Abstract. Background Cisplatin is the treatment of choice for cancer such as ovarian and small cell lung cancer (SCLC). However in these types of cancer, cisplatin chemotherapy often becomes ineffective due to development of resistance (1, 2). Many investigations of drug resistance have been performed on cells or tumors already resistant to chemotherapy (1-3). In some cases, these studies have identified potential causes of resistance. For example, numerous studies have described an increase in glutathione-S-transferase (GST) in cisplatinresistant ovarian cancer and SCLC (1-3). Resistant tumors and cells have also been used to investigate treatment methods that increase tumor cell sensitivity or reverse drug resistance. However, treatments designed to overwhelm or reverse a tumor's resistance mechanisms are likely to also weaken the patient's normal cells. Thus the clinical success of these treatments may be limited by their severe toxicity (1-3). In contrast, an agent capable of preventing tumor cells from developing resistance need not weaken normal cells and thus may be better tolerated by patients (4). However this prevention strategy poses special challenges compared to reversal studies.In order to test an agent's ability to prevent resistance, it is necessary to identify a time by which resistance would have predictably developed. We previously designed models of ovarian cancer in which resistance occurred within 7 days of initial treatment (4,5). Using these models, we found that the selenium compound selenite prevents the development of resistance to platinum-based chemotherapy (6-8). We also examined causes of resistance in ovarian cancer models, and reported an increase in glutathione or its related enzyme GST in these ovarian tumor xenografts and cells as they develop resistance (4, 9).The most lethal form of lung cancer is SCLC, which rapidly develops resistance to chemotherapy (10). Numerous studies have examined chemotherapy resistance in SCLC cells and tumors (11)(12)(13)(14)(15)(16)(17)(18)(19)(20), including the reversal of resistance (19,20). However to our knowledge, none have focused on its prevention. We designed an in vivo model of the development of resistance to cisplatin in mice bearing SCLC xenografts. Cells from these xenografts, tested in vitro, were found to reflect the relative resistance of the tumor from which they were derived. We also tested cells from these xenografts for GST activity, a known mechanism of resistance in SCLC (18,19), and found that cells from the resistant xenograft have significantly higher GST activity than those from the control xenografts. This evidence supports the use of the in vivo model to test whether agents capable of inhibiting GST activity are effective in preventing the development of cisplatin-resistant 745