Abstract 985: Design of a model for the development of cisplatin resistance in H526 human small cell lung cancer xenografts.

Abstract

Abstract Treatment of Small Cell Lung Cancer (SCLC) often fails due to the rapid development of resistance to chemotherapy drugs. Reversal of resistance has proven to be difficult to achieve; thus, we have suggested an alternative strategy - prevention of its development [Frenkel & Caffrey, Current Pharmaceutical Design, (2001) 7: 1595-1614]. In order to investigate this possibility we previously designed a model of the development of cisplatin resistance in ovarian cancer xenografts, which mimics the development of clinical resistance in ovarian cancer patients [Caffrey & Frenkel, Cancer Chemotherapy Pharmacology (2000) 46: 74-78]. We used this model to identify compounds which are able to prevent resistance; these are being further investigated in a Phase I clinical trial. We have now designed an analogous model of the development of resistance in SCLC xenografts. Mice were injected sc with H526 SCLCL cells. Those bearing visible tumors were injected i.p. with a single “pretreatment” dose of cisplatin ranging from 0.75 - 3.0 mg/kg. On the 3rd, 5th or 7th day after this pretreatment, mice were injected i.p. with a single “high” dose of cisplatin (3.0 mg/kg). This high dose decreased the growth rate of control (PBS pretreated) tumors by 40%. Tumors whose growth curve was decreased by less than 40% were considered resistant. Our results indicated that several potential models resulted in a low incidence of resistance. However, pretreatment with 1.5 mg/kg followed seven days later by high dose treatment of 3.0 mg/kg consistently resulted in the development of cisplatin-resistant tumors. This model can be used to screen a variety of agents for their ability to prevent the induction of platinum resistance in SCLC tumors. Supported by a grant from the PA State System of Higher Education. Citation Format: Paula B. Caffrey, Gerald D. Frenkel. Design of a model for the development of cisplatin resistance in H526 human small cell lung cancer xenografts. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 985. doi:10.1158/1538-7445.AM2013-985