Linomide, a
quinoline-3-carboxamide, has growth-inhibitory effects against a series of Dunning R-3327 rat
prostatic cancers in vivo [Ichikawa et al.:
Cancer Res 52:3022-3028, 1992]. In addition, we have demonstrated that daily
linomide treatment can inhibit angiogenic responses in nontumor-bearing rats and reduce
tumor blood flow in
tumor-bearing rats [Vukanovic et al.:
Cancer Res 53:1833, 1993]. In the present study we have demonstrated that the reduced
tumor blood flow is due to
linomide's ability to inhibit
tumor angiogenesis, as documented by decreased number of blood vessels in prostatic
carcinomas growing in rats treated daily with
linomide. Due to
linomide's ability to inhibit
tumor angiogenesis, and since
tumor angiogenesis is required not only for the growth of the primary
cancer but also for its ability to metastasize, the effect of
linomide on
metastasis was directly tested using a quantitation
metastasis assay. These in vivo experiments demonstrated that daily
linomide treatment decreased by 3-fold the extent of dissemination of
cancer cells to the lungs. To test if this antimetastatic response is due to direct effects of
linomide on the metastatic cells themselves as well as an induced effect upon inhibition of
tumor angiogenesis, additional studies were performed. These studies demonstrated that
linomide is not converted in vivo to metabolite(s) which are directly cytotoxic or
cytostatic to the
prostatic cancer cells themselves. These studies also demonstrated that
linomide does not decrease the attachment, migration, or invasive abilities of metastatic
cancer cells. These results suggest that the major mechanism for the antitumor and antimetastatic effects of
linomide is via its inhibition of
tumor angiogenesis. Additional studies have demonstrated that in vivo
linomide treatment results in the apoptotic death of thymocytes. This cytotoxic effect is not required for
linomide's antitumor effect, nor is it due to elevated plasma levels of
glucocorticoid.