Data from Sustained Supratherapeutic Paclitaxel Delivery Enhances Irreversible Sarcoma Cell Death

Abstract

<div>Abstract<p>Risk of locoregional recurrence after sarcoma resection is high, increasing both morbidity and mortality. Intraoperative implantation of paclitaxel (PTX)-eluting polymer films locally delivers sustained, supratherapeutic PTX concentrations to the tumor bed that are not clinically feasible with systemic therapy, thereby reducing recurrence and improving survival in a murine model of recurrent sarcoma. However, the biology underlying increased efficacy of PTX-eluting films is unknown and provides the impetus for this work. <i>In vitro</i> PTX efficacy is time and dose dependent with prolonged exposure significantly decreasing PTX IC<sub>50</sub> values for human chondrosarcoma (CS-1) cells (153.9 nmol/L at 4 hours vs. 14.2 nmol/L at 30 hours, <i>P</i> = 0.0001). High-dose PTX significantly inhibits proliferation with <i>in vivo</i> PTX films delivering a dose >130 μmol/L directly to the tumor thereby irreversibly arresting cell cycle and inducing apoptosis in CS-1 as well as patient-derived liposarcoma (LP6) and leiomyosarcoma (LMS20). Supratherapeutic PTX upregulates the expression of p21 in G<sub>2</sub>–M arrested cells, and irreversibly induces apoptosis followed by cell death, within 4 hours of exposure. Microarray analyses corroborate the finding of poor DNA integrity commonly observed as a final step of apoptosis in CS-1 cells and tumor. Unlike low PTX concentrations at the tumor bed during systemic delivery, supratherapeutic concentrations achieved with PTX-eluting films markedly decrease sarcoma lethality <i>in vivo</i> and offer an alternative paradigm to prevent recurrence.</p></div>