Sustained Supratherapeutic Paclitaxel Delivery Enhances Irreversible Sarcoma Cell Death.

Autor:	Blessing WA; Division of Thoracic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Digesu CS; Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts., Liu R; Division of Thoracic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Mahvi DA; Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Tal-Mason A; Division of Thoracic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Kumar A; Division of Thoracic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Hachey KJ; Department of Surgery, Boston Medical Center, Boston, Massachusetts., Colby AH; Departments of Biomedical Engineering, Chemistry, and Medicine, Boston University, Boston, Massachusetts., Korunes-Miller JT; Departments of Biomedical Engineering, Chemistry, and Medicine, Boston University, Boston, Massachusetts., Agar N; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Regan MS; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Shih A; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Raut CP; Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.; Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts., Grinstaff MW; Departments of Biomedical Engineering, Chemistry, and Medicine, Boston University, Boston, Massachusetts., Colson YL; Division of Thoracic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2022 Nov 03; Vol. 21 (11), pp. 1663-1673.
DOI:	10.1158/1535-7163.MCT-21-0750
Abstrakt:	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. In vitro PTX efficacy is time and dose dependent with prolonged exposure significantly decreasing PTX IC50 values for human chondrosarcoma (CS-1) cells (153.9 nmol/L at 4 hours vs. 14.2 nmol/L at 30 hours, P = 0.0001). High-dose PTX significantly inhibits proliferation with in vivo 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 G2-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 in vivo and offer an alternative paradigm to prevent recurrence. (©2022 American Association for Cancer Research.)
Databáze:	MEDLINE
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