Prima-1 induces apoptosis in bladder cancer cell lines by activating p53

OBJECTIVES: Bladder cancer represents 3% of all carcinomas in the Brazilian population and ranks second in incidence among urological tumors, after prostate cancer. The loss of p53 function is the main genetic alteration related to the development of high-grade muscle-invasive disease. Prima-1 is a small molecule that restores tumor suppressor function to mutant p53 and induces cancer cell death in various cancer types. Our aim was to investigate the ability of Prima-1 to induce apoptosis after DNA damage in bladder cancer cell lines. METHOD: The therapeutic effect of Prima-1 was studied in two bladder cancer cell lines: T24, which is characterized by a p53 mutation, and RT4, which is the wild-type for the p53 gene. Morphological features of apoptosis induced by p53, including mitochondrial membrane potential changes and the expression of thirteen genes involved in apoptosis, were assessed by microscopic observation and quantitative real-time PCR (qRT-PCR). RESULTS: Prima-1 was able to reactivate p53 function in the T24 (p53 mt) bladder cancer cell line and promote apoptosis via the induction of Bax and Puma expression, activation of the caspase cascade and disruption of the mitochondrial membrane in a BAK-independent manner. CONCLUSION: Prima-1 is able to restore the transcriptional activity of p53. Experimental studies in vivo may be conducted to test this molecule as a new therapeutic agent for urothelial carcinomas of the bladder, which characteristically harbor p53 mutations

Diagnostic accuracy of tumor markers for hepatocellular carcinoma: a systematic review

Background and aims The role of alphafetoprotein (AFP) in the diagnosis and surveillance of hepatocellular carcinoma (HCC) is getting smaller owing to the advances in imaging modalities. The aims of this study were to assess the diagnostic accuracy of tumor markers in small HCC and to find the optimal cutoff value of each tumor marker for efficient surveillance. Methods Studies in all languages were identified by searching MEDLINE from 1982 to 2002. Studies were included when they showed sensitivity and specificity for HCCs 5 cm or smaller and recruited only patients with chronic hepatitis or liver cirrhosis as control. We assessed diagnostic odds ratios (DORs) for the evaluation of diagnostic accuracy of tumor markers and positive likelihood ratios (LRs+) to find the optimal cutoff value. DORs and LRs+ were combined according to the random effect model. The summary receiver operating characteristics (ROC) curve was also assessed. Results Seventeen articles on three tumor markers—AFP, des-gamma-carboxyprothrombin (DCP), and Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3)—were enrolled after full-text evaluation. AFP was inferior to DCP and AFP-L3 in both DOR (4.50 vs. 8.16 and 10.50) and area under the ROC curve (0.647 vs. 0.688 and 0.695). Optimal cutoff values that provide the best LR+ were 200 ng/ml for AFP, 40 mAU/ml for DCP, and 15% for AFP-L3. Conclusions Diagnostic accuracy of AFP in small HCC was substantially limited. Surveillance including other tumor markers with optimal cutoff value should be conducted to confirm the efficacy of the policy