Schedule treatment design and quantitative in vitro evaluation of chemotherapeutic combinations for metastatic prostate cancer therapy

Abstract

Preclinical evaluation is essential for a rational design of combination chemotherapy as some agents, with known mechanisms of action and non-overlapping toxicities may increase the therapeutic index of anticancer drugs, whose clinical success is hindered by side effects and drug resistance. The present study investigated new drug combinations with potential outcome for the treatment of metastatic prostate cancer. This final clinical stage exhibits predominantly hormone-refractory prostate cancer (HRPC) cells but also a minority of hormone responsive cells. Growth inhibition activity of simultaneous and sequential combinations was evaluated by resazurin assay. In vitro evaluation of synergism, additivity, or antagonism, against prostate cancer cell lines, was performed by the median effect analysis. The importance of dosage, exposure time, drug ratio, and type of treatment were investigated and compared. Most simultaneous combinations of two drugs with different mechanisms of action or of two topoisomerase II inhibitors resulted in mild antagonism of antiproliferative effects, particularly notorious at high cell death. Imatinib-mitoxantrone and ciprofloxacin-etoposide combinations were exceptions, as they yielded additivity and dose reduction index (DRI) values of 2.6 and 3.5-fold for mitoxantrone and etoposide, respectively. Sequential combinations (ciprofloxacin or imatinib pre-treatment) revealed additive growth inhibition effects, translated in much higher DRI values (from 7.0 to 15.3-fold). Moderate synergism was restricted to sequential ciprofloxacin combinations at high cell death. Ciprofloxacin and imatinib significantly improve growth inhibition activity of standard antineoplastic drugs in a schedule-dependent manner and, therefore, may have an important role as adjuvant therapeutic agents in a clinical setting.