Eradication of human medulloblastoma tumor xenografts with a combination of O-6-benzyl-2 '-deoxyguanosine and 1,3-bis(2-chloroethyl)-1-nitrosoureal

O-6-Benzyl-2'-deoxyguanosine (dBG), a water-soluble inhibitor of O-6-methyl guanine-DNA methyltransferase (MGMT), potentiates the efficacy of 1,3-bis(2 -chloroethyl)I-nitrosourea (BCNU) against MGMT-positive, BCNU-resistant Dao y human medulloblastoma tumor xenografts in athymic mice (S. C. Schold et a t, Cancer Res., 56: 2076-2081, 1996), Such potentiation was comparable to t hat observed ed for O-6-benzylguanine, the prototype MGMT inhibitor that is currently undergoing clinical trials, In this study, we optimized the ther apeutic effect of the dBG and BCNU combination against brain tumor xenograf ts without inducing substantial toxicity in the host by adjusting the doses of both compounds. dBG was escalated from 133 mg/m(2) to 200 and 300 mg/m( 2), whereas corresponding doses of BCNU were reduced from 25 mg/m(2) to 17 and 11 mg/m(2), respectively. The growth delays of 30.2, 38.4, and 22.3 day s, respectively, observed for the above regimens suggest that the optimal d rug combination is not achieved with maximum doses of dBG, In fact, the hig hest doses of dBG (300 mg/m(2)) contributed to more frequent BCNU-related t oxicities, despite the reduced BCNU dosage, and a reduction of the therapeu tic effect. Toxicity was related to the depletion of MGMT activity in the g ut of host mice and was manifested by edema, inflammation, and hemorrhage i n the bowel wall by subsequent BCNU administration. With additional dosage adjustments, we found that tumor suppression of >90 days without toxicity w as observed at 200 mg/m(2) dB6 and 23 mg/m(2) BCNU, At these doses, tumors were eradicated (regressed to an undetectable size for >90 days) in 8 of 12 animals. Thus, dBG is the first of the MGMT inhibitors to show a curative effect in combination with BCNU against a human central nervous system turn er xenograft in athymic mice.