Biodistribution of O6-benzylguanine and its effectiveness against human brain tumor xenografts when given in polyethylene glycol or cremophor-EL.
O6-Benzylguanine effectively inactivates the DNA-repair protein O6-alkylguanine-DNA alkyltransferase in tumor cells and has been shown to increase the cytotoxicity of chloroethylnitrosoureas. This study was undertaken to ascertain the optimal vehicle for further toxicological evaluation and eventual clinical trials of O6-benzylguanine. The solubility, metabolism, bioavailability and effectiveness of O6-benzylguanine as an adjuvant therapy with BCNU were compared using two vehicles, cremophor-EL and PEG 400. Nude mice bearing s.c. D456 MG glioblastoma xenografts were injected i.p. with 10-30 mg/kg O6-benzylguanine dissolved in either 40% PEG 400/saline or 10% cremophor-EL/saline. The number of tumor regressions noted after treatment with 10 mg/kg O6-benzylguanine followed by 12.7 mg/kg BCNU were 8/9 for the drug dissolved in PEG and 1/10 for the drug given in cremophor-EL. Using the same treatment regimen but increasing the dose of O6-benzylguanine to 30 mg/kg led to a growth delay of 45.2 and 11.5 days for the drug dissolved in PEG 400 and cremophor-EL, respectively, although the number of regressions observed were the same for both treatments. 8-[3H]-O6-Benzylguanine was more rapidly distributed to the tumor when it was delivered in PEG vehicle than when it was given in cremophor-EL. In contrast, there was a 3-fold greater amount of O6-benzylguanine in the small intestine of mice at 1 h after i.p. injection of the drug in cremophor-EL as compared with PEG 400. The rate and extent of metabolism in the liver was the same, whether the parent drug was given in PEG 400 or in cremophor-EL. These studies demonstrate that O6-benzylguanine is a more effective enhancer of the antitumor activity of BCNU when it is given in PEG 400 than when it is delivered in cremophor-EL, which may be due to a more rapid distribution of the drug to the tumor.
Dolan
M E
ME
Division of Hematology-Oncology, University of Chicago Medical Center, IL 60637.
Pegg
A E
AE
Moschel
R C
RC
Vishnuvajjala
B R
BR
Flora
K P
KP
Grever
M R
MR
Friedman
H S
HS
D000277:Adjuvants, Pharmaceutic / Q000008:administration & dosage*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002330:Carmustine / Q000008:administration & dosage; D002648:Child; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D005990:Glycerol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D012995:Solubility; D014018:Tissue Distribution
D000277:Adjuvants, Pharmaceutic; D000970:Antineoplastic Agents; C064976:O(6)-benzylguanine; D011092:Polyethylene Glycols; D006147:Guanine; C000515:cremophor EL; D005990:Glycerol; D002330:Carmustine