TPI-287, a new taxane family member, reduces the brain metastatic colonization of breast cancer cells
Mené sur un modèle murin, cette étude montre qu'un composé apparenté à la famille des taxanes (TPI-287) est susceptible de franchir la barrière hémato-encéphalique et de prévenir la formation de métastases cérébrales d'un cancer du sein
Brain metastases of breast and other cancers remain resistant to chemotherapeutic regimens that are effective systemically, in part due to the blood-brain barrier. We report that TPI-287, a new microtubule stabilizing agent, displays in vitro cytotoxic activity similar to taxanes and epothilones. Unlike the taxanes, TPI-287 is permeable through the blood-brain barrier. Brain-to-plasma ratios of TPI-287 after a single injection typically exceeded 1 and were as high as 63.8 in the rat and 14.1 in the mouse. A brain-tropic derivative of the MDA-MB-231 "triple negative" breast cancer cell line, 231-BR, was used to test whether TPI-287 may be efficacious at preventing or treating brain metastases. TPI-287 had growth inhibitory effects comparable to paclitaxel when 231-BR tumor cells were injected into the mammary fat pad. Brain metastatic colonization was determined by intracardiac injection of 231-BR cells, with treatment beginning on day 3-4 post-injection, culminating in a histologic count of brain metastases in brains necropsied days 25-28 post-injection. In this assay, paclitaxel, ixabepilone and nab paclitaxel did not have significant inhibitory activity. TPI-287 was ineffective in the same assay using a 6 mg/kg qw schedule; however an 18 mg/kg dose delivered on days 3, 7 and 11 significantly reduced the outgrowth of brain metastases (55% reduction, p=0.028), and reduced proliferation in brain metastases (16% reduction, p=0.008). When TPI-287 treatment was delayed until days 18, 22, and 26 post-injection, efficacy was reduced (17% reduction, NS). The data suggest that TPI-287 may have efficacy when administered early in the course of the disease.
http://mct.aacrjournals.org/content/early/2012/05/23/1535-7163.MCT-12-0061.abstract