Zhou R, Mazurchuk RV, Tamburlin JH, Harrold JM, Mager DE, Straubinger RM
Differential pharmacodynamic effects of paclitaxel formulations in an intracranial rat brain tumor model. [JOURNAL ARTICLE]
J Pharmacol Exp Ther 2009 Oct 27.
Nano- and micro-particulate carriers can exert beneficial impact upon the pharmacodynamics of anticancer agents. To investigate the relationships between carrier and antitumor pharmacodynamics, paclitaxel incorporated in liposomes (L-pac) was compared to the clinical standard formulated in Cremophor-EL/ethanol (Cre-pac) in a rat model of advanced primary brain cancer. Three maximum-tolerated-dose regimens given by iv administration were investigated: 50 mg/kg on day 8 (d8) after implantation of 9L gliosarcoma tumors; 40 mg/kg on d8 and d15; 20 mg/kg on d8, d11 and d15. Body weight change and neutropenia were assessed as pharmacodynamic markers of toxicity. The pharmacodynamic markers of antitumor efficacy were increase in lifespan (ILS) and tumor volume progression, measured non-invasively by magnetic resonance imaging. At equivalent doses, neutropenia was similar for both formulations, but weight loss was more severe for Cre-pac. No regimen of Cre-pac extended survival, whereas L-pac at 40 mg/kg x2 doses was well-tolerated and mediated 26%ILS (p<0.0002) compared to controls. L-pac at a lower cumulative dose (20 mg/kg x3) was even more effective (40%ILS; p<0.0001). In striking contrast, the identical regimen of Cre-pac was lethal. Development of a novel semi-mechanistic pharmacodynamic model permitted quantitative hypothesis testing with the tumor volume progression data, and suggested the existence of a transient treatment effect that was consistent with sensitization or 'priming' of tumors by more frequent L-pac dosing schedules. Therefore, improved antitumor responses of carrier-based paclitaxel formulations can arise both from dose escalation, owing to reduced toxicity, and from novel carrier-mediated alterations of antitumor pharmacodynamic effects.
More from this journal |
