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=11-12/group) received (a). vehicle, (b).
ZD6126 at 100 mg x kg day(-1) i.p. one time per week or (c)
ZD6126 at 100 mg x kg day(-1) 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 x kg(-1) mouse(-1) 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 (P<0.001)).
ZD6126 also led to a significant decrease in the incidence of
peritoneal carcinomatosis (10 out of 12 controls, vs one out of 12
ZD6126) (P<0.01). 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 (P<0.001)), consistent with the vascular-targeting activity of
ZD6126. Mice treated with
ZD6126 demonstrated a 59% decrease in
PCNA-positive cells (P< 0.02), indicating reduced tumour cell proliferation. In addition, tumours treated with
ZD6126 exhibited a 40% decrease in microvessel density (P<0.05). 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.