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Combination of eribulin plus gemcitabine in L-sarcomas

2018; Elsevier BV; Volume: 29; Linguagem: Inglês

10.1093/annonc/mdy299.055

1569-8041

David S. Moura, María López-Álvarez, A. Salinas-Villegas, Paloma Sánchez-Bustos, Nadia Hindi, Mihai Roca, Javier Martín‐Broto,

Sarcoma Diagnosis and Treatment

Background: Eribulin (Halaven®; Eisai Co., Tokyo, Japan) is a synthetic analogue of halichondrin B that was approved for advanced liposarcoma. Eribulin, besides its well stablished cytotoxic activity, induces vascular remodelling and increased tumor perfusion, as well as inhibits pericyte- and endothelial-driven angiogenesis, which could facilitate the distribution of other drugs within the tumor. Altogether, we hypothesize that eribulin and gemcitabine, acting in different cell cycle phases and modulating distintly tumour microenvironment, could be synergistic, without overlapping toxicity. Methods: CP0024 human leiomyosarcoma primary cell line, SK-UT-1 human leiomyosarcoma cell line and, 93T449 and 94T778 human liposarcoma cell lines were treated with increased concentrations of eribulin (1x10-7M to 1x10-11M) or gemcitabine (1x10-9M to 1x10-13M) to determine IC50 values. Combination index values of eribulin plus gemcitabine were calculated, after treating L-sarcoma cell lines with both drugs using the following administration sequences: concomitant (E+G), eribulin followed by gemcitabine (E→G) and gemcitabine followed by eribulin (G→E). Cell viability, at 72 hours, was measured by MTS cell proliferation assay. Results: The IC50 values determined for eribulin ranged between 0.28nM (SK-UT-1) and 1.98nM (94T778), while IC50 values of gemcitabine ranged between 2.10nM (SK-UT-1) and 7.02nM (94T778). The combination index values at ED50 (the effective doses at which 50% of cell killing occurred) ranged: between 0.27 (SK-UT-1) and 0.89 (94T778), when cell lines were treated with E+G; between <0.10 (SK-UT-1) and 0.33 (CP0024) when treated with G→E; and between <0.10 (SK-UT-1) and 0.20 (CP0024) when cells were treated with E→G. All the cell lines showed a higher synergism when treated using the E→G administration sequence. Conclusions: Eribulin and gemcitabine combination is synergic in L-sarcoma cell lines. The administration of eribulin, followed by gemcitabine is the recommended administration sequence for further studies. The mechanisms underlying eribulin plus gemcitabine synergy, as well as predictive biomarkers of response to the combination, will be evaluated in in vitro and in vivo models of L-sarcoma. Legal entity responsible for the study: Instituto de Biomedicina de Sevilla. Funding: Eisai Co., Ltd. Disclosure: D.S. Moura: Corporate-sponsored research fees: Eisai. Co. Ltd. J. Martin-Broto: Corporate-sponsored research fees: Eisai. Co., Ltd., Novartis, PharmaMar; Honoraria or consultation fees: Lilly, Novartis, PharmaMar; Company sponsored speaker’s bureau: PharmaMar. All other authors have declared no conflicts of interest.