title: 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.
abstract: 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.
authors.affiliation: Department of Neurological Surgery, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: S N
authors.initials: SN
authors.lastname: Kurpad
authors.forename: M E
authors.initials: ME
authors.lastname: Dolan
authors.forename: R E
authors.initials: RE
authors.lastname: McLendon
authors.forename: G E
authors.initials: GE
authors.lastname: Archer
authors.forename: R C
authors.initials: RC
authors.lastname: Moschel
authors.forename: A E
authors.initials: AE
authors.lastname: Pegg
authors.forename: D D
authors.initials: DD
authors.lastname: Bigner
authors.forename: H S
authors.initials: HS
authors.lastname: Friedman
mesh_terms: D019883:Alkyl and Aryl Transferases; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002330:Carmustine / Q000627:therapeutic use*; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007269:Injections, Intra-Arterial; D051381:Rats; D011923:Rats, Nude; D014166:Transferases / Q000037:antagonists & inhibitors*; D014183:Transplantation, Heterologous
chemical_list: D018906:Antineoplastic Agents, Alkylating; C064976:O(6)-benzylguanine; D006147:Guanine; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C050956:DNA alkyltransferase; D002330:Carmustine