Toxicity of intracranial and intraperitoneal O6-benzyl guanine in combination with BCNU delivered locally in a mouse model.
The DNA-repair protein, O6-alkylguanine-DNA alkyl transferase, may account for resistance of CNS tumors to DNA-alkylating drugs, such as bis-(2-chloroethyl)-1-nitrosourea (BCNU). The therapeutic effects of BCNU can be potentiated by inhibiting the repair protein with an alkylated guanine analog, O6-benzyl guanine (O6BG). To investigate potential toxicity of this inhibition, we examined the effects of O6BG in mice treated with intracranial (i.c.) BCNU given via a biodegradable polymer.



Mice were treated with escalating doses of BCNU chronically delivered i.c., and with chronically delivered O6BG. The O6BG was delivered via a 7-day intraperitoneal (i.p.) or i.c. osmotic minipump. Toxicity of the combination therapies was measured from survival data. Bone marrow response was estimated from white blood cell counts.



Combining systemic (i.p.) O6BG with locally (i.c.) delivered BCNU resulted in a decrease in the maximum tolerated dose (MTD) of local BCNU. With local delivery of O6BG, the MTD of BCNU in combination with O6BG was increased.



Based on the results of this study, a dose escalation study will be necessary when combining systemic O6BG with the higher doses of i.c. BCNU.
Guarnieri
Michael
M
Department of Neurological Surgery, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Biser-Rohrbaugh
Ann
A
Tyler
Betty M
BM
Gabikian
Patrik
P
Bunton
Tracie E
TE
Wu
Qing Ze
QZ
Weingart
Jon
J
Carson
Benjamin S
BS
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D001855:Bone Marrow Diseases / Q000139:chemically induced*; D002330:Carmustine / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D004357:Drug Synergism; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity*; D007249:Inflammation; D015918:Infusion Pumps, Implantable; D007263:Infusions, Parenteral; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D010296:Parietal Lobe; D010529:Peritoneal Cavity
D004343:Drug Implants; C064976:O(6)-benzylguanine; D006147:Guanine; D002330:Carmustine