Treatment of subcutaneous and intracranial brain tumor xenografts with O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea.

Abstract

O6-Alkylguanine-DNA alkyltransferase (AT) is a cellular protein that protects cells from the cytotoxic effects of nitrosoureas by repairing alkyl lesions at the O6 position of guanine. We have studied the ability of O6-benzylguanine to deplete AT activity in brain tumor xenografts and thereby increase the sensitivity of these tumors to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). In toxicity studies, pretreatment of athymic mice with O6-benzylguanine increased the toxicity of BCNU significantly. After i.p. injection of O6-benzylguanine into athymic mice carrying subcutaneous (s.c.) D341MED, a human medulloblastoma xenograft with a high AT activity, the AT activity of the tumors became undetectable within 1 h and remained depleted until 36 h. In s.c. xenografts to D341MED, treatment with O6-benzylguanine followed 1 h later by BCNU produced a significantly greater growth delay (14.8 days) than was seen with BCNU alone (2.3 days). A lower pretreatment dose of O6-benzylguanine produced a significantly smaller therapeutic effect. Delaying the administration of BCNU until 36 h after O6-benzylguanine resulted in a growth delay (1.2 days) that was not significantly different from that produced by the control or BCNU alone. In athymic mice with intracranial (i.c.) xenografts of D341MED, pretreatment with O6-benzylguanine followed 1 h later by BCNU produced a significantly increased survival as compared with that of the control, BCNU alone, O6-benzylguanine alone, and O6-benzylguanine followed 36 h later by BCNU. In experiments with s.c. xenografts of D245MG, a human glioma xenograft with undetectable AT activity, pretreatment with O6-benzylguanine 1 h prior to BCNU produced a significantly greater effect than was seen with BCNU treatment alone. The combination regimen, however, was not as effective as an equitoxic dose of BCNU alone. These studies suggest that O6-benzylguanine may be a useful adjuvant to nitrosourea therapy in human malignancies that exhibit a range of AT activities and that dose and timing are important variables in achieving therapeutic success. These data also indicate that therapeutic potentiation of BCNU by O6-benzylguanine can be achieved in i.c. tumors. As a result, this approach may be useful in the treatment of neoplasms of the central nervous system.

• Authors: G M Felker, H S Friedman, M E Dolan, R C Moschel, C Schold
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 32 Issue 6 Pg. 471-6 ( 1993) ISSN: 0344-5704 [Print] Germany
• PMID: 8258196 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• O(6)-benzylguanine
• Guanine
• Methyltransferases
• O(6)-Methylguanine-DNA Methyltransferase
• Carmustine

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Brain Neoplasms (drug therapy)
• Carmustine (administration & dosage)
• Drug Synergism
• Guanine (administration & dosage, analogs & derivatives)
• Humans
• Medulloblastoma (drug therapy)
• Methyltransferases (antagonists & inhibitors)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Transplantation
• O(6)-Methylguanine-DNA Methyltransferase
• Time Factors