title: Cataloging antineoplastic agents according to their effectiveness against platinum-resistant and platinum-sensitive ovarian carcinoma cell lines.
abstract: Although epithelial ovarian cancers (EOCs) are initially treated with platinum-based chemotherapy, EOCs vary in platinum responsiveness. Cataloging antineoplastic agents according to their effectiveness against platinum-resistant and platinum-sensitive EOC cell lines is valuable for development of therapeutic strategies to avoid platinum inefficacy and to exploit platinum sensitivity. TOV-21G devoid of FANCF expression, OV-90 and SKOV-3 were employed as examples of platinum-sensitive, platinum-intermediate and platinum-resistant cell lines, respectively. Antineoplastic agents examined included mitomycin C, doxorubicin, etoposide, gemcitabine, chlorambucil, paclitaxel, triapine and X-rays. Their effectiveness against cell lines was analyzed by clonogenic assays. Cytotoxic profiles of mitomycin C and carboplatin were similar, with mitomycin C exhibiting greater potency and selectivity against TOV-21G than carboplatin. Cytotoxic profiles of doxorubicin, etoposide and X-rays overlapped with that of carboplatin, while OV-90 overexpressing Rad51 was more resistant to chlorambucil than SKOV-3. The efficacy of paclitaxel and triapine was independent of platinum sensitivity or resistance. Consistent with these cytotoxic profiles, cisplatin/mitomycin C, triapine, and paclitaxel differed in the capacity to induce phosphorylation of H2AX, and produced unique inhibitory patterns of DNA/RNA syntheses in HL-60 human leukemia cells. Paclitaxel and triapine in combination produced additive antitumor effects in M109 murine lung carcinoma. In conclusion, mitomycin C is potentially more effective against Fanconi anemia pathway-deficient EOCs than carboplatin. Doxorubicin and etoposide, because of their overlapping cytotoxic properties with carboplatin, are unlikely to be efficacious against platinum-refractory EOCs. Paclitaxel and triapine are effective regardless of platinum sensitivity status, and promising in combination for both platinum-sensitive and platinum-refractory EOCs.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, United States.
authors.forename: Kimiko
authors.initials: K
authors.lastname: Ishiguro
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, United States.
authors.forename: Yong-Lian
authors.initials: YL
authors.lastname: Zhu
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, United States.
authors.forename: Z Ping
authors.initials: ZP
authors.lastname: Lin
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, United States.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Penketh
authors.affiliation: Department of Pharmacology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, United States.
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Shyam
authors.affiliation: Department of Pharmacology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, United States.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, United States.
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Baumann
authors.affiliation: Department of Pharmacology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, United States.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Sartorelli
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, United States.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rutherford
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, United States.
authors.forename: Elena S
authors.initials: ES
authors.lastname: Ratner
keywords: Fanconi anemia pathway; carboplatin; mitomycin C; paclitaxel; platinum responsiveness; triapine