roquinimex and Neoplasm-Metastasis

It has been demonstrated that quinoline-3-carboxamide, linomide, inhibited angiogenesis and reduced the volume of tumors grown from human hormone-resistant prostate cancer cell lines after subcutaneous implantation in mice. However, subcutaneous xenograft models may not mimic human conditions due to the absence of prostatic stromal cells at the ectopic site. Therefore, we investigated the influence of linomide on local tumor growth and metastasis of the human hormone-resistant prostate cancer cell line PC-3 in an orthotopic model.. In 30 athymic nude mice, 5x10(5) PC-3 cells were injected into the dorsal prostate after surgical exposure. After 7 days, group 1 (n = 15 mice) received linomide 100 mg/kg/day in the drinking water (per os). The other 15 mice (group 2) served as controls. All mice were sacrificed after 38 days followed by macroscopical and histological evaluation of local tumor growth and metastasis. Microvessel density was determined by immunohistochemical staining for von Willebrand factor as well as silver staining followed by morphometric analysis in an area of highest vessel density.. In the control group, local tumorigenicity and locoregional lymph node metastasis was 100%. The mean weight of the local tumor was 894 mg (395- 1,261 mg). The mean transversal diameter of the lymph node metastases was 4.0 mm (1.5-5. 4 mm). In the treatment group, local tumor growth and lymph node metastasis was 100% with a mean local tumor weight of 869 mg (232-1, 131 mg) and a mean lymph node metastasis diameter of 4.6 mm (1.3-5.9 mm). Microvessel density of the local tumor in the control and treatment group did not differ significantly.. Contrary to the results reported in subcutaneous animal models, linomide per os has no effect on net tumor growth and metastasis after orthotopic implantation of the human hormone-resistant prostate cancer cell line PC-3 in nude mice.

Topics: Angiogenesis Inhibitors; Animals; Cell Division; Humans; Hydroxyquinolines; Male; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Prostatic Neoplasms; Tumor Cells, Cultured

Angiogenesis and antiangiogenesis, as applied to oncology, are phenomena in which (1) tumors acquire a new blood vascular system from the host that is needed for their growth progression and metastasis; and (2) factors are produced that interfere with neovascularization, thereby inhibiting growth and metastasis of the tumor. Linomide, a chemical antiangiogenesis agent, inhibited the growth of transplanted tumors in mice and rats and inhibited the early development of metastasizing tumors induced in the prostate-seminal vesicle (P-SV) complex of genetically susceptible Lobund-Wistar (L-W) rats.. L-W rats with small induced P-SV tumors were treated with a recommended dosage of linomide (100 mg/kg BW/day) by the intraperitoneal and oral routes. The rats were monitored for the next 1-2 months, and the primary and metastatic tumors were compared with related data in drug-free tumor-bearing control rats.. P-SV tumors in linomide-treated and untreated control rats continued to grow, except that in the former (1) the tumors were marginally smaller, (2) the centers of the primary P-SV tumors had failed to grow, (3) the peripheral areas of the tumors contained actively proliferating tumor cells, and (4) metastatic P-SV tumors in the lungs were disrupted with focal areas of necrosis, but areas of intact tumor cells survived. Spread of tumor cells into the peritoneal cavity was not inhibited. Rats on orally administered linomide lived significantly longer than rats inoculated by the intraperitoneal route and untreated control rats. The dosage of linomide used showed evidence of toxicity.. Although primary and metastatic P-SV tumors were damaged in L-W rats treated with linomide, this antiangiogenic drug was of minimal therapeutic benefit to rats in which a palpable P-SV tumor had developed before onset of treatments.

Topics: Animals; Antineoplastic Agents; Body Weight; Genital Neoplasms, Male; Hydroxyquinolines; Male; Neoplasm Metastasis; Neovascularization, Pathologic; Prostatic Neoplasms; Rats; Rats, Wistar; Seminal Vesicles

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.

Topics: Alkylation; Animals; Antineoplastic Agents; Cell Adhesion; Cell Death; Cell Movement; Glucocorticoids; Hydroxyquinolines; Male; Neoplasm Invasiveness; Neoplasm Metastasis; Neovascularization, Pathologic; Prostatic Neoplasms; Rats; Rats, Inbred Strains; Thymus Gland; Time Factors