Docetaxel-dasatinib combination: A strategy to overcome unfavorable treatment outcomes due to dose reduction

Docetaxel is a highly potent chemotherapeutic agent used in the management of many cancers. Adverse effects associated with its use are the reasons clinicians usually resort to dose reduction and/or dose delays for patients. Dose reductions ≥15% are considered suboptimal doses and are reported to be associated with unfavorable treatment outcomes. The aim of this project was to redesign the delivery system of docetaxel and evaluate the dose-sparing effect of a cytostatic agent - dasatinib on docetaxel when used in combination. Using the nanoprecipitation method, docetaxel was entrapped in a polymer (Polycaprolactone) matrix as nanoparticles with poloxamer F-108 as the stabilizer. A triple negative breast cancer cell line (MDA-MB-231) was used as a model for cancer cells. The 50% inhibitory concentrations (IC50) were determined for each drug in solution and as nanoparticles using the Alamar blue proliferation assay. Simultaneous and sequential combinations of the two drug formulations were conducted and their effect on cell proliferation determined using the Alamar blue assay. The average size of nanoparticles ranged between 188.0 and 212.0 nm which is optimum for uptake and accumulation in the tumor microenvironment. The polycaprolactone matrix delayed the release the docetaxel, thus direct death of cells was avoided immediately after dosing until the drug was released. Simultaneous use of dasatinib with docetaxel yielded only mild synergy, however, pre-treating MDA-MB-231 cells with dasatinib for 2 hours prior to docetaxel administration resulted in about 10–14% more death of cells than in the group not given this regimen. Dasatinib has a dose-sparing effect on docetaxel. Further studies need to be conducted to confirm the use of dasatinib as premedication in docetaxel treatment regimen for breast cancer. Obtaining equivalent response using a lower dose of docetaxel will result in fewer adverse effects, prevent treatment delays and subsequently avoid treatment failures.