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

Cancer Chemother Pharmacol. 1993;32(6):471-6. doi: 10.1007/BF00685892.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Brain Neoplasms / drug therapy*
  • Carmustine / administration & dosage
  • Drug Synergism
  • Guanine / administration & dosage
  • Guanine / 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


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