Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

At the present time, there is no reliable laboratory marker for the diagnosis and prognosis of clear cell renal cell carcinoma (RCC), while about 20% of small tumours detected by modern imaging techniques are benign and the clinical course is difficult to predict with considerable differences for the same stage and same grade. The molecular identification of clear cell RCC cells could satisfy these new requirements in the context of diagnosis of atypical or small renal tumours, allowing a more refined prognostic assessment, which is currently uncertain. Some of the antigens used for molecular diagnosis of clear cell RCC, such as cadherin-6, are present in the normal kidney, while others are newly formed antigens (TuM2PK, MN/CA9, CA12, calpain) or ectopic (PSMA, PSA, KLKI, cytokeratin 7 vimentin) or induce abnormal glycosylation (sialyl Lewis'X, galectins) indicating the malignant nature of the cells. The tumour's capacity for progression is related to dysregulations of the cycle (ras, Pax2, Tiam 1, waf/p21), division (tetracyclines, MIB1, PCNA, Nor Ag), apoptosis (bcl2, p53, CD95/Apo1), and the capacities for tissue invasion (proteases), disorganization (cadherin, catenins) or nidation (ICAM-1, CD44). Finally, chromosomal anomalies (mutations, translocations) also occur. MN/CA9, cadherin-6, vimentin, mucin 1 and DNA content are particularly useful for the diagnosis and/or prognosis of clear cell RCC. These markers can be analysed by extremely sensitive cytometric (flow cytometry, plate cytometry) or molecular methods (RT-PCR, in situ hybridization). These techniques lower the limit of detection of tumour cells in biological products (aspiration cytology, microbiopsy) and eventually in circulating blood. Proteomic and genomic methods (biochips) should considerably accelerate research in this field leading to the development of routine clinical applications.
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PMID:[Molecular and cytometric analysis of renal cell carcinoma cells. Concepts, techniques and prospects]. 1270 48

Radical prostatectomy as a primary treatment for clinically localized prostate cancer has increased dramatically over the past decade due to prostate-specific antigen (PSA) screening and the awareness of the increased incidence of localized disease. Despite the stage migration to increase clinically localized disease, there are still vast numbers of men who harbor occult extraprostatic extension and develop recurrence after surgery. The study of molecular markers in the blood or tissue of surgical patients prior to treatment, called " molecular staging, " is the focus of this review. The reverse transcriptase- polymerase chain reaction (RT-PCR) test for PSA gene expression in peripheral blood or bone marrow has received considerable attention since its first report in 1992. The test detects messenger RNA species for prostate-specific/abundant genes such as PSA and prostate-specific membrane antigen. These messenger RNAs were not detected in normal blood or bone marrow, but were detected in some prostate cancer patients presumably due to circulating prostatic epithelial cells. These prostate epithelial cells are thought to be occult metastases cells, and early studies correlated a positive RT-PCR test with surgical pathology adverse features such as positive margins. Despite the many studies over the past few years, there have been inconsistent results, and the most recent studies have not been able to confirm clinical utility. Bone marrow RT-PCR has been more promising; however, it is still a research tool that needs further study. The study of molecular markers in tissue material, ie, prostate biopsy samples prior to radical prostatectomy, is problematic due to the sampling error inherent in a multifocal heterogeneous tumor such as prostate cancer. The tumor suppressor proteins p53 and p27, Bcl-2 oncoprotein, Ki-67 proliferation index protein, E-cadherin, and microvessel density have been assessed in preradical prostatectomy needle biopsy. Results have been conflicting, and none are yet accepted as a clinically useful marker. Current and future work is focusing on analysis of multiple gene expressions or proteins simultaneously via gene chip or proteomics technology. While these expression profiles might be of value in whole prostate surgical specimens where tissues are well characterized, it is unclear how this new technology will be applied to the needle biopsy samples. Although molecular staging of radical prostatectomy patients has been under study for a decade, all assays remain research tools. Still, this area holds great promise for improving the accuracy of staging and providing a more accurate prognosis of individual men with clinically localized prostate cancer.
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PMID:Molecular markers in prostate cancer: the role in preoperative staging. 1504 12

The phosphoinositide 3-kinase (PI3K) pathway is activated in most advanced prostate cancers, yet so far treatments with PI3K inhibitors have been at best tumorostatic in preclinical cancer models and do not show significant antitumor efficacy in clinical trials. Results from tissue culture experiments in prostate cancer cells suggest that PI3K inhibitors should be combined with other cytotoxic agents; however, the general toxicity of such combinations prevents translating these experimental data into preclinical and clinical models. We investigated the emerging concept of tumor-targeted synthetic lethality in prostate cancer cells by using the pan-PI3K inhibitor ZSTK474 and the immunotoxin J591PE, a protein chimera between the single-chain variable fragment of the monoclonal antibody J591 against the prostate-specific membrane antigen (PSMA) and the truncated form of the Pseudomonas aeruginosa exotoxin A (PE38QQR). The combination of ZSTK474 and J591PE increased apoptosis within 6 hours and cell death (monitored at 24-48 hours) in the PSMA-expressing cells LNCaP, C4-2, and C4-2Luc but not in control cells that do not express PSMA (PC3 and BT549 cells). Mechanistic analysis suggested that induction of apoptosis requires Bcl-2-associated death promoter (BAD) dephosphorylation and decreased expression of myeloid leukemia cell differentiation protein 1 (MCL-1). A single injection of ZSTK474 and J591PE into engrafted prostate cancer C4-2Luc cells led to consistent and stable reduction of luminescence within 6 days. These results suggest that the combination of a PI3K inhibitor and a PSMA-targeted protein synthesis inhibitor toxin represents a promising novel strategy for advanced prostate cancer therapy that should be further investigated.
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PMID:Combination of the PI3K inhibitor ZSTK474 with a PSMA-targeted immunotoxin accelerates apoptosis and regression of prostate cancer. 2420 96

In many tumors, including prostate cancer, anti-apoptotic members of the Bcl-2 family are overexpressed and cause cell death resistance, which is a typical hallmark of cancer. Different therapeutic approaches, therefore, aim to restore the death mechanisms for enhanced apoptosis. Our recombinant immunotoxin D7(VL-VH)-PE40 is composed of the scFv D7(VL-VH) against the prostate-specific membrane antigen (PSMA) on the surface of prostate cancer cells and of the cytotoxic domain of the bacterial toxin Pseudomonas Exotoxin A (PE40). Since Pseudomonas Exotoxin A-based immunotoxins are known to preferentially inhibit the expression of the anti-apoptotic protein Mcl-1, the rationale was to test our immunotoxin in combination with the BH3 mimetic ABT-737, which specifically inhibits Bcl-2, Bcl-xl, and Bcl-w for enhanced induction of apoptosis in prostate cancer cells. The immunotoxin showed high and specific binding and cytotoxicity against PSMA expressing prostate cancer cells marked by a direct inhibition of Mcl-1. The combination of the immunotoxin with a subtoxic concentration of ABT-737 caused additive or even synergistic effects, which were based on an enhanced apoptosis induction as detected by poly(ADP-ribose) polymerase (PARP) and Caspase-3 cleavage in Western blot. Our study shows that the combination therapy of immunotoxin plus ABT-737 is a promising approach for the future treatment of advanced prostate cancer to improve therapeutic efficacy and to reduce adverse side effects.
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PMID:Synergistic cytotoxicity of a prostate cancer-specific immunotoxin in combination with the BH3 mimetic ABT-737. 2918 5