IN-VITRO CYTOTOXICITY AND CHEMOSENSITIZING ACTIVITY OF THE DUAL FUNCTION NITROIMIDAZOLE RB-6145

Purpose: To determine the cytotoxicity and chemosensitizing potential of RB 6145 in mouse KHT/iv and human A549 tumor cells. Methods and Mat erials: RSU 1069, the lead compound in a series of nitroimidazoles con taining an alkylating aziridine function, has been shown to possess a high degree of selective cytotoxicity for hypoxic cells in addition to being a potent sensitizer of radiation and chemotherapy. Unfortunatel y, preliminary clinical studies have revealed a dose-limiting gastroin testinal toxicity for RSU 1069. Recently RB 6145, the ring-opened anal ogue of RSU 1069, has been found to be less emetic than RSU 1069. In t he present studies, we assessed both the differential hypoxic cell cyt otoxicity of RB 6145 and its chemosensitizing potential when combined concomitantly with variable doses of the activated form of cyclophosph amide (4-hydroperoxy-cyclophosphamide, 4-OOH-CP) or the nitrosourea CC NU. Results: As we had observed previously for RSU 1069, RB 6145 was f ound to be less cytotoxic to human than rodent tumor cells. In additio n, the degree of selective cytotoxicity toward hypoxic cells was (a) l ess in A549 than in KHT/iv cells (factor of 9 vs. 80) but (b) comparab le to that seen with RSU 1069. For both cell lines, inclusion of the s ensitizer enhanced the cell killing of the chemotherapeutic agent 4-OO H-CP by a factor of similar to 1.5-1.7-fold. When combined with CCNU, RB 6145 increased the killing of A549 cells similar to 15-fold. Simila r hypoxic cell preferential cytotoxicity and enhancement in anti-tumor treatment efficacy were seen when A549 cells were exposed to the R en antiomer of RB 6145 (PD 144872) either alone or in combination with CC NU. Conclusion: These data support the notion that further considerati on should be given to the clinical application of these bioreductive a gents.