cis-Diamminedichloroplatinum-resistant cell lines derived from human epithelial ovarian carcinoma express increased susceptibility to angiogenesis inhibitor TNP-470.

Abstract

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.

• Authors: Masaki Tamura, Koichi Takakuwa, Kenichi Tanaka
• Journal: Gynecologic oncology (Gynecol Oncol) Vol. 92 Issue 2 Pg. 530-6 (Feb 2004) ISSN: 0090-8258 [Print] United States
• PMID: 14766244 (Publication Type: Journal Article)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Cyclohexanes
• DNA, Neoplasm
• Neoplasm Proteins
• RNA, Neoplasm
• Sesquiterpenes
• Cisplatin
• O-(Chloroacetylcarbamoyl)fumagillol

Topics

• Adenocarcinoma (blood supply, drug therapy)
• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Carcinoma, Endometrioid (blood supply, drug therapy)
• Cell Division (drug effects)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• Cyclohexanes
• Cystadenocarcinoma, Serous (blood supply, drug therapy)
• DNA, Neoplasm (biosynthesis)
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Female
• Humans
• Mice
• Mice, Nude
• Neoplasm Proteins (biosynthesis)
• O-(Chloroacetylcarbamoyl)fumagillol
• Ovarian Neoplasms (blood supply, drug therapy)
• RNA, Neoplasm (biosynthesis)
• Sesquiterpenes (pharmacology)
• Xenograft Model Antitumor Assays