Antitumor effects of an imidazoquinoline in renal cell carcinoma.

OBJECTIVES: To evaluate the effects of imidazoquinolines in renal cell carcinoma (RCC). METHODS: In vitro experiments were carried out using mouse (RENCA) and human (CAKI-1, CAKI-2, and A-498) RCC cell lines. Toll-like receptor-7 (TLR7) expression was assessed by Western blot. We determined the ability of imidazoquinolines to induce apoptosis and inhibit cell viability in vitro. For in vivo experiments, RENCA cells were injected into the tail vein of syngeneic mice. One week after injection, mice were given oral imidazoquinoline or placebo for 14 days. Mice were then sacrificed, and lungs were inspected for tumor nodules. Immunohistochemical staining was used to assess apoptosis in vivo. RESULTS: Toll-like receptor-7 was expressed in all cell lines tested, with RENCA cells showing the highest level of expression. Imidazoquinolines inhibited in vitro cell viability of RENCA, CAKI-2, and A-498 cell lines in a time-dependent manner. Viability of CAKI-1 was not inhibited significantly. Apoptosis induction was pronounced in RENCA cells treated with imidazoquinoline. Compared with placebo, oral imidazoquinoline significantly reduced the number of pulmonary metastasis and increased cell death in vivo. CONCLUSIONS: Imidazoquinolines inhibit cell viability and cause deoxyribonucleic acid fragmentation leading to apoptosis in RCC cell lines, potentially working through the TLR7 expressed by RCC cell lines. Preliminary data from a mouse model of metastatic RCC also suggest antitumor effects and induction of apoptosis in vivo.

Antitumor effects of imidazoquinolines in urothelial cell carcinoma of the bladder.

PURPOSE: 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. MATERIALS AND 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.

Five-alpha-reductase expression in benign and malignant urothelium: correlation with disease characteristics and outcome.

OBJECTIVES: To evaluate 5-alpha-reductase (5alphaR) expression in benign and malignant urothelium and to assess the relationship between 5alphaR expression and tumor stage, tumor grade, and clinical outcome in patients with urothelial carcinoma/transitional cell carcinoma. METHODS: We performed immunohistochemistry for 5alphaR on 53 urothelial specimens from 36 patients with transitional cell carcinoma treated at our institution between June 2002 and July 2003. For each tumor and the adjacent nontumor urothelium, a semiquantitative staining score was calculated. We used t tests and analysis of variance to compare the staining score across groups. Kaplan-Meier and logistic regression analyses were performed to assess the relationship between 5alphaR expression and clinical outcome. RESULTS: 5alphaR was expressed throughout the non-neoplastic urothelium. Nontumor urothelium had greater mean staining scores than did tumor specimens (160.1 versus 105.5, P <0.01). Low staining scores were associated with high grade (P <0.05), Stage pT3, pT4, and pTis (P <0.05), and disease progression (P <0.05). A staining score less than the median was a risk factor for progression (odds ratio 6.2, P <0.01) on univariate regression analysis. Patients with a staining score less than the median had a greater likelihood of disease progression (log-rank P <0.05) and cause-specific mortality (log-rank P <0.05). CONCLUSIONS: We demonstrated 5alphaR expression in human urothelium and found that expression is decreased in transitional cell carcinoma in relation to tumor grade and stage. Decreased 5alphaR expression was associated with disease progression and cause-specific mortality.

Relation of cigarette smoking and alcohol use to colorectal adenomas by subsite: the self-defense forces health study.

While smoking has consistently been shown to be related to increased risk of colorectal adenomas, few studies have addressed the association between smoking and site-specific colorectal adenomas. The reported association between alcohol use and colorectal adenomas has been inconsistent. We evaluated risks of adenomas at the proximal colon, distal colon, and rectum in relation to cigarette smoking and alcohol use, and their interaction. Subjects were 754 cases with histologically proven colorectal adenomas and 1547 controls with normal colonoscopy among male officials of the Self-Defense Forces (SDF) undergoing total colonoscopy at two SDF hospitals. Statistical adjustment was made for hospital, rank, body mass index, physical activity, and either smoking or alcohol drinking. Cigarette smoking was significantly associated with an increased risk of adenomas, regardless of the location of the adenomas, but the increased risk associated with smoking was more pronounced for rectal adenomas. Alcohol use was associated with moderately increased risks of distal colon and rectal adenomas, but not of proximal colon adenomas. Cigarette smoking, but not alcohol drinking, was associated with greater increases in the risk of large adenomas and of multiple adenomas across the colorectum. There was no measurable interaction of cigarette smoking and alcohol drinking on colorectal adenomas. The findings corroborate an increased risk of colorectal adenomas associated with smoking and a weak association between alcohol use and colorectal adenomas. Further studies are needed to confirm whether smoking is more strongly related to rectal adenomas, large adenomas, or multiple adenomas.