Modulation of melphalan and cisplatin cytotoxicity in human ovarian cancer cells resistant to alkylating drugs.
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 topoisomerase I inhibitor topotecan was able to increase melphalan 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 lonidamine 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 melphalan cytotoxic activity was determined by flunarizine in OAW42MER resistant cells and, to a lesser extent, in OAW42 sensitive cells. However, the calcium blocker failed to modulate cisplatin activity in both cell lines.
Gornati
D
D
Divisione di Oncologia Sperimentale C, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy.
Zaffaroni
N
N
Villa
R
R
De Marco
C
C
Silvestrini
R
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D015152:Blotting, Northern; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003470:Culture Media / Q000032:analysis; D003537:Cystadenoma / Q000188:drug therapy* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005260:Female; D005444:Flunarizine / Q000494:pharmacology; D006801:Humans; D008558:Melphalan / Q000494:pharmacology*; D009553:Nimodipine / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015347:RNA Probes; D012334:RNA, Neoplasm / Q000032:analysis / Q000302:isolation & purification; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D002121:Calcium Channel Blockers; D003470:Culture Media; D015347:RNA Probes; D012334:RNA, Neoplasm; D009553:Nimodipine; D014700:Verapamil; D002945:Cisplatin; D008558:Melphalan; D005444:Flunarizine