O⁶-benzylguanine-mediated enhancement of nitrosourea activity in Mer^- central nervous system tumor xenografts - Implications for clinical trials

Purpose: To evaluate the role of 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU) plus O⁶-benzylguanine (O⁶-BG) in the treatment of both Mer⁺ and Mer^- tumors. Methods: The effect of pretreatment with O⁶-BG on the activity of BCNU against Mer^- human central nervous tumor xenografts D-54 MG and D- 245 MG was evaluated in athymic nude mice. Results: BCNU (1.0 LD₁₀; dose lethal to 10% of treated animals) produced growth delays of 8.9 days and 7.5 days and tumor regressions in six of ten and one of nine animals against D-54 MG, which was derived from a human malignant glioma xenograft. Dose reduction of BCNU to 0.38 LD₁₀ eliminated antitumor activity. The combination of BCNU (0.38 LD₁₀) plus O⁶-BG produced growth delays of 8.8 days and 7.9 days, with tumor regressions in four of ten and two of nine animals, respectively. BCNU (1.0 LD₁₀) produced a growth delay of 49.8 days and ten of ten tumor regressions against D-245 MG, which was derived from a glioblastoma multiforme. BCNU (0.38 LD₁₀) produced a growth delay of 19.4 days, with nine of ten tumor regressions. The combination of BCNU (0.38 LD₁₀) plus O⁶-BG produced a growth delay of 65.7 days and seven of eight tumor regressions. Conclusion: These results suggest that the combination of BCNU plus O⁶-BG may be a rational intervention for both Mer⁺ as well as Mer^- tumors.