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Capacity of Individual Chronic Lymphatic Leukemia Lymphocytes and Leukemic Blast Cells for Repair of O⁶-Ethylguanine in DNA: Relation to Chemosensitivity in Vitro and Treatment Outcome¹

Department of Internal Medicine (Cancer Research) [M. R. M., S. S.] and Institute of Cell Biology (Cancer Research) [F. S., J. T., C. B., M. F. R.], West German Cancer Center Essen, University of Essen Medical School, D-45122 Essen, Germany

The elimination kinetics of the alkylation product O⁶-ethylguanine (O⁶eGua) from nuclear DNA were determined in individual lymphocytes or blast cells isolated from 27 patients with chronic lymphatic leukemia (CLL) and 26 patients with de novo acute myeloid leukemia (AML). A monoclonal antibody-based immunocytological assay was used for quantification of O⁶eGua in DNA of individual cells after pulse exposure of cells to N-ethyl-N-nitrosourea (EtNU). In cell specimens from a given patient, no major subpopulations with significantly different capacities for repair of O⁶eGua were observed. The time required to remove 50% of induced O⁶eGua residues varied interindividually between 0.5 and 8.4 h in CLL lymphocytes and between 0.8 and 6.3 h in leukemic blast cells. An inverse relationship was found between the rate of removal of O⁶eGua from DNA and the chemosensitivity of cells to EtNU, 1,3-bis(2-chloroethyl)-1-nitrosourea or mafosfamide in vitro. High rates of O⁶eGua repair and pronounced resistance to mafosfamide, 1,3-bis(2-chloroethyl)-1-nitrosourea, and EtNU in vitro were found in samples from 8 CLL patients nonresponsive to chemotherapy with alkylating agents. In AML patients treated with anthracyclines and 1-ß-D-arabinofuranosylcytosine, no relation was found between DNA repair capacity and treatment outcome. However, increased P-glycoprotein expression was observed between specimens derived from AML patients who had failed to reach complete remission (n = 12) after chemotherapy versus responsive patients (n = 14). DNA repair rate was not related to chemosensitivity to Adriamycin and 1-ß-D-arabinofuranosylcytosine in vitro, nor were cellular glutathione content, glutathione S-transferases activity, or P-glycoprotein expression.

¹ This work was supported by a grant from the Dr. Mildred Scheel Stiftung (W69/91/Mül).

² To whom requests for reprints should be addressed, at Innere Klinik und Poliklinik (Tumorforschung), Westdeutsches Tumorzentrum Essen, Universitätsklinikum Essen, Hufelandstrasse 55, D-45122 Essen, Germany.

Received 3/ 1/94. Accepted 6/ 8/94.