Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We followed our initial genome-wide association study (GWAS) of 527,869 SNPs on 1,172 individuals with prostate cancer and 1,157 controls of European origin-nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial prospective study-by testing 26,958 SNPs in four independent studies (total of 3,941 cases and 3,964 controls). In the combined joint analysis, we confirmed three previously reported loci (two independent SNPs at 8q24 and one in HNF1B (formerly known as TCF2 on 17q); P < 10(-10)). In addition, loci on chromosomes 7, 10 (two loci) and 11 were highly significant (between P < 7.31 x 10(-13) and P < 2.14 x 10(-6)). Loci on chromosome 10 include MSMB, which encodes beta-microseminoprotein, a primary constituent of semen and a proposed prostate cancer biomarker, and CTBP2, a gene with antiapoptotic activity; the locus on chromosome 7 is at JAZF1, a transcriptional repressor that is fused by chromosome translocation to SUZ12 in endometrial cancer. Of the nine loci that showed highly suggestive associations (P < 2.5 x 10(-5)), four best fit a recessive model and included candidate susceptibility genes: CPNE3, IL16 and CDH13. Our findings point to multiple loci with moderate effects associated with susceptibility to prostate cancer that, taken together, in the future may predict high risk in select individuals.
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PMID:Multiple loci identified in a genome-wide association study of prostate cancer. 1826 96

The discovery of hypothalamic hormones was briefly reviewed. The development of new hormonal methods for the therapy of various cancers based on analogues of hypothalmic hormones is then presented. My group isolated luteininzing hormone-releasing hormone (LH-RH), also known as Gn-RH, from pig hypothalmi, elucidated its amino acid sequence, and synthesized it in 1971. The interest in medical applications of LH-RH led to the synthesis of LH-RH analogues by various groups. LH-RH agonists substituted in positions 6 or 10 including Decapeptyl, Leuprolide and Zoladex are much more active than LH-RH and on continuous administration produce inhibition of pituitary and gonads. Chronic administration of LH-RH agonists is being utilized for the treatment of prostate and breast cancer. Octapeptide analogues of somatostatin have various applications in Oncology. In 1980 we developed a new endocrine therapy for advanced prostate cancer based on agonists of LH-RH, which is now preferred by 70-90% of prostate cancer patients for primary treatment. LH-RH antagonists such as Cetrorelix can be used for therapy of BPH. On the basis of the presence of specific receptors for hypothalamic peptides on human cancers, we developed targeted cytotoxic analogues of LH-RH, somatostatin, and bombesin/GRP linked to doxorubicin or 2-pyrrolinodoxorubicin. These analogues inhibit the growth of experimental human prostate, breast, ovarian and endometrial cancer, renal cell carcinoma, pancreatic, colorectal and gastric cancers, small cell lung carcinoma (SCLC) and non-SCLC, brain tumors, melanomas, and lymphomas. Cytotoxic LH-RH analogues are now in clinical trials. Recently we demonstrated that growth hormone-releasing hormone (GH-RH) also serves as an autocrine growth factor in many cancers. Antagonistic analogues of GH-RH synthesized in our laboratory inhibit the growth of diverse tumors. The discovery of LH-RH and somatostatin has led to clinical use of their analogues in the field of cancer treatment and GH-RH antagonists also show a great promise.
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PMID:New approaches to the therapy of various tumors based on peptide analogues. 1849 Dec 50

