1497

The development of drug resistance is a major problem in cancer chemotherapy. Most attempts to circumvent resistance have involved the use of agents to reverse resistance after it has arisen. We have suggested an alternative approach: the use of agents to prevent the development of resistance during chemotherapy, and we have been investigating the use of selenium compounds as preventive agents [Frenkel, G.D. and Caffrey, P.B., A prevention strategy for circumventing drug resistance in cancer chemotherapy. Current Pharmaceutical Design 7: 1595-1614 (2001)]. The prevention approach is particularly relevant in ovarian cancer where the majority of tumors are chemosensitive at diagnosis, but treatment often fails nevertheless, due to the development of resistance during initial chemotherapy. Since platinum-based chemotherapy is the treatment of choice for ovarian cancer, we have examined the ability of selenite to prevent the induction of drug resistance by carboplatin in human ovarian tumor xenografts (derived from A2780 cells). The sensitivity/resistance of a tumor to platinum compounds was determined by measuring tumor growth after a single high dose of carboplatin (50 mg/kg ip) or cisplatin (5.2 mg/kg ip). The growth of control tumors was completely (although temporarily) stopped by these doses; however, pre-treatment with a single low dose of carboplatin (15 mg/kg ip) resulted in the rapid development of resistance to these high doses. Pre-treatment with selenite (3 x 1.5 mg/kg ip) prevented this carboplatin-induced resistance. We also have examined the effectiveness of selenite in combination with these platinum compounds in inhibiting tumor growth during a 3-week course of treatment. The combinations of selenite (1.5 mg/kg, 3 x weekly) with cisplatin (5.2 mg/kg, 2 x weekly) or with carboplatin (20 mg/kg, 2 x weekly) were significantly more effective than either platinum drug alone, despite the fact that selenite itself had no effect on tumor growth. These findings have led to the initiation of a clinical trial on the prevention of carboplatin-induced resistance by selenite and its effect on the chemotherapy of ovarian cancer. The current status of this ongoing Phase I trial at the Cancer Institute of New Jersey is described in another presentation [Gounder, M. et al] at this meeting. This research was supported in part by a grant from the New Jersey Commission on Cancer Research.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]