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Lack of Evidence for a Polymorphism at Codon 160 of Human O⁶-Alkylguanine-DNA Alkyltransferase Gene in Normal Tissue and Cancer¹

Section of Hematology-Oncology and Cancer Research Center, The University of Chicago, Chicago, Illinois 60637 [M. H. W., K. E. L., O. I. O., M. E. D.]; Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas 75235 [D. M. K.]; Department of Pediatrics and Pathology, Duke University, Durham, North Carolina 27710 [H. S. F.]

O⁶-benzylguanine (BG) is a potent, specific inactivator of the DNA repair protein O⁶-alkylguanine-DNA alkyltransferase (AGT), which enhances sensitivity to nitrosoureas in cells and tumor-bearing animals. BG is presently undergoing clinical trials for development as an agent to enhance the therapeutic index of alkylating agent chemotherapy. It has been reported that a polymorphism exists in the human agt gene, with about 15% of the Japanese population having arginine at codon 160 instead of glycine on the polypeptide (Y. Imai et al., Carcinogenesis, 16: 2441–2445, 1995). The resultant mutant AGT protein is equally effective against both methylated DNA as compared with wild type protein. However, this mutant AGT protein was less sensitive to inactivation by BG with a 20-fold increase in the ED₅₀ value. This observation raised the possibility that a subpopulation of patients may be resistant to BG due to a single base change. We have demonstrated that this alteration also reduces the sensitivity to O⁶-benzyl-8-oxoguanine, an equally potent, yet much longer-lived human metabolite of BG. To test the possibility that this germ-line mutation of the agt gene might explain resistance to BG and O⁶-benzyl-8-oxo-guanine of patients on our Phase I clinical trials, we evaluated the DNA from lymphocytes of 18 patients. The G160R mutation was not found in any of the 18 patients. To determine the frequency of this mutation in the United States population, DNA from 181 healthy individuals were investigated and, again, the mutation was not observed in this cohort. Therefore, if the mutation exists, it is in statistically <1.6% of the United States noncancerous population. To investigate the possibility that this mutation might be somatic, we evaluated genomic DNA samples from 94 human primary cancers of four different histological subtypes (brain, colon, esophageal, and head and neck). Again, none were found to have the G160R mutation.

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