Renal cell carcinoma (RCC), one of the most incurable malignancies, is highly resistant to chemotherapy and radiotherapy. Cytokine immunotherapy has been the standard approach, but the overall response rate is still very low. Administration of agonistic anti-4-1BB monoclonal antibody (mAb) has been shown to induce regression of several animal tumors but its effect on RCC is unknown. We show here that monotherapy with either anti-4-1BB mAb or the cytotoxic drug, 5-fluorouracil (5-FU), has little effect on established RCC, Renca tumors, but combination therapy with anti-4-1BB mAb and 5-FU eradicates the tumors in more than 70 % of mice. The regressing tumor tissues from mice receiving the combination therapy contained more apoptotic tumor cells and tumor infiltrating lymphocytes than tumor tissues from mice receiving 5-FU or anti-4-1BB mAb monotherapy. The number of lymphocytes in the spleens and tumor-draining lymph nodes (TDLNs) of the combination therapy mice was greatly increased compared to that of control or 5-FU monotherapy mice. Mice that had recovered due to the combination therapy rapidly rejected rechallenge with the tumor, pointing to the establishment of long-lasting tumor-specific memory. Our results indicate that targeting tumors with 5-FU, and immune cells with 4-1BB stimulation, could be a useful strategy for treating incurable RCC. ' 2008 Wiley-Liss, Inc.Key words: 5-FU; anti-4-1BB mAb; combined therapy; renal cell carcinoma Renal cell carcinoma (RCC) is highly metastatic and generally resistant to radiotherapy, chemotherapy and other systemic therapies. For example, 5-FU and related compounds produce an objective response rate of only 5%. Cytokine immunotherapy using interferon-a or IL-2 gives better responses and has now become the mainstay systemic treatment for RCC. However, even cytokine immunotherapy is still limited by toxic side effects and low response rates (11-19%).

BackgroundThe hTERT (human telomerase reverse transcriptase) gene contains five variable number tandem repeats (VNTR) and previous studies have described polymorphisms for hTERT-VNTR2-2nd. We investigated how allelic variation in hTERT-VNTR2-2nd may affect susceptibility to prostate cancer.MethodsA case-control study was performed using DNA from 421 cancer-free male controls and 329 patients with prostate cancer. In addition, to determine whether the VNTR polymorphisms have a functional consequence, we examined the transcriptional levels of a reporter gene linked to these VNTRs and driven by the hTERT promoter in cell lines.ResultsThree new rare alleles were detected from this study, two of which were identified only in cancer subjects. A statistically significant association between rare hTERT-VNTR2-2nd alleles and risk of prostate cancer was observed [OR, 5.17; 95% confidence interval (CI), 1.09-24.43; P = 0.021]. Furthermore, the results indicated that these VNTRs inserted in the enhancer region could influence the expression of hTERT in prostate cancer cell lines.ConclusionsThis is the first study to report that rare hTERT VNTRs are associated with prostate cancer predisposition and that the VNTRs can induce enhanced levels of hTERT promoter activity in prostate cancer cell lines. Thus, the hTERT-VNTR2-2nd locus may function as a modifier of prostate cancer risk by affecting gene expression.

No abstract