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 outcome.
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-beta-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-beta-D-arabinofuranosylcytosine in vitro, nor were cellular glutathione content, glutathione S-transferases activity, or P-glycoprotein expression.
Müller
M R
MR
Department of Internal Medicine (Cancer Research), West German Cancer Center, Essen.
Seiler
F
F
Thomale
J
J
Buschfort
C
C
Rajewsky
M F
MF
Seeber
S
S
D000208:Acute Disease; D002330:Carmustine / Q000494:pharmacology; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000494:pharmacology; D003561:Cytarabine / Q000494:pharmacology; D004260:DNA Repair; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D005038:Ethylnitrosourea / Q000494:pharmacology; D005978:Glutathione / Q000032:analysis; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008214:Lymphocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome
D003561:Cytarabine; C007673:6-ethylguanine; C048341:mafosfamide; D006147:Guanine; D004317:Doxorubicin; D003520:Cyclophosphamide; D005978:Glutathione; D005038:Ethylnitrosourea; D002330:Carmustine