CELLULAR MARKERS BASED ON DNA DAMAGE AND REPAIR (BER, MMR),
EXPRESSION OF MLH1, MSH2, FasR, AND CELL DEATH OF LYMPHOCYTES
AS PREDICTIVE PARAMETERS FOR CLINICAL RESPONSE
TO CHEMOTHERAPY OF MELANOMA
V. A. Tronov,1, * D. N. Artamonov,2 M. E. Abramov,3 L. B. Gorbacheva 2
1 N. N. Semenov Institute of Chemical Physics RAS,
2 N. M. Emanuel Institute of Biochemical Physics RAS, and
3 N. N. Blochin Cancer Research Center RAMS, Moscow RAS;
* e-mail: vtronov@yandex.ru
Melanoma is a highly aggressive neoplastic disease attributed to transformed melanocytes. The efficacy of
regimens of cytotoxic chemotherapy for advanced stage patients does not exceed 20 %. Search for lymphocyte
markers of patients' sensitivity to chemotherapy provides a rational basis for development of cytotoxic chemotherapy.
Using blood lymphocytes we evaluated efficacy of BER and MMR, expression of MLH1, MSH2 and
FasR, and cell death in melanoma patients relative to clinical response to chemotherapy. We found that
LDCI-chemotherapy (lomustine, dacarbazine, cisplatin and interferon gamma), induced AP sites and DNA
ss-breaks which repaired trough BER pathway. However, neither initial DNA damage nor the rate of their repair
correlated with clinical response. This result prompts us to think that this type of damage is not crucial in cytotoxic
effect of LDCI-regimen of chemotherapy. DNA ds-breakes appeared downstream ss-breakes were attributed
to repair of O6-methylguanine by MMR mechanism in PHA-stimulated lymphocytes. The number of ds-breakes
appeared by 48 correlated with positive clinical response of patients to chemotherapy. The same link was observed
between clinical response and the number of dead lymphocytes. However, there was no correlation between
clinical response and expression of MLH1 + MSH2 and FasR. These results imply possible contribution of crosslink
repair through NER pathway to formation of DNA ds-breaks as well as to cytotoxicity of LDCI-therapy.
The observed link between high level of secondary ds-breaks and positive response to chemotherapy indicates
the potential of these instruments to serve as prognostic end point in clinical trials.
Key words: melanoma, lymphocytes, chemotherapy, cell markers, DNA strand breaks, DNA repair
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