Intraarterial O6-benzylguanine enables the specific therapy of nitrosourea-resistant intracranial human glioma xenografts in athymic rats with 1,3-bis(2-chloroethyl)-1-nitrosourea.

The prognosis for patients with malignant gliomas continues to be dismal. The high degree of resistance of gliomas to nitrosourea-based chemotherapy is one major factor in poor treatment outcome. The identification of O6-alkylguanine-DNA alkyltransferase (AGAT) as a major determinant of nitrosourea resistance has resulted in the development of several agents to inactivate this repair protein and counteract tumor cell resistance. However, a major problem in preclinical trials has been the marked nitrosourea dose limitations imposed by the prior administration of AGAT-depleting agents. We investigated the AGAT depletion and selective enhancement of BCNU activity of intraarterial (i.a.) O6-benzylguanine (O6BG) in the human malignant glioma xenograft D-456 MG growing intracranially (i.e.) in athymic rats. Whereas i.a. O6BG at 2.5 mg/kg produced 100% inhibition of D-456 MG AGAT i.e. activity 8 h after administration, intraperitoneal (i.p.) O6BG at this dose produced only 40% inhibition, requiring dose escalation to 10 mg/kg to produce 100% AGAT depletion. Prior administration of i.p. O6BG (10 mg/kg) and i.a. O6BG (2.5 mg/kg) limited maximum tolerated intravenous (i.v.) BCNU doses (37.5 mg/kg when given alone) to 6.25 and 25 mg/kg, respectively. Higher doses of BCNU alone or in combination with O6BG produced histopathologic evidence of cerebral and hepatic toxicity. Therapy experiments revealed a significantly improved median survival for rats treated with O6BG i.a. (2.5 mg/kg) plus BCNU i.v. (25 mg/kg, days 61 and 59 in duplicate experiments) compared with saline (day 21. P = 0.001). O6BG i.a. or i.p. (days 22 and 23, P = 0.001), BCNU i.v. (37.5 mg/kg, day 29, P = 0.001), and O6BG i.p. (10 mg/kg), plus BCNU i.v. (6.25 mg/kg, day 37, P < 0.001). Therefore, O6BG i.a., by virtue of rapid AGAT depletion and selective uptake into i.c. tumors, offers significant potential for regional chemomodulation of AGAT-mediated nitrosourea resistance in malignant human gliomas with concomitant reduction of systemic toxicity.

Duke Scholars

Author Roger Edwin McLendon Pathology

Author Darell Doty Bigner Neurosurgery

Author Henry Seth Friedman Neurosurgery, Neuro-Oncology