ZD6126 inhibits orthotopic growth and peritoneal carcinomatosis in a mouse model of human gastric cancer

Abstract

The purpose of this study was to examine the effects of ZD6126, a novel vascular-targeting agent, on tumour growth and angiogenesis in an orthotopic model of gastric cancer. TMK-1 human gastric adenocarcinoma cells were injected into the gastric wall of nude mice. After the tumours were established (day 14), therapy was initiated. Mice (n ¼ 11 -12/group) received (a) vehicle, (b) ZD6126 at 100 mg kg day À1 i.p. one time per week or (c) ZD6126 at 100 mg kg day À1 i.p. five times per week. Tumour mass, volume and the presence or absence of peritoneal carcinomatosis were determined at sacrifice on day 38. Tumours from each group were stained for markers of blood vessels, proliferation and apoptosis. To further define the time frame of the vascular-targeting effects of chronic therapy with ZD6126, TMK-1 cells were again injected into the gastric wall of mice in a second experiment. On day 14, a single i.p. injection of ZD6126 100 mg kg À1 mouse À1 or vehicle was delivered. Groups of three mice each were killed and the tumours harvested at days 1, 3 and 5 post-ZD6126 injection. Tumours were processed and stained for endothelial and tumour cell apoptosis and proliferation. No overt toxicity was observed with ZD6126 therapy. ZD6126 led to a marked inhibition of tumour growth (82% decrease vs control (Po0.001)). ZD6126 also led to a significant decrease in the incidence of peritoneal carcinomatosis (10 out of 12 controls, vs one out of 12 ZD6126) (Po0.01). Histological analysis of tumours revealed large regions of central necrosis in the treated group, as well as a dramatic increase in tumour cell apoptosis (7.4-fold increase (Po0.001)), consistent with the vascular-targeting activity of ZD6126. Mice treated with ZD6126 demonstrated a 59% decrease in PCNA-positive cells (Po 0.02), indicating reduced tumour cell proliferation. In addition, tumours treated with ZD6126 exhibited a 40% decrease in microvessel density (Po0.05). Results from mice treated with a single injection of ZD6126 demonstrated the acute effects this agent has on the tumour vasculature. The ratio of endothelial cell apoptosis to endothelial cell proliferation was increased within 24 h of a single injection. In conclusion, ZD6126 significantly inhibited tumour growth and metastasis in an orthotopic model of human gastric adenocarcinoma, without detectable problematic adverse effects. These data suggest that ZD6126 may be worthy of investigation in the treatment of primary gastric adenocarcinoma.

In vitro and in vivo evaluation of tumor targeting styrene‐maleic acid copolymer‐pirarubicin micelles: Survival improvement and inhibition of liver metastases

“…Necrosis seen after drug treatment was heterogeneous as has been reported previously. (35)(36)(37) Necrosis was incomplete in some tumors with residual cells persisting at the periphery. These cells appeared swollen (cytomegaly) or at various stages of mitotic arrest (Figs 6,7).…”

Sequence dependent antitumour efficacy of the vascular disrupting agent ZD6126 in combination with paclitaxel

“…Among these, ZD6126 is a synthetic water-soluble phosphate prodrug, which is rapidly converted in vivo into the tubulin-binding ZD6126 phenol, a microtubule destabilising colchicine analogue. The effects of the compound on endothelial cells in vitro and on neo-vessels in vivo are well documented Davis et al, 2002;Micheletti et al, 2003), as is its ability to induce tumour necrosis in experimental models Siemann and Rojiani, 2002b;McCarty et al, 2004;Taraboletti et al, 2005;Skliarenko et al, 2006).…”

Real-time bioluminescence and tomographic imaging of gastric cancer in a novel orthotopic mouse model

“…In addition, the orthotopic cancer model reflects a relevant site to assess therapeutic outcomes, avoiding the false-positive drug responses caused by other cancer models (19). Although the orthotopic gastric cancer model has been employed in previous studies (20)(21)(22), little attention has been paid to its direct use for in vivo longitudinal monitoring and drug evaluation.…”