INHIBITION OF ANGIOGENESIS AND METASTASES OF THE LEWIS LUNG-CELL CARCINOMA BY THE QUINOLINE-3-CARBOXAMIDE, LINOMIDE(R)

Linomide(R) has antitumor effects when administered in vivo but not in vitro. Recent data indicate that at least part of this effect can be attributed to anti-angiogenic properties. The aim of the present inves tigation was to study the anti-angiogenic effects of Linomide on early tumor-induced angiogenesis in vivo, using a newly developed skinfold chamber technique in the mouse, and to relate this to the effect of Li nomide on the number of metastases that develop from a s.c. implanted tumor. Tumor spheroids of Lewis lung cell carcinoma (LLC) with a diame ter of about 800 mu m were implanted in dorsal skinfold chambers inser ted on CB6/Fl mice. Tumor cells were pre-labelled with a fluorescent v ital dye (CMTMR), which allowed the estimation of the growth of the im planted tumor spheroids. Linomide, given orally from day 7 to day 11, reduced the incidence of lung metastasis arising from LLC tumors at da y 21 in a dose-dependent manner; a 55% reduction being found at a dose of 50 mg/kg/day (N=19 for the controls and N=10 for treatment groups) . In the dorsal skinfold chamber; the vascular network in Linomide tre ated animals (100 mg/kg/day, N=22) was more heterogenous, large areas within the tumor being completely avascular, in addition, capillary de nsity at the tumor site was reduced by 34% 6 days after implantation a nd by 39% after 14 days. In the control group (N=16), tumor volume dou bling time was not significantly differ ent in the early avascular par t of the observation period as compared to the Inter vascular phase; t his indicates that the growth of these micro-tumors in the early avasc ular phase is not angiogenesis dependent. However; in the Linomide tre ated animals tumor volume doubling time was significantly prolonged by 42% during the later part of the observation period. Taken together; the data indicate that the prolongation of the tumor doubling time is due to the anti-angiogenic activity of Linomide.