Cisplatin-DNA Damage and Repair in Peripheral Blood Leukocytes in Vivo and in Vitro

Abstract

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 ofcancer 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). These data suggest that blood tissue and tumor tissue may process platinum-DNA adducts similarly on a molecular level and that human T lymphocytes are a suitable target for a prospective study of the impact of DNA repair on clinical response to platinum compounds.

Investigation of The DNA Damage of White Blood Cell in Cancer Patients Under Chemotherapy and Normal People

“…Further, it is logical to argue that applying each of the drugs tends to have a significant DNA damaging possibility. The experiment supports this study finding carried out by Dabholkar et al, (2012), where they documented that the existence of the subsequent exposure in the process of the chemotherapy in the white blood cells of the cancer patients, there is numerous single-strand break that is experienced for the DNA fragment, which is responsible for being measured by comet assay are highly provoked. This research finding is responsible for explaining the aspect that was experienced in this survey.…”

Prediction of response to chemotherapy by ERCC1 immunohistochemistry and ERCC1 polymorphism in ovarian cancer

“…The response of tumor cells to platinum-based drugs involves DNA repair mechanisms (2) . Platinum-DNA adducts are repaired by nucleotide excision repair (3) , which is constituted by nucleotide excision repair proteins that recognize the DNA damage and excise the platinum-DNA adducts from the injured DNA strand.…”

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“…Factors studied by Eastman included DNA repair, cytosolic inactivation of drug, and alterations in intracellular drug accumulation. Reed and colleagues have studied this question in human ovarian cancer cell lines [39], and in human T lymphocyte cell lines [40,41]. In both situations studied by Reed, DNA repair appeared to be the most important contributor to cellular resistance to cisplatin, at low levels of resistance.…”