Abstract 2542: Lurbinectedin (PM01183) synergizes in vivo the antitumor activity of doxorubicin in SCLC tumor xenografts

Abstract

Abstract Background: Lurbinectedin (PM01183) is a synthetic tetrahydroisoquinoline alkaloid currently evaluated as single agent and in combination in phase I and II clinical trials for solid tumors and hematological malignancies. In living cells, PM01183-DNA adducts stall replication and transcription giving rise to double strand breaks, inducing accumulation of cells in the S-phase of the cell cycle and triggering apoptosis. Studies aimed at defining the in vivo synergism of PM01183 and doxorubicin in the treatment of Small Cell Lung Cancer (SCLC) xenografted tumors are presented here. Material and Methods: Athymic nude mice were implanted with SCLC cells (NCI-H82 or NCI-H526). Mice bearing tumors (ca. 150 mm3) were allocated (N = 6-8/group) to experimental groups, namely: placebo; PM01183 at MTD (0.18 mg/kg), 0.75MTD, 0.5MTD and 0.25MTD; doxorubicin at their MTD (8.0 mg/kg), 0.75MTD, 0.5MTD and 0.25MTD; and, PM01183 combined with doxorubicin at (1+1), (0.75+0.75), (0.50+0.50) and (0.25+0.25) MTDs. All treatments were given intravenously once per week during the placebo-treated survival time. The antitumor effect induced by the treatments was analyzed using two-tailed Mann-Whitney U test. Also, the synergism was defined by the combination index (CI) determined by the CI-isobol method. Results: In both experiments, the combination of PM01183 and doxorubicin resulted in stronger antitumor effect (P<0.05) than that obtained with the more active single agent at the highest dose (MTD level). Analyses of the results by the CI-isobol method indicated that, after the treatment with PM01183 plus doxorubicin in the SCLC models resulted in an additive (at Fa = 0.97, CI = 1.05) or synergistic (at Fa = 0.97, CI = 0.66) effect. Conclusion: An improved (additive or synergism) in vivo antitumor activity was recorded after the treatment with PM01183 plus doxorubicin of mice bearing SCLC xenografted tumors. Citation Format: Maria Jose Guillen, Oscar Cataluña, Mandy Palomares, Raquel Lopez, Praxedes Nuñez, Carmen Cuevas, Pablo M. Aviles. Lurbinectedin (PM01183) synergizes in vivo the antitumor activity of doxorubicin in SCLC tumor xenografts. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2542. doi:10.1158/1538-7445.AM2015-2542