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- W2980018068 abstract "2446 Background: MGCD0103 is a novel orally available and isotype-selective HDAC inhibitor whose clinical activity has been shown in multiple phase II trials in patients with relapsed or refractory Hodgkin lymphoma, high-risk myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Here we explored the combination effects of MGCD0103 with taxanes on anti-tumor activity in several solid tumor xenograft models in mice in vivo and investigated the putative mechanism of their interaction. Method: MGCD0103 was orally administrated to the athymic nude mice implanted with human tumors using an intermittent dosing regimen (3 times a week) for 2 or 6 weeks. Taxol or Taxotere was administered as a bolus intravenous infusion. Tumor volume was calculated during the treatment and tumor weight at final date was measured for final evaluation. In addition, we measured the expression of angiogenesis related factors in the tumor tissue from the mice administrated with MGCD0103. The contribution of thrombospondin-1 (TSP-1) induced by MGCD0103 to the growth suppression of endothelial cells (ECs) by Taxol was investigated. Result: In xenograft models of human prostate, non-small cell lung (NSCLC), and gastric tumor in mice, MGCD0103 was observed to be as active as taxanes in inhibiting tumor growth in vivo. The combination of Taxol (or Taxotere) with MGCD0103 showed better anti-tumor effect in comparison to each treatment alone. Moreover, tumor regression was observed after combination of a taxane with MGCD0103 in the NCI-H460 human NSCLC xenograft model, even though treatment was initiated when the tumor was at an advanced stage. In addition, we observed the induced expression of an anti-angiogenesis factor, thrombospondin 1 (TSP-1), and reduced expression of two angiogenesis factors, VEGF and bFGF, in tumor tissues from mice treated with MGCD0103. Consistent with the effect of MGCD0103 on the expression of anti-angiogenesis/angiogenesis factors in vivo, addition of TSP-1 potentiated the cytotoxic effect of taxanes on ECs in vitro. Conclusion: MGCD0103 in combination with Taxol or Taxotere showed potent anti-tumor activity in vivo in preclinical models. Our results provide a rationale for on-going clinical trials of MGCD0103 in combination with Taxotere in patients with solid tumors." @default.
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- W2980018068 date "2008-05-01" @default.
- W2980018068 modified "2023-09-23" @default.
- W2980018068 title "MGCD0103, an oral isotype-selective HDAC inhibitor, significantly enhances the anti-tumor efficacy of Taxane via the unique modulation of angiogenesis gene expressions" @default.
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