Antitumor effects of imidazoquinolines in urothelial cell carcinoma of the bladder.
OBJECTIVE
Imidazoquinolines (Toll-like receptor-7 agonists) are a class of synthetic immune modulating agents. Imiquimod, a member of this drug family, is currently used as first line topical therapy for genital condyloma. It recently showed clinical efficacy against several benign and malignant skin lesions, including actinic keratosis and basal cell carcinoma. Working primarily through the stimulation of a proinflammatory immune response, the mechanism of action of imiquimod may be similar to that through which bacillus Calmette-Guerin is thought to act. We hypothesized that imidazoquinolines have therapeutic potential against bladder cancer. We determined the in vitro and in vivo effects of imidazoquinolines against bladder cancer cells.


METHODS
The human and murine J82, T24, TCC-SUP (American Tissue Culture Collection, Manassas, Virginia) and MBT-2 bladder cancer cell lines were cultured in normal culture medium or medium supplemented with imidazoquinoline. Effects on cell viability, apoptosis induction and cytokine production were evaluated. In addition, the effects of imidazoquinoline on in vivo bladder tumor growth were determined via intravesical instillation in an orthotopic bladder tumor model in the mouse.


RESULTS
A dose dependent decrease in cell viability was observed in all tumor cell lines treated with imidazoquinoline. In addition, imidazoquinoline significantly induced apoptosis and cytokine production. In in vivo experiments most mice treated with imidazoquinoline showed only an intense inflammatory response with no evidence of tumor, while control mice showed tumor growth.


CONCLUSIONS
Imidazoquinolines have potent direct activity against bladder cancer cells by decreasing cell viability and inducing apoptosis and cytokine production. In addition, in vivo data suggest antitumor effects in an orthotopic bladder cancer mouse model. Therefore, imidazoquinolines may have therapeutic potential as a synthetic intravesical agent against bladder cancer.
Smith
Eric B
EB
Department of Urology, New York-Presbyterian Hospital, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021, USA.
Schwartz
Michael
M
Kawamoto
Hideki
H
You
Xueke
X
Hwang
David
D
Liu
Huixian
H
Scherr
Douglas S
DS
D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D000077271:Imiquimod; D051379:Mice; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology*
D000634:Aminoquinolines; D000970:Antineoplastic Agents; D016207:Cytokines; D051199:Toll-Like Receptor 7; D000077271:Imiquimod