Abstract Abstract #2138 Background: The tumor vasculature is an established target for the therapy of solid tumors. IDN5404 is a thiocolchicine dimer with antitubulin and topisomerase 1 inhibitor properties. In this study, nab-formulated IDN5404 was examined for antitumor effects in three xenograft models and for antiangiogenic as well as vascular disrupting activity (VDA) in the avian embryonic chorioallantoic membrane (CAM) assays.
 Materials and Methods: Subcutaneous human breast (MX-1 and MDA-MB-231), colon (HT29), and prostate (PC3) tumors were grown in athymic nude mice and treated intravenously (IV) with nab-5404 alone at 10, 20, 30, or 40 mg/kg (q3dx4 or q4dx3) and in combination with IV or intraperitoneal (IP) nab-paclitaxel (Abraxane; 10, 15 or 30 mg/kg, qdx5 or q4dx3). The effect of dose, schedule, and sequence of combination regimen was tested. Nab-5404 was administered 24-hr before, concurrently or 24-hr after Abraxane administration. The effect of nab-5404 on embryonic angiogenesis was examined in vivo using the standard chick CAM assay with 3-day old embryos (n = 18). The quail CAM assay was used to determine the time course of VDA. Quail embryos (n = 36) were exposed to nab-5404 (1 to 16 µg/ml) on day 7 and digital CAM images were acquired over a 60 min period for scoring VDA.
 Results: Significant dose-dependent tumor growth inhibition (TGI) was observed in all xenograft models. In the MX-1 and HT29 models, nab-5404 (30 mg/kg, q3dx4) exhibited potent antitumor activity (P < 0.0001, ANOVA, vs. saline) alone and in combination with Abraxane (TGI for MX-1: 65% and 76%; TGI for HT29: 44% and 74% respectively). Nab-5404 was similarly effective with the q4dx3 schedule. In addition, when Nab-5404 (20 mg/kg, q4dx3) was administered 24-hr before, concurrently or 24-hr after Abraxane (5 mg/kg, q4dx3), the combination resulted in TGI of >99%, 88%, and 72% respectively. Using the in vivo chick CAM assay, nab-5404 inhibited embryonic angiogenesis by over 90% at 5 µg/CAM without affecting viability. Furthermore, rapid collapse of blood vessels was observed within 30 min in the viable quail CAM assay when embryos were exposed to nab-5404 at 4-16 µg/ml.
 Discussion: Nab-5404 alone and in combination with Abraxane demonstrated significant TGI in xenograft models of human breast, colon or prostate cancer. This effect was shown to be due to the rapid VDA of nab-5404. Maximum antitumor activity was seen when nab-5404 was administered 24 hr before Abraxane. Nab-5404, a microtubule-destabilizing vascular disruptive agent, potentiates the cytotoxic effects of nab-paclitaxel, a microtubule-stabilizing agent and the data suggest that these two agents may be utilized effectively in combination. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2138.