Enhancement of Alkylating Agent Activity by SR-4233 in the FSaIIC Muraine Fibrosarcoma

Abstract

Background: The most commonly used antineoplastic drugs are more cytotoxic toward normally oxygenated tumor cells than toward hypoxic tumor cells. Purpose and Methods: To examine the ability of SR-4233, a new cytotoxic agent, to overcome the resistance of hypoxic tumor cells to antitumor alkylating agents, we tested the cytotoxic effect of SR-4233 alone and in combination with varying doses of cisplatin (CDDP), cyclophosphamide (CPM), carmustine (BCNU), or melphalan (l-PAM) on tumor cells and bone marrow cells isolated from C3H/FeJ mice bearing the FSallC fibrosarcoma. Results: When SR-4233 alone was given, tumor cell killing was limited. When SR-4233 was administered just before single-dose treatment with CDDP, CPM, BCNU, or L-PAM, however, marked dose enhancement leading to increased cytotoxic effects on tumor cells and on bone marrow cells was observed. Similar experiments with tumor cell sub-populations, selected by Hoechst 33342 dye diffusion, confirmed that while cy-totoxicity to both bright (oxygenated) and dim (hypoxic) cells was increased by combining each alkylating agent with SR-4233, the enhancement of the effect was relatively greater in the sub-population of dim cells. The delay in the growth of tumors in animals treated with the combination of SR-4233 and CDDP, CPM, or L-PAM was 1. 6-fold to 53-fold greater than that in animals treated with each alkylating agent alone. Conclusion: Our results suggest that SR-4233 may have the potential to improve the clinical efficacy of commonly used antitumor alkylating agents. [J Nat! Cancer Inst 84: 187–193, 1992]