O-6-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)-1-nitrosourea (BCNU ) plus O-6-benzylguanine (O-6-BG) in the treatment of both Mer(+) and Mer(- ) tumors. Methods: The effect of pretreatment with O-6-BG on the activity o f 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 le thal 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 redu ction of BCNU to 0.38 LD10 eliminated antitumor activity. The combination o f BCNU (0.38 LD10) plus O-6-BG produced growth delays of 8.8 days and 7.9 d ays, with tumor regressions in four of tell and two of nine animals, respec tively. BCNU (1.0 LD10) produced a growth delay of 49.8 days and tell of te n 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 ni ne of ten tumor regressions. The combination of BCNU (0.38 LD10) plus O-6-B G produced a growth delay of 65.7 days and seven of eight tumor regressions . Conclusion: These results suggest that the combination of BCNU plus O-6-B G may be a rational intervention for both Mer(+) as well as Mer(-) tumors.