AKR1C3 (also known as 17beta-hydroxysteroid dehydrogenase type 5 or 3alpha-hydroxysteroid dehydrogenase type 2) functions as a 3-keto, 17-keto and 20-ketosteroid reductase and as a 3alpha-, 17beta- and 20alpha-hydroxysteroid oxidase. Relatively high mRNA expression of AKR1C3 was found in human prostate and mammary gland where it is implicated in regulating ligand access to the androgen and estrogen receptor, respectively. AKR1C3 is an interesting target for the development of agents for treating hormone-dependent forms of cancer like prostate cancer, breast cancer, and endometrial cancer. However, only a few clinically promising and selective inhibitors have been reported so far. Very potent inhibitors of AKR1C3 are the non-steroidal anti-inflammatory drugs, e.g. indomethacin or flufenamic acid. Also dietary phytoestrogens such as coumestrol, quercetin, and biochanin were reported to inhibit the enzyme in low micromolar concentrations. In this study, some dietary flavonoids and other phenolic compounds were tested for their ability to specifically inhibit AKR1C3. Carbonyl reduction of the anticancer drug oracin, which is a very good substrate for AKR1C3 and which could be well monitored by a sensitive HPLC system with fluorescence detection, was employed to determine the inhibitory potency of the compounds. Our results reveal that AKR1C3 could be potentially un-competitively inhibited by 2'-hydroxyflavanone, whose IC(50) value of 300nM is clinically promising. Moreover, since the inhibition is selective towards AKR1C3, 2'-hydroxyflavanone could be useful for treating or preventing hormone-dependent malignancies like prostate and breast cancer.
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PMID:AKR1C3 as a potential target for the inhibitory effect of dietary flavonoids. 1900 64

Selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene can act as estrogen receptor (ER) antagonists or agonists depending on the cell type. The antagonistic action of tamoxifen has been invaluable for treating breast cancer, whereas the agonist activity of SERMs also has important clinical applications as demonstrated by the use of raloxifene for osteoporosis. Whereas the mechanism whereby SERMs function as antagonists has been studied extensively very little is known about how SERMs produce agonist effects in different tissues with the two ER types; ERalpha and ERbeta. We examined the regulation of 32 SERM-responsive regions with ERalpha and ERbeta in transiently transfected MCF-7 breast, Ishikawa endometrial, HeLa cervical and WAR-5 prostate cancer cells. The regions were regulated by tamoxifen and raloxifene in some cell types, but not in all cell lines. Tamoxifen activated similar number of regions with ERalpha and ERbeta in the cell lines, whereas raloxifene activated over twice as many regions with ERbeta compared to ERalpha. In Ishikawa endometrial cancer cells, tamoxifen activated 17 regions with ERalpha, whereas raloxifene activated only 2 regions, which might explain their different effects on the endometrium. Microarray studies also found that raloxifene regulated fewer genes than tamoxifen in U2OS bone cancer cells expressing ERalpha, whereas tamoxifen was equally effective at regulating genes with ERalpha and ERbeta. Our studies indicate that tamoxifen is a non-selective agonist, whereas raloxifene is a relative ERbeta-selective agonist, and suggest that ERbeta-selective SERMs might be safer for treating clinical conditions that are dependent on the agonist property of SERMs.
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PMID:Cell type- and estrogen receptor-subtype specific regulation of selective estrogen receptor modulator regulatory elements. 1905 7

Steroid sulfatase (STS) regulates the hydrolysis of steroid sulfates to their unconjugated forms. Estrone sulfate and dehydroepiandrosterone sulfate can be hydrolyzed by STS to estrone and dehydroepiandrosterone, respectively, with these steroids being the precursors for the synthesis of more biologically active estrogens or androgens. A number of potent STS inhibitors have now been developed including STX64, which entered a phase I trial for the treatment of postmenopausal women with advanced metastatic hormone-dependent breast cancer. The results from this phase I trial were encouraging, suggesting that STS inhibitors may also have a role in the treatment of other hormone-dependent cancers including those of the endometrium, ovary, and prostate. In this paper the potential use of STS inhibitors to treat these hormone-dependent cancers is reviewed. In addition, results from in vitro studies show that Ishikawa endometrial cancer cells, OVCAR-3 ovarian cancer cells, and LNCaP prostate cancer cells all possess significant STS activity. Furthermore, STS activity in these cells can be almost completely inhibited by STX64 or the second-generation STS inhibitor, STX213. Results from these investigations therefore suggest that STS inhibitors could have therapeutic potential for the treatment of a range of hormone-dependent cancers.
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PMID:The development of steroid sulfatase inhibitors for hormone-dependent cancer therapy. 1925 Jan 95

