Cisplatin-DNA damage and repair in peripheral blood leukocytes in vivo and in vitro.
We have extended our studies on the relationship between cisplatin/carboplatin-induced DNA damage in readily accessible tissue(s) and clinical response to therapy. Such an approach may assist in the study of cancer drug resistance and in establishing parameters for assessing human populations for sensitivity to DNA damaging agents in the environment. Platinum-DNA adduct levels were measured by atomic absorbance spectrometry. DNA repair capacity was assessed in human T-lymphocytes by the ability to repair cisplatin lesions in cellular DNA or in transfected plasmid DNA. In a "blinded" study of 21 patients receiving combination cisplatin/carboplatin drug therapy, there was a direct relationship between DNA damage in leukocytes and disease response (summary two-sided p = 0.00011). The cohort of patients had 15 different tumor types, suggesting that blood tissue and tumor tissue of an individual may process platinum-DNA damage similarly regardless of the tissue of origin of the tumor. In leukocytes in vivo, persistence and accumulation were prominent features of the cisplatin-DNA adduct profile. Functional DNA repair capacity has been studied in eight human leukocyte cell lines in vitro (three, T-cells; three, B-cells; one, monocytic; one, promyelocytic), using a host cell reactivation assay with cisplatin-damaged pRSVcat. In the three T cell lines studied, host cell reactivation efficiency was directly related to the cells' abilities to repair cisplatin-damaged cellular DNA (correlation coefficient = 0.993).(ABSTRACT TRUNCATED AT 250 WORDS)
Dabholkar
M
M
Section of Genitourinary Cancer, National Cancer Institute, Bethesda, MD 20892.
Bradshaw
L
L
Parker
R J
RJ
Gill
I
I
Bostick-Bruton
F
F
Muggia
F M
FM
Reed
E
E
D016190:Carboplatin / Q000008:administration & dosage; D002460:Cell Line; D002945:Cisplatin / Q000008:administration & dosage / Q000032:analysis*; D015331:Cohort Studies; D004247:DNA / Q000032:analysis*; D018736:DNA Adducts; D004249:DNA Damage; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D013601:T-Lymphocytes / Q000737:chemistry*
D018736:DNA Adducts; D004273:DNA, Neoplasm; C057270:cisplatin-DNA adduct; D004247:DNA; D016190:Carboplatin; D002945:Cisplatin