Carboxyamido-triazole (CAI) reverses the balance between proliferation and apoptosis in a rat bladder cancer model.
Carboxyamido-triazole (CAI) is an orally bioavailable calcium influx and signal transduction inhibitor that has been shown to be anti-invasive, anti-angiogenic and anti-metastatic in different human tumors including transitional cell carcinoma. This study was undertaken to further evaluate the activity of CAI in a rat bladder cancer model. A transitional cell carcinoma (TCC) was chemically induced by intravesical installation of methyl-nitrosurea (MNU) in the bladder of female Fischer 344 rats. First, a toxicity study was performed which revealed no side-effects of CAI in the animals up to a dose of 250 mg/kg CAI. For treatment, a dose of 100 mg/kg CAI dissolved in PEG-400 vehicle was chosen. Oral administration of CAI continuously daily for 4 weeks (group A), 3 days/week over 6 weeks (group B), or intravesically twice a week for 6 weeks (group C) caused a reduction of spontaneous development of TCC. Lower stage and grade of tumors were seen in all CAI-treated animals. Under CAI treatment, the apoptotic rate in tumors increased, whereas the proliferation rate decreased, as shown by TUNEL assay and KI-67-immunhistochemistry, respectively. The highest efficacy was seen in group B, with 5 out of 10 animals tumor-free. Intravesical application (group C) resulted in 3 out of 10 animals tumor-free. Normal urothelium was not affected by CAI. This animal model confirms the anti-tumor effect of CAI and shows induction of apoptosis and growth inhibition in bladder cancer by the drug.
Perabo
Frank G E
FG
Department of Urology, University of Bonn, 53105 Bonn, Germany. perabo@lycos.com
Demant
André W
AW
Wirger
Andreas
A
Schmidt
Doris H
DH
Sitia
Mario
M
Wardelmann
Eva
E
Müller
Stefan C
SC
Kohn
Elise C
EC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D002273:Carcinogens; D002295:Carcinoma, Transitional Cell / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D008770:Methylnitrosourea; D051381:Rats; D011916:Rats, Inbred F344; D014230:Triazoles / Q000494:pharmacology* / Q000633:toxicity; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*
D000970:Antineoplastic Agents; D002273:Carcinogens; D014230:Triazoles; D008770:Methylnitrosourea; C062058:carboxyamido-triazole