In addition to cancer of the lower female genital tract, human papillomaviruses (HPV) are associated with a large number of benign, precancer and cancer lesions at different anatomic sites in both genders. Malignant tumours and their precursors are usually attributed to the oncogenic (high-risk, HR) HPV types, whereas benign lesions (papillomas) are associated with the low-risk (LR) HPV types, most notably with HPV6 and HPV11. Until recently, the main interest in HPV research has been focused on HR-HPV types and their associated pathology, and much less attention has been paid to the lesions caused by the LR-HPV types. With the recent licensing of an effective prophylactic vaccine against the 2 most important LR-HPV types (HPV6 and HPV11), it has become timely to make a systematic survey on the annual disease burden due to these 2 HPV genotypes in our country. These types of data should form the foundation for all calculations of the annual costs needed to treat these diseases by conventional means. Accurate estimates of disease burden are also mandatory for all modelling of the cost-effectiveness of prophylactic HPV6 and HPV11 vaccines. If proven useful for any of these purposes, this document will have fulfilled its purpose. In the first step, published HPV literature was used to create a list of benign, premalignant and malignant lesions associated with this virus at different anatomic sites. GLOBOCAN 2004 (IARC) database was used to derive the global numbers of incident cases for each of these malignancies in 2002, and the Finnish Cancer Registry (FCR) website for obtaining these (y 2005) numbers in Finland. The evidence linking HPV to each individual tumour category was classified as: 1) established, 2) emerging, and 3) controversial. All published evidence was weighted for each individual malignant, premalignant and benign lesion, anatomic region by region, while assessing the attributable fraction of HPV6/11 genotypes in each lesion. Because benign and most of the precancer lesions are not registered by FCR or GLOBOCAN, different approaches had to be used to derive the best estimates for their incidence, based on published literature or other registries (e.g. genital wart registry of the UK and Wales, and mass screening registry of FCR). With a lack of reasonable consensus, a lower and an upper limit was set for the range of estimates. In cases with different age-specific incidence (e.g. genital warts), the population pyramid of Finland was used to calculate the incident cases. Where well established, the different incidence rates among males and females were used to calculate the numbers of incident cases by gender. The malignant neoplasms with established or emerging evidence on the causal role of HPV are listed by their ICD-10 codes in Table I. Included in this list are also 2 controversial malignancies (colorectal cancer and endometrial cancer), of which the contradictory HPV data are critically discussed. The third major cancer in this same category (prostate cancer) was not included in the list, because the data are clearly insufficient to categorize this entity even among the emerging HPV associated malignancies. Estimated disease burden due to HPV6/11 in Finland, calculated as numbers of annual new cases by anatomic region and tumour type is given in Table II, and summarized in Figure 1. The present analysis implicates that a minimum of 12,666 to 13,066 new cases of HPV6- or HPV11-associated clinical lesions would be detected each y in Finland, if all were registered. Notably, these numbers represent the disease burden due to these 2 HPV types. However, these clinical lesions only represent a small minority of the total viral burden due to the infections by these 2 HPV genotypes. This is because the vast majority of all infections by these ubiquitous viruses are latent, being transient in nature and spontaneously resolving within a few months (up to 1 y), without ever developing a clinically detectable disease. This spontaneous clearance does not make these latent infections less important, however, because as long as the virus reservoir exists, it serves as the source of viral transmission to susceptible individuals, with a multitude of HPV6/11 associated pathologies as a potential outcome, as described in this document. The implications of these data in the era of effective prophylactic HPV vaccination against HPV6 and HPV11 should be clear.
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PMID:Annual disease burden due to human papillomavirus (HPV) 6 and 11 infections in Finland. 1940 60

