1. Overcoming High Trabectedin Resistance of Soft-tissue Sarcoma With Recombinant Methioninase: A Potential Solution of a Recalcitrant Clinical Problem.
- Author
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Morinaga S, Han Q, Mizuta K, Kang BM, Sato M, Bouvet M, Yamamoto N, Hayashi K, Kimura H, Miwa S, Igarashi K, Higuchi T, Tsuchiya H, Demura S, and Hoffman RM
- Subjects
- Humans, Cell Line, Tumor, Sarcoma drug therapy, Sarcoma pathology, Fibrosarcoma drug therapy, Fibrosarcoma pathology, Drug Synergism, Trabectedin pharmacology, Carbon-Sulfur Lyases administration & dosage, Carbon-Sulfur Lyases pharmacology, Drug Resistance, Neoplasm drug effects, Tetrahydroisoquinolines pharmacology, Tetrahydroisoquinolines administration & dosage, Antineoplastic Agents, Alkylating pharmacology, Antineoplastic Agents, Alkylating therapeutic use, Dioxoles pharmacology, Dioxoles therapeutic use, Dioxoles administration & dosage, Recombinant Proteins pharmacology
- Abstract
Background/aim: Drug resistance has been a recalcitrant problem for sarcoma patients for many decades. Trabectedin is a second-line chemotherapy for soft-tissue sarcoma that often leads to resistance and death of the patients. The objective of the present study was to address the issue of trabectedin-chemoresistance in HT1080 fibrosarcoma cells by combining recombinant methioninase (rMETase) with trabectedin and examining their efficacy on trabectedin-resistant fibrosarcoma cells in vitro., Materials and Methods: Trabectedin-resistant HT1080 (TR-HT1080) cells were generated by subjecting HT1080 human fibrosarcoma cells to increasing trabectedin concentrations (3.3-8 nM). IC
50 values for trabectedin and rMETase were compared for HT1080 and TR-HT1080 cells. TR-HT 1080 cells were placed into four groups to determine synergy of rMETase and trabectedin on TR-HT1080 cells: a control group with no treatment; a group treated with trabectedin (3.3 nM); a group treated with rMETase (0.75 U/ml); and a group treated with both trabectedin (3.3 nM) and rMETase (0.75 U/ml)., Results: The IC50 value of trabectedin- on TR-HT1080 cells was 42.9 nM, whereas the IC50 value of trabectedin on the parental HT1080 cells was 3.3 nM, indicating a 13-fold increase. The combination of rMETase (0.75 U/ml) and trabectedin (3.3 nM) was synergistic on TR-HT1080 cells resulting in an inhibition of 64.2% compared to trabectedin alone (5.7%) or rMETase alone (50.5%) (p<0.05). rMETase increased the efficacy of trabectedin 11-fold on trabectedin-resistant fibrosarcoma cells., Conclusion: The combined administration of trabectedin and rMETase was synergistic on the viability of TR-HT1080 cells in vitro. The combination of rMETase and trabectedin has promising clinical potential for overcoming chemo-resistance of soft-tissue sarcoma., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)- Published
- 2024
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