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.

CONCLUSION

These results suggest that the clinical application of TNP-470 may be one of the possible treatments for the CDDP-resistant ovarian carcinomas.