Antiangiogenic activity of 4'-thio-beta-D-arabinofuranosylcytosine.

Academic Article

Abstract

  • 4'-Thio-beta-D-arabinofuranosylcytosine (T-araC), a new-generation deoxycytidine nucleoside analogue, showed significant efficacy against numerous solid tumors in preclinical studies and entered clinical development for cancer therapy. It is a structural analogue of cytarabine (araC), a clinically used drug in the treatment of acute myelogenous leukemia, which has no or very limited efficacy against solid tumors. In comparison with araC, the excellent in vivo activity of T-araC against solid tumors suggests that, in addition to inhibition of DNA synthesis, T-araC may target cellular signaling pathways, such as angiogenesis, in solid tumors. We studied T-araC and araC for their antiangiogenic activities in vitro and in vivo. Both compounds inhibited human endothelial cell proliferation with similar IC50s. However, only T-araC inhibited endothelial cell migration and differentiation into capillary tubules. T-araC also abrogated endothelial cell extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, a key signaling molecule involved in cellular processes of angiogenesis. Results from chick chorioallantoic membrane angiogenesis assays revealed that T-araC significantly inhibited the development of new blood vessels in vivo, whereas araC showed much less effect. The findings of this study show a role of T-araC in antiangiogenesis and suggest that T-araC combines antiproliferative and antiangiogenic activity in one molecule for a dual mechanism of drug action to achieve the excellent in vivo efficacy against several solid tumors. This study also provides important information for optimizing dosage and sequence of T-araC administration in clinical investigations by considering T-araC as both an antiproliferative and an antiangiogenic agent.
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    Keywords

  • Angiogenesis Inhibitors, Animals, Arabinonucleosides, Cell Line, Tumor, Chick Embryo, Chorioallantoic Membrane, Endothelial Cells, Humans, Male, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Neovascularization, Pathologic, Neovascularization, Physiologic, Phosphorylation, Prostatic Neoplasms
  • Digital Object Identifier (doi)

    Authorlist

  • Roy AM; Tiwari KN; Parker WB; Secrist JA; Li R; Qu Z
  • Start Page

  • 2218
  • End Page

  • 2224
  • Volume

  • 5
  • Issue

  • 9