PURPOSE Studies on quality of life (QOL) among women with endometrial cancer have shown that patients who undergo pelvic radiotherapy report lower role functioning and more diarrhea and fatigue. In the Post Operative Radiation Therapy in Endometrial Cancer (PORTEC) trial, patients with endometrial carcinoma were randomly assigned to receive external-beam radiotherapy (EBRT) or vaginal brachytherapy (VBT). QOL was evaluated by using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and subscales from the prostate cancer module, PR-25, and the ovarian cancer module, OV-28. PATIENTS AND METHODS PORTEC-2 accrued 427 patients between 2002 and 2006, of whom 214 were randomly assigned to EBRT, and 213 were randomly assigned to VBT. Three-hundred forty-eight patients (81%) were evaluable for QOL. QOL outcomes were analyzed at a median follow-up of 2 years. Results At baseline after surgery, patient functioning was at the lowest level, and it increased during and after radiotherapy to reach a plateau after 12 months. Patients in the VBT group reported better social functioning (P < .002) and lower symptom scores for diarrhea, fecal leakage, the need to stay close to the toilet, and limitation in daily activities because of bowel symptoms (P < .001). At baseline, 15% of patients were sexually active; this increased significantly to 39% during the first year (P < .001). Sexual functioning and symptoms did not differ between the treatment groups. CONCLUSION Patients who received EBRT reported significantly higher levels of diarrhea and bowel symptoms. This resulted in a higher need to remain close to a toilet and, as a consequence, more limitation of daily activities because of bowel symptoms and decreased social functioning. Vaginal brachytherapy provides a better QOL, and should be the preferred treatment from a QOL perspective.
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PMID:Quality of life after pelvic radiotherapy or vaginal brachytherapy for endometrial cancer: first results of the randomized PORTEC-2 trial. 1954 4

A clear relationship between diabetes and cancer has been demonstrated. An increased incidence of several cancers is observed in diabetic patients, notably pancreatic, hepatic, colo-rectal, breast, urinary tract and endometrial cancer. By contrast a decreased incidence of prostate cancer is observed in diabetes patients implying a protective effect. Multiple potential mechanisms have been proposed but they remain hypothetical.
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PMID:[Diabetes and cancer: an injurious association]. 2061 54

Ridaforolimus (AP23573; MK 8669) is an analog of sirolimus and a small molecule inhibitor of the mammalian target of rapamycin for the treatment of cancer. Both intravenous and oral formulations of the compound are being tested in clinical trials for the treatment of soft-tissue and bone sarcomas. It is in phase III development for sarcoma in the EU and US, and phase II for breast cancer, endometrial cancer, non-small cell lung cancer, and prostate cancer in the US and other markets in the world. This review discusses the key development milestones and therapeutic trials of this drug.
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PMID:Ridaforolimus. 2094 47

Specific receptors for luteinizing hormone-releasing hormone (LH-RH), somatostatin, bombesin, and other peptides are found on various cancers. We review the development of cytotoxic analogs of LH-RH, somatostatin, and bombesin/gastrin releasing peptide (GRP) designed for targeting chemotherapy to peptide receptors on various cancers. Cytotoxic analogs of LH-RH, AN-152 and AN-207, containing doxorubicin (DOX) or 2-pyrrolino-DOX (AN-201), respectively, target LH-RH receptors and may be used for the treatment of prostatic and urinary bladder (urothelial), breast, ovarian and endometrial cancers, non-Hodgkin's lymphomas, melanomas, and renal cell carcinomas. DOX and AN-201 have also been incorporated into the cytotoxic analogs of somatostatin, AN-162 and AN-238, respectively, which are targeted to receptors for somatostatin in prostatic, mammary, ovarian, gastric, renal, colorectal and pancreatic cancers, non-Hodgkin's lymphomas, as well as glioblastomas and lung cancers. They are found to suppress the growth of these tumors and their metastases. A cytotoxic analog of bombesin/GRP, AN-215, containing 2-pyrrolino-Dox, has also been synthesized and shown to inhibit growth of various human cancer lines expressing receptors for bombesin/GRP. The toxicity, pharmacokinetics and maximum tolerated doses of AN-152 were assessed in a phase I clinical trial in women with ovarian or endometrial cancer. Disease stabilization and objective responses were found. Analog AN-152 is now in phase II clinical trials. Phase I/II studies with AN-152 in men with hormone-independent relapsed prostate cancer and patients with pancreatic and bladder cancers are pending. Targeted cytotoxic peptide analogs could provide a more efficacious and less toxic therapy for various cancers.
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PMID:Use of analogs of peptide hormones conjugated to cytotoxic radicals for chemotherapy targeted to receptors on tumors. 2103 24


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