cis-Diamminedichloroplatinum-resistant cell lines derived from human epithelial ovarian carcinoma express increased susceptibility to angiogenesis inhibitor TNP-470.
OBJECTIVE
To elucidate the efficacy of TNP-470 on ovarian carcinomas by using cis-diamminedichloroplatinum (CDDP)-resistant cell lines.


METHODS
The susceptibility of human ovarian carcinoma-derived cell lines and its resistant cell lines against cis-diamminedichloroplatinum (CDDP) to angiogenesis inhibitor, TNP-470, were analyzed using three human cultured cell lines derived from ovarian carcinoma (TYK, KF-92, and Nakajima) and each CDDP-resistant cell line (TYK-R, TYK-R', KF/ra, KF/rb, Nakajima-S1, and Nakajima-S2).


RESULTS
TNP-470 revealed suppression of thymidine incorporation by all of the nine cell lines linearly dependent on the concentration of TNP-470. Significant suppression was not observed for either uridine or leucine incorporation by all nine cell lines. To elucidate the site of each cell line, in which TNP-470 revealed the antitumor effect, the incorporation of (3)H-TNP-470 by cultured cells or by DNA extracted from cultured cells was examined in the cell lines, and the ratio of (3)H-TNP-470 incorporation by DNA to (3)H-TNP-470 incorporation by cultured cells ranged from 2.3% to 4.4% in three parent cell lines. The ratio in the CDDP-resistant cell lines ranged from 11.0% to 46.7%. The ability of TNP-470 to inhibit neoplastic growth in vivo was evaluated using KF-92, KF/ra, KF/rb, Nakajima, Nakajima-S1, and Nakajima-S2. Concerning KF-92, KF/ra, and KF/rb, 30 mg/kg of TNP-470 significantly suppressed the tumorigenicity of KF-92, 10 and 30 mg/kg of TNP-470 suppressed the tumorigenicity of KF/ra, and 30 mg/kg of TNP-470 suppressed the tumorigenicity of KF/rb. Concerning Nakajima, Nakajima-S1, and Nakajima-S2, TNP-470 revealed no inhibitory effect on the tumorigenicity of Nakajima. Contrary, significant inhibition was observed when 30 mg/kg of TNP-470 was used to the CDDP-resistant cell lines Nakajima-S1 and Nakajima-S2.


CONCLUSIONS
These results suggest that the clinical application of TNP-470 may be one of the possible treatments for the CDDP-resistant ovarian carcinomas.
Tamura
Masaki
M
Department of Obstetrics and Gynecology, Niigata University School of Medicine, Niigata 951-8510, Japan.
Takakuwa
Koichi
K
Tanaka
Kenichi
K
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018269:Carcinoma, Endometrioid / Q000098:blood supply / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D003510:Cyclohexanes; D018284:Cystadenocarcinoma, Serous / Q000098:blood supply / Q000188:drug therapy; D004273:DNA, Neoplasm / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D012334:RNA, Neoplasm / Q000096:biosynthesis; D012717:Sesquiterpenes / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D003510:Cyclohexanes; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D012717:Sesquiterpenes; D002945:Cisplatin; D000077609:O-(Chloroacetylcarbamoyl)fumagillol