Antitumour effects of the angiogenesis inhibitor AGM-1470 on rat urinary bladder tumours induced by N-butyl-N-(4-hydroxybutyl) nitrosamine.
OBJECTIVE
To examine the antitumour effects of the angiogenesis inhibitor AGM-1470 (TNP-470) on rat urinary bladder tumours induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN).


METHODS
Fischer-344 rats were allocated to one of four groups of 15 rats each; in group 1, rats were administered AGM-1470 intraperitoneally, with group 2 acting as the control and given only saline; in group 3, AGM-1470 was instillation intravesically and group 4 acting as control (intravesical saline). All rats were given 0.05% BBN in their drinking water for 8 weeks and then given water with no BBN. AGM-1470 was administered at a dose of 30 mg/kg every other day for 6 weeks in group 1 and at 15 mg/kg once a week for 6 weeks in group 3. This treatment was commenced at 21 weeks after the start of BBN treatment, when tumorigenesis was apparent in all rat bladders; approximately 70-80% of the tumours were carcinomas. All rats were killed in the 27th week. The antitumour effects of AGM-1470 on the BBN-induced bladder tumours were evaluated macroscopically and histologically. The inhibitory effect of AGM-1470 on endothelial cell proliferation was assessed in groups 1 and 2 by immunohistochemical staining for Factor VIII-related antigen and by counting the microvessels.


RESULTS
The number and volume of bladder tumours were significantly less in group 1 than group 2. In the latter, at least one bladder tumour developed in each of the 15 rats. Histologically, transitional cell carcinoma (TCC) was found in 13 rats and papilloma in two, with invasive cancer in three of the 13 TCCs. Bladder tumours developed in only four of the 15 rats in group 1. Carcinomas were found in three of these four rats and no invasive cancer was detected. The rats in group 1 had significantly fewer microvessels than the controls. The rats in group 4 also showed slightly but insignificantly less tumour growth and fewer carcinomas. In neither experiment were any major side-effects seen except for mild weight loss after AGM-1470 treatment.


CONCLUSIONS
AGM-1470 inhibited the growth and malignant progression of BBN-induced bladder tumours in rats, apparently mainly by the inhibition of tumour vessel development. The intraperitoneal administration of AGM-1470 produced better results than did intravesical instillation. These results suggest that the angiogenesis inhibitor AGM-1470 is a promising agent for the treatment of human bladder cancer.
Osawa
S
S
Department of Urology, Nippon Medical School, Tokyo, Japan.
Terashima
Y
Y
Kimura
G
G
Akimoto
M
M
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D002085:Butylhydroxybutylnitrosamine; D002273:Carcinogens; D003510:Cyclohexanes; D005260:Female; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D051381:Rats; D011916:Rats, Inbred F344; D012717:Sesquiterpenes / Q000627:therapeutic use*; D001749:Urinary Bladder Neoplasms / Q000098:blood supply / Q000139:chemically induced / Q000188:drug therapy*
D000903:Antibiotics, Antineoplastic; D002273:Carcinogens; D003510:Cyclohexanes; D012717:Sesquiterpenes; D002085:Butylhydroxybutylnitrosamine; D000077609:O-(Chloroacetylcarbamoyl)fumagillol