O6-benzylguanine-mediated enhancement of chemotherapy

Mol Cancer Ther. 2002 Sep;1(11):943-8.

Abstract

We have previously demonstrated (A. E. Pegg, Cancer Res., 50: 6119-6129, 1990) that O6-benzylguanine (O6-BG) enhances nitrosourea, temozolomide, and cyclophosphamide activity in malignant glioma xenografts growing in athymic nude mice. More recently, we have demonstrated (V. J. Patel et al., Clin. Cancer Res., 6: 4154-4157, 2000; P. Pourquier et al., Cancer Res., 61: 53-58, 2001) that the combination of temozolomide plus irinotecan (CPT-11) displays a schedule-dependent enhancement of antitumor activity secondary to trapping of topoisomerase I by O6-methylguanine residues in DNA. These studies suggested that there might be favorable therapeutic interactions between O6-BG and combinations of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) plus cyclophosphamide or temozolomide plus CPT-11, respectively. Our present results indicate that the combination of cyclophosphamide plus BCNU plus O6-BG produces growth delays modestly-to-markedly-superior to combinations of cyclophosphamide with BCNU. Although the combination of temozolomide and CPT-11 reveals a marked increase in activity compared with either agent used alone, the addition of O6-BG to this combination dramatically increased the growth delay of the O6-alkylguanine-DNA alkyltransferase (AGT)-positive malignant glioma D-456 MG. These results suggest that a Phase I trial of CPT-11 plus temozolomide plus O6-BG in AGT-positive tumors may be an important intervention to maximize the therapeutic benefits of the combination of CPT-11 and temozolomide.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents, Alkylating / pharmacology
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacology
  • Carmustine / pharmacology
  • Central Nervous System Neoplasms / pathology
  • Cyclophosphamide / pharmacology
  • DNA / metabolism
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Female
  • Guanine / analogs & derivatives*
  • Guanine / pharmacology*
  • Humans
  • Irinotecan
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Transplantation
  • Protein Synthesis Inhibitors / pharmacology
  • Temozolomide

Substances

  • Antineoplastic Agents
  • Antineoplastic Agents, Alkylating
  • Enzyme Inhibitors
  • Protein Synthesis Inhibitors
  • O(6)-benzylguanine
  • Guanine
  • Irinotecan
  • Dacarbazine
  • Cyclophosphamide
  • DNA
  • Carmustine
  • Camptothecin
  • Temozolomide