Clinical Cancer Research, Vol 3, Issue 6 955-961, Copyright © 1997 by American Association for Cancer Research

ARTICLES

Apoptosis as a determinant of tumor sensitivity to topotecan in human ovarian tumors: preclinical in vitro/in vivo studies

C Caserini, G Pratesi, M Tortoreto, B Bedogne, N Carenini, R Supino, P Perego, SC Righetti and F Zunino
Division of Experimental Oncology B, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy.

Preclinical and clinical studies have documented the pharmacological interest in camptothecin derivatives in the treatment of resistant tumors. In particular, topotecan, a water-soluble derivative, exhibited promising activity in pretreated ovarian carcinoma. The present study investigated the pattern of tumor response in two human ovarian carcinoma xenografts and in their cisplatin-resistant sublines characterized by different mechanisms of drug resistance. In IGROV-1/Pt1 cells, cisplatin resistance has been ascribed to a reduced susceptibility to apoptosis as a consequence of p53 mutation and inactivation of its function. In the A2780 cisplatin-resistant subline, which retained the wild-type p53 gene status, the development of resistance has been possibly related to increased cell ability to repair drug-induced DNA damage. The in vivo results of the present study showed that topotecan could overcome the resistance in A2780/CP but not in IGROV-1/Pt1 tumor xenografts. The pattern of tumor response following in vivo topotecan treatment correlated with drug ability to induce apoptosis but not with its in vitro antiproliferative activity. The antitumor efficacy of topotecan in the four tumors reflected a different cell response to drug-induced DNA damage, as suggested by different perturbations of cell cycle progression. Indeed, only in the subline refractory to topotecan in vivo, IGROV-1/Pt1, did we observe a persistent arrest of the cells in the S-phase, resulting in a cytostatic and not a cytotoxic effect, since a low level of apoptosis was induced by the drug. In conclusion, the current results support that determination of drug-induced apoptosis is a useful predictor of tumor response to topotecan in ovarian carcinomas and suggest that p53 gene status may be a critical determinant of cell response to topoisomerase inhibitors.

This article has been cited by other articles:

				M. B. Flick, D. O'Malley, T. Rutherford, S. Rodov, M. Kamsteeg, X.-Y. Hao, P. Schwartz, B. M. Kacinski, and G. Mor Apoptosis-Based Evaluation of Chemosensitivity in Ovarian Cancer Patients Reproductive Sciences, May 1, 2004; 11(4): 252 - 259. [Abstract] [PDF]

				O. S. Frankfurt and A. Krishan Microplate Screening for Apoptosis with Antibody to Single-Stranded DNA Distinguishes Anticancer Drugs from Toxic Chemicals J Biomol Screen, April 1, 2003; 8(2): 185 - 190. [Abstract] [PDF]

				A. Nakashio, N. Fujita, S. Rokudai, S. Sato, and T. Tsuruo Prevention of Phosphatidylinositol 3'-Kinase-Akt Survival Signaling Pathway during Topotecan-induced Apoptosis Cancer Res., September 1, 2000; 60(18): 5303 - 5309. [Abstract] [Full Text]