In vivo model development of cisplatin-resistant and -sensitive A2780 human ovarian carcinomas

Abstract

The human ovarian carcinoma, A2780, and a derived cisplatin-resistant subline, A2780 cDDP, were developed as in vivo sc models in athymic mice. The tumor volume doubling time (TVDT) of both lines was calculated for tumors of between 250 mg and 1 gm, determined in both unselected (unstaged) tumor-bearing mice as well as mice whose tumors were (staged) between 50 and 200 mg when selected for observation. Similar mean TVDT (+/- SD) of 2.3 (+/- 0.5) and 2.7 (+/- 1.1) days for unstaged A2780 and A2780/cDDP tumors, respectively, and 2.2 (+/- 0.5) and 2.5 (+/- 0.7) days for staged A2780 and A2780/cDDP tumors, respectively, were observed. Each of the tumor settings just described was used to assess cisplatin's antitumor activity following ip and iv injections. Antitumor activity was expressed predominantly as gross log cell kill (LCK) and occasionally as percent inhibition. The staged tumor models used with iv cisplatin therapy evolved as the preferred system. Against staged A2780, the mean maximum LCK (+/- SD) associated with iv cisplatin therapy was 2.5 (+/- 1.0) based on 9 experiments, whereas with iv cisplatin versus staged A2780/cDDP yielded 0.5 (+/- 0.3) mean maximum LCK in 16 experiments. The sensitive and cisplatin-resistant staged tumor models were also used to evaluate three platinum analogs, carboplatin, iproplatin, and tetraplatin. All three cisplatin analogs were active (greater than or equal to 1 LCK) versus A2780 but not A2780/cDDP. Thus, the A2780 and A2780/cDDP tumor models demonstrated reproducible sensitivity and resistance, respectively, to cisplatin, and provide an in vivo system for evaluating cisplatin analogs.