B. Schwartz, G. Bacher, P. Komarnitsky
Nov 1, 2007
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Journal
Molecular Cancer Therapeutics
Abstract
B283 Indibulin (N-(pyridin-4-yl)-[1-(4-chlorbenzyl)-indol-3-yl]-glyoxyl-amid; ZIO-301 or D-24851) is a novel synthetic, orally active antimitotic agent that binds tubulin, destabilizes tubulin polymerization, and arrests tumor cell growth at the G2/M phase. Tubulin inhibitors such as taxanes and vinca alkaloids are currently widely used to treat cancers although they are associated with serious side effects, most notably neuropathy. Taxanes stabilize tubulin polymers, while indibulin, vinca alkaloids, and colchicines destabilize polymerization. Each class of these agents has distinct tubulin binding sites. However, indibulin is unique in that it does not affect polymerization of mature neuronal tubulins; this property translates into lack of neurotoxicity, as observed in animal models and in ongoing Phase I clinical trials. Indibulin is active in a panel of human, murine, and rat tumor cell lines in vitro and in human tumor xenografts. Indibulin is also active in multidrug-resistant tumor cell lines including taxane- and vinblastin-resistant cell lines. Angiogenesis is a critical event in tumor growth and metastasis, and tumor cell migration is a prerequisite for metastasis. The effect of indibulin on either of these processes was investigated in assays of cell motility and angiogenesis both invitro and in vivo. Indibulin inhibited cell migration of MO4 cells, a fibrosarcoma cell line, in a dose-dependent manner with IC50 ~40 nM. In vivo antimetastatic potential of indibulin was evaluated in the murine RENCA tumor model. Indibulin treatment reduced the number of RENCA lung metastases by up to 2.5-fold compared to untreated mice. Antiangiogenic activity of indibulin was indicated by its cytotoxicity for human endothelial cells in in vitro assays. This observation was supported by the demonstration of complete inhibition of endothelial tube formation in vitro at low indibulin concentrations (100 nM). Indibulin’s antiangiogenic properties in vivo are being investigated in the mouse Matrigel plug model. Indibulin concentrations that exhibit activity in these models are well within the plasma concentrations of indibulin observed in patients in ongoing Phase I clinical studies. Preclinical data suggest that indibulin has a unique molecular mechanism, targeting specific subsets of cellular microtubules and affecting cancer cell growth through several well-defined pathways. In the Phase I studies, several biomarkers are being evaluated to correlate preclinical observations with clinical activity. The effect of indibulin on angiogenesis is being evaluated by measuring plasma VEGF and G-CSF levels. Additionally, functional imaging including PET scans are being performed. Circulating tumor cells and paired tumor biopsies are being analyzed to assess clinical efficacy and correlate with the proposed mechanism of action for indibulin. Preliminary data from these clinical studies will be reported.