotecan was able to increase melphalen cytotoxic activity in sensitive and resistant cell lines. Topotecan also positively modulated cisplatin activity, although to a variable extent in the two cell lines, as a function of treatment schedule. The energolytic compound ionidamine markedly enhanced the cytotoxicity of melphalan and cisplatin, with a potentiating effect in the OAW42MER resistant cells almost 2-fold that of in the OAW42 sensitive cells. No significant potentiation was observed by using calcium channel blockers, such as verapamil and nimodipine. Conversely, an increase in melphalen cytotoxic activity was determined by flunarizine in OAW42MER resistant cells and, to a lesser extent, in OAW42 sensitive cells. However, the calcium blocker falled to modulate cisplatin activity in both cell lines.

Original languageEnglish
Pages (from-to)509-516
Number of pages8
JournalAnti-Cancer Drugs
Volume8
Issue number5
Publication statusPublished - 1997

Keywords

  • Alkylating drugs
  • Cisplatin
  • Melphalan
  • OAW42
  • OAW42MER

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology

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