Description
Even with breakthroughs in medical research, cancer remains the second leading cause of death in populations younger than 85 years old. The costs incurred either as health expenditures or lost productivity as a result of the cancer deaths total in the hundreds of billions. Therefore, it is imperative that the best treatment options in terms of efficacy, cost and quality of life are made available to the patients. In the past, standard treatment for cancer was chemotherapy. While effective in combating cancer, there are often undesirable side-effects, with hematological adverse effects being the most common. The most reported is neutropenia, a lack of neutrophils, which can impair the patients' defense mechanism for fighting off infections. In an attempt to decrease the toxicity profile of the treatments, rationally designed drugs or targeted therapies are being developed, such as kinase inhibitors. Another approach undertaken by oncologists is combining more than one drug to treat the cancers, aptly called combination therapy. The ability to know whether the effects of combining drugs will produce a synergistic, additive or similar toxicity profile as the monotherapies will provide invaluable data for patient treatment plans. The purpose of this study is to propose a predictive method for determining the adverse effects of combining classical chemotherapy and a targeted therapy on bone marrow cells. Five compounds, three of which are kinase inhibitors, sorafenib, imatinib and a CHK-1 compound; a taxane, paclitaxel; and a classical nucleoside analog, gemcitabine were tested using differentiated in vitro human bone marrow mononuclear cells, which can give rise to various hematopoietic lineages. The range of concentrations used for the in vitro assay bracket the clinical plasma exposure. A dose-dependent decrease in cell viability in the progenitor population was determined using cellular ATP as the biomarker. An additive response was obtained through the combination of gemcitabine and the CHK-1 compound and paclitaxel and sorafenib at two of the lowest concentrations of the classical chemotherapeutics. The effects observed with paclitaxel and imatinib were more than those observe with the monotherapies alone. To a much lesser extent, gemcitabine combined with sorafenib or imatinib produced a nonadditive response. In summary, these results demonstrate the feasibility of using human bone marrow mononuclear cells to test different combination therapies for oncology and can subsequently be used as a research tool for predicting neutropenia for various single or combination therapies for either developing compounds or established therapies.
