Prognostic value of gamma H2AX in pre-chemotherapy peripheral blood leukocytes from cancer patients treated with platinum analogs

SOTTILE FLEURY ML; GARCÍA MB; FLORES LEIVA RJ; REDONDO AL; IBARRA J; VARGAS ROIG LM; NADIN S.B.

Mendoza

Congreso; XXXVI Reunión Científica Anual de la Sociedad de Biología de Cuyo; 2018

Sociedad de Biología de Cuyo

Cisplatin (cisPt) is a widely used chemotherapeutic drug for the treatment of solid tumors. Its mechanism of action is based on the formation of DNA-interstrand and -intrastrand crosslinks, which interfere with normal DNA function. Histone H2AX phosphorylation (γH2AX) facilitates the recruitment of DNA damage repair proteins to the chromatin surrounding DNA lesions. The expression of γH2AX has been proposed as a tool to monitor DNA damage and repair in translational cancer research. The aim of our work was to determine the prognostic and predictive value of γH2AX in peripheral blood leukocytes (PBL) from cancer patients treated with cisPt. We isolated PBL from 6 healthy persons and 32 cancer patients (mean follow-up 13 months) before chemotherapy. PBL were exposed in vitro to cisPt (200 μM, 1 h). Cells were harvested both immediately after cisPt exposure and after 24 h and 48 h. γH2AX expression was evaluated by immunocytochemistry. At basal conditions, there were no statistically significant differences in the number of γH2AX foci per nucleus and in the percentage of γH2AX-positive cells between healthy subjects and cancer patients. PBL from healthy individuals and patients showed a significant increase (P ˂ 0.05) in the number of γH2AX foci per nucleus 24 h after cisPt. However, γH2AX foci per nucleus decreased after 48 h of recovery in PBL from healthy subjects, but they were not modified in PBL from cancer patients. Statistically significant differences between patients with complete clinical response to chemotherapy and those with partial response, stable or progressive disease were not found for the number of γH2AX foci per nucleus. A high number of γH2AX foci per nucleus in cancer patients were associated with better overall survival (P˂0.05). Our preliminary findings indicate that detection of number of γH2AX foci per nucleus in pre-chemotherapy PBL from cancer patients may be a useful prognostic marker for cancer patients treated with platinum-based chemotherapy.