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Synergistic efficacy of O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in a human colon cancer xenograft completely resistant to BCNU alone.

Abstract
The DNA repair protein O6-alkylguanine-DNA alkyltransferase (alkyltransferase) repairs cytotoxic DNA damage formed by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). High levels of this repair protein cause tumor drug resistance to nitrosoureas. To investigate the ability of a direct alkyltransferase inhibitor, O6-benzylguanine, to reverse the nitrosourea resistance of human colon cancer cells, we studied the VACO 6 cell line which has high alkyltransferase and is completely resistant to BCNU at maximal tolerated doses in the xenograft model. O6-Benzylguanine at 0.5 microgram/mL for 1 hr inactivated VACO 6 alkyltransferase by > 98% and reduced the IC50 of BCNU by 3- to 4-fold. Further analysis indicated that these two agents act in a highly synergistic fashion. In xenograft bearing athymic mice, dose-dependent depletion of hepatic and tumor alkyltransferase was noted. To maintain alkyltransferase depletion in the xenograft for at least 24 hr, two doses of 60 mg/kg O6-benzylguanine were given 1 hr prior and 7 hr after BCNU. Under these conditions, VACO 6 xenografts became responsive to BCNU with significant reductions (P < 0.001) in the tumor growth rate. The combination increased toxicity to the host, reducing the maximum tolerated dose of BCNU by approximately 50%. This study provides definitive evidence that high alkyltransferase activity is responsible for BCNU resistance in human colon cancer xenografts and that with careful drug scheduling, O6-benzylguanine can sensitize a tumor which is completely unresponsive to BCNU alone. Further studies which optimize the therapeutic index of BCNU and O6-benzylguanine in vivo will define the schedule to be used in broader preclinical studies.
AuthorsS L Gerson, E Zborowska, K Norton, N H Gordon, J K Willson
JournalBiochemical pharmacology (Biochem Pharmacol) Vol. 45 Issue 2 Pg. 483-91 (Jan 26 1993) ISSN: 0006-2952 [Print] England
PMID8435098 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • O(6)-benzylguanine
  • Guanine
  • Transferases
  • Alkyl and Aryl Transferases
  • DNA alkyltransferase
  • Carmustine
Topics
  • Alkyl and Aryl Transferases
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
  • Body Weight (drug effects)
  • Carmustine (administration & dosage, therapeutic use)
  • Colonic Neoplasms (drug therapy, mortality, pathology)
  • Drug Resistance
  • Drug Synergism
  • Guanine (administration & dosage, analogs & derivatives, pharmacology)
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Transplantation
  • Transferases (antagonists & inhibitors)
  • Tumor Cells, Cultured (drug effects, enzymology)

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