Impact of platinum-based chemotherapy on circulating nucleic acid levels, protease activities in blood and disseminated tumor cells in bone marrow of ovarian cancer patients.

Abstract

There is an unmet need for biomarkers for the prediction and monitoring of anticancer therapies. Here, we measured the concentrations of nucleosomes and DNA, protease and caspase activities in serum of 62 patients with ovarian cancer before and after first-line carboplatin/taxane-based chemotherapy and of 28 healthy individuals by Cell Death Detection ELISA, PicoGreen, Protease Fluorescent Detection Kit and Caspase-Glo3/7 Assay, respectively. By immunocytochemistry, we analyzed bone marrow (BM) aspirates for disseminated tumor cells (DTCs) using the monoclonal antibody A45-B/B3. The measurements in blood and BM were correlated to clinical outcome (median follow-up time: 18 months). Significant correlations between circulating nucleosome and DNA concentrations (p = 0.0001), nucleosome concentrations and caspase activities (p = 0.031) and circulating DNA concentrations and protease activities (p = 0.0001) were detected. Before therapy, the occurrence of DTCs correlated with increasing serum protease activities (p = 0.030) and higher tumor stages (p = 0.029), and after therapy, it correlated with a higher risk of relapse (p = 0.040). Higher protease activities in serum were associated with advanced tumor stages (p = 0.045). We observed a significant relationship between residual tumor load of >1 cm after primary surgery and serum DNA levels (p = 0.0001), and both parameters were associated with a higher risk of relapse (p = 0.0001 and p = 0.020, respectively) and a poorer overall survival (p = 0.021 and p = 0.010, respectively). These findings suggest that the residual tumor load might contribute to elevated DNA levels in blood. Serum DNA levels together with BM status for DTCs have the potential to become suitable biomarkers to predict the prognosis of ovarian cancer patients undergoing platinum-based chemotherapy.