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Relationships between the Formation of O⁶-Methyldeoxyguanosine by 1-p-Carboxyl-3,3-dimethylphenyltriazene in DNA and O⁶-Alkylguanine-DNA Alkyltransferase in Human Peripheral Leukocytes¹

CRC Department of Carcinogenesis, Paterson Institute for Cancer Research [S. M. L., P. J. O., G. P. M., D. P. C.], and CRC Department of Medical Oncology, Christie Hospital National Health Service Trust [S. M. L., N. T., D. C.], Manchester, M20 9BX, UK

There is increasing experimental evidence to indicate that O⁶-methyldeoxyguanosine (O⁶-MedG) formation in DNA is a critical cytotoxic event following exposure to certain antitumor alkylating agents and that the DNA repair protein O⁶-alkylguanine-DNA-alkyltransferase (ATase) can confer resistance to these agents. We recently demonstrated a wide interindividual variation in the depletion and subsequent regeneration of ATase in peripheral blood lymphocytes of patients treated with 24-h continuous infusion of 1-p-carboxyl-3,3-dimethylphenyltriazene (CB10-277) for metastatic melanoma. We have now measured the formation of O⁶-MedG in the DNA of peripheral leukocytes of nine patients receiving this treatment regimen. This lesion could be detected in DNA within 1 h and a progressive increase in adduct levels occurred during the CB10-277 infusion and for 24 h after completion. Considerable interindividual variation was observed in the peak O⁶-MedG levels, with values ranging from 3.0 to 23.8 µmol O⁶-MedG/mol deoxyguanosine (mean, 12.3 ± 6.4 µmol O⁶-MedG/mol deoxyguanosine) following the first treatment cycle, possibly as a consequence of differences in the capacity of patients to metabolize CB10-277 to a methylating agent. There was, nevertheless, a clear temporal relationship between the progressive formation of leukocyte O⁶-MedG and lymphocyte ATase depletion. Repeated-measures regression showed that this was statistically significant (P < 0.001) during the CB10-277 infusion. A significant inverse correlation was also seen between pretreatment lymphocyte ATase activity and peak O⁶-MedG levels in leukocyte DNA (r = -0.73) and the area under the leukocyte O⁶-MedG concentration-time curve (r = -0.76). Metabolism of CB10-277 to a methylating agent could be one factor that combines with DNA repair capacity to determine clinical response, because the two responses observed in this series occurred in the two patients with the highest leukocyte O⁶-MedG levels and also the lowest pretreatment ATase activity. Hematological toxicity developed in the same two patients.

¹ Supported by funds from the Christie Hospital (National Health Service) Trust Endowment Fund, North West Regional Health Authority, and the Cancer Research Campaign (UK).

² To whom requests for reprints should be addressed.

Received 1/10/94. Accepted 5/24/94.

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