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Accumulation of O⁶-Methylguanine in Human Blood Leukocyte DNA during Exposure to Procarbazine and Its Relationships with Dose and Repair¹

Program of Chemical Carcinogenesis, National Hellenic Research Foundation, Institute of Biological Research, 48 Vassileos Constantinou Avenue [V. L. S., S. K., S. A. K.], and Lymphoma Clinic, Hematology Unit, University of Athens School of Medicine [V. A. B., G. A. P], Athens 11635, Greece

O⁶-Methylguanine was measured by a competitive repair assay in blood leukocyte DNA of seven patients with Hodgkin's or non-Hodgkin's lymphoma during therapeutic exposure to procarbazine involving three daily p.o. doses (50 mg each) for 10 days (corresponding to 2.1 mg/kg/day for a 70-kg human). Adduct accumulation was observed in all seven cases, reaching levels up to 0.28 fmol/µg of DNA (0.45 µmol/mol of guanine). In one individual, maximal levels of adduct were reached after 7 days of exposure, followed by a steady decline, whereas in all other individuals continuous accumulation was observed throughout the exposure period. In four individuals for which data were available for Day 11 (12 to 16 h after the final intake of procarbazine), decreased amounts of O⁶-methylguanine were observed relative to the last previous measurements. The accumulation of O⁶-methylguanine was linearly correlated (P < 0.01) with the cumulative dose of procarbazine, with a slope of 0.011 fmol of O⁶-methylguanine/µg of DNA per mg/kg of body weight or 2.68 x 10^-4 fmol of O⁶ methylguanine DNA per mg/m². (Two h after the administration of single p.o. doses of 1 to 10 mg/kg of procarbazine to rats, O⁶-methylguanine formation in leukocyte DNA was just under half that in liver DNA and showed a linear relationship with dose with a slope of 0.017 fmol/µg of DNA per mg/kg of body weight or 5.67 x 10^-4 fmol of O⁶-methylguanine/µg of DNA per mg/m². A negative correlation (P < 0.05) between the rate of accumulation of O⁶-methylguanine in different individuals and lymphocyte O⁶-alkylguanine-DNA alkyltransferase (AGT) was observed, demonstrating a probable protective effect of AGT against the accumulation of O⁶-methylguanine during exposure to methylating agents. This observation supports the suggestion of a possible role of procarbazine-induced O⁶-methylguanine in the pathogenesis of acute nonlymphocytic leukemia appearing after treatment with chemotherapeutic protocols which include procarbazine, based on the finding of low lymphocyte AGT levels in patients with such therapy-related neoplastic disease (Sagher et al., Cancer Res., 48: 3084–3089, 1988). Lymphocyte AGT levels were mainly in the range of 5 to 10 fmol/µg of DNA and showed no consistent variation during procarbazine exposure.

¹ This work was supported by grants awarded to S. A. K. by the European Economic Community (Contract EV4V-0062) and the International Agency for Research on Cancer (Collaborative Research Agreement BRI/89/09).

² To whom requests for reprints should be addressed.

Received 9/18/89. Revised 1/ 4/90.

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