Abstract A16: Antitumor activity of CYT997: A phase II vascular disrupting agent administered orally in combination with cisplatin in a colon adenocarcinoma xenograft model
Authors: Powell Andrew K. , Shnyder Steven D. , Cooper Patricia A. , Nelson Stuart , Burns Christopher J. , Fida Rose , Smith Gregg D. 
Published: June 2012

CYT997 is an orally bioavailable small molecule vascular-disrupting agent (VDA) that is currently being investigated in Phase II clinical studies. In vitro efficacy studies have demonstrated that CYT997 exhibits potent antiproliferative activity against the DLD-1 cell line (IC50 21 nM), with a similar potency to doxorubicin, paclitaxel and vincristine (IC50 8 – 53 nM). The antitumor and vascular targeting activity of CYT997 has been demonstrated in the current series of studies following alternate dosing regimens (single dose vs metronomic sub-maximal daily dose) and in combination with a standard chemotherapeutic agent, cisplatin.

Female Balb/C immunodeficient nude mice were implanted subcutaneously with DLD-1 human colon adenocarcinoma fragments and efficacy was assessed via tumor caliper measurements, in addition to histological assessment of tumor vascular shutdown (Hoechst 33342 staining) and necrotic area (haematoxylin and eosin staining). Animals were administered CYT997 (dihydrochloride salt) by oral gavage and efficacy was expressed relative to vehicle control.

Administration of CYT997 resulted in a time and concentration dependent shutdown of tumor vasculature. Following a single CYT997 administration (40 mg/kg), vascular shutdown was extensive and rapid (ca 95% ablation compared with vehicle control at 1h post-dose; p&lt;0.01). Significant vascular shutdown was maintained in tumors 4 days post treatment (ca 67% shutdown; p&lt;0.05) and subsequent histological examination demonstrated increased necrosis (ca 280% increase; p&lt;0.05) of the tumor in mice treated with CYT997 compared with vehicle control. A single oral dose at 10 mg/kg (ca 1/5th the maximum tolerated dose), resulted in statistically-significant shutdown of tumor vasculature in this model (61 – 94% shutdown at 1 h post-dose compared to vehicle control; p&lt;0.05).

Daily oral administration of CYT997 (10 mg/kg/day) resulted in sustained shutdown of tumor vasculature over 10 days of treatment (57% shutdown compared to vehicle control; p&lt;0.05), which was associated with a significant increase (ca 44% increase; p&lt;0.05) in the necrotic area of the tumor relative to control. The efficacy of the metronomic CYT997 dosing schedule was assessed in combination with weekly administration of cisplatin (6 mg/kg i.p.). Despite some toxicity associated with the second cycle of cisplatin administration, the greatest tumor growth delay was observed in the combination group (2.7 days), relative to cisplatin (1.9 days) or CYT997 (1.8 days) alone.

These findings demonstrate that CYT997 exhibits rapid and long lasting antivascular effects following a single oral dose or following sub-maximal metronomic dosing. There is clear potential for increased anti-tumor efficacy when CYT997 is dosed in combination with other common anticancer therapies.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A16.