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)

The human aldo-keto reductase 1C (AKR1C) isozymes are implicated in the pre-receptor regulation of steroid receptors, nuclear orphan receptors and membrane-bound ligand-gated ion channels. Human AKR members that may regulate the local concentration of steroid hormones include: AKR1C1, AKR1C2, AKR1C3, AKR1C4 and AKR1D1. Since, these enzymes are pluripotent, the physiological role for the human AKR1C isozymes is determined by their tissue-specific expression patterns and their substrate availability in target tissues. AKRs work in concert with short-chain dehydrogenases/reductases as switches to control ligand access to nuclear receptors. Consequently, they are potential targets in treating prostate cancer, breast cancer, endometriosis and endometrial cancer.
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PMID:The roles of aldo-keto reductases in steroid hormone action. 1564 14

The available monolayer culture systems for the study of bone metastases constitute a suboptimal simulation of the in vivo pathophysiology of bone metastases, and therefore, do not provide sufficient information to assess the morphologic evidence of bone reaction to cancer cells, the nature of cell-specific mediators of osteolysis and osteoplasia and the response to treatment. Therefore, we have developed a three-dimensional (3-D) type I collagen gel system that allows co-culture of human osteoblasts (MG-63) with cancer cells, such as MCF-7, MDA-MB-231 or ZR-75 breast cancer cells, PC-3 prostate cancer, KLE endometrial cancer cells and Calu-1 lung cancer cells. We used type I collagen purified from rat tail tendons and the 3-D system was prepared by mixing MG-63 cells with type I collagen in 24-well plates. The 3-D system was inoculated with cancer cells and processed with standard cell culture procedures. After 1 week of culture, the matrix gel was fixed with formalin and embedded in paraffin. Serial sections were stained with trichrome Masson stain and modified Masson-Goldner stain, as well as analyzed by in situ hybridization, immunohistochemistry and the TUNEL technique for semi-quantitative detection of apoptotic cell death, assessing the response to adriamycin therapy. The inoculation of PC-3 cells in this collagen matrix produced a blastic reaction, documented by an increased number of MG-63 cells and increased density of type I collagen. The human KLE cells and inoculation of cell-free media produced no reaction, while ZR-75, MCF-7 and Calu-1 cells produced local degradation of the collagen matrix. In situ hybridization revealed the expression of Insulin-like growth factor 1 (IGF-1) and urokinase-type plasminogen activator (uPA) mRNA, while immunohistochemistry detected differential expression of uPA and cathepsin D. Adriamycin induced apoptotic cell death in prostate cancer cells and estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells, while adriamycin did not induce apoptosis but cytostasis in ER+ MCF-7 cells. The adriamycin-induced apoptosis was inhibited by co-culture with osteoblast-like cells (MG-63). We conclude that this 3-D culture system is a useful in vitro model allowing the analysis of local mediators of osteolytic and osteoblastic reactions to bone metastases and treatment response.
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PMID:Three-dimensional type I collagen co-culture systems for the study of cell-cell interactions and treatment response in bone metastases. 1575 11

Granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim [Leukine]) is a powerful cytokine that is able to stimulate the generation of dendritic cells. Adjuvant treatment with continuous low-dose GM-CSF has been shown to prolong survival of stage III/IV melanoma patients. Data on continuous low-dose GM-CSF therapy in tumors other than prostate cancer are still lacking. This pilot trial was initiated in order to evaluate the efficacy and tolerability of continuous low-dose GM-CSF as salvage in various chemotherapy-refractory carcinomas. A total of 19 patients who had failed a median of 4 prior chemotherapies were included. Their malignancies included metastatic breast cancer, recurrent ovarian carcinoma, metastatic endometrial carcinoma, and recurrent squamous cell cancer of the cervix uteri. Continuous low-dose GM-CSF was delivered subcutaneously at a daily starting dose of 125 microg. GM-CSF was increased at 25-microg increments until a maximum of 250 microg was reached or when mild leukocytosis (10-20 g/L) was achieved, providing that the relative eosinophil count did not exceed 15%. Therapy was continued until progression or refusal by the patient. Toxicity was generally mild. Only one patient was withdrawn due to grade 3 fatigue. In three additional patients, temporary dose reduction was necessary because of grade 1 injection site reactions, which recovered spontaneously. Mild to moderate leukocytosis was obvious in 10 patients. Systemic hypersensitivity-like reactions did not occur and no patient required hospitalization for other life-threatening side effects. The objective response rate was 37%: 1 complete and 6 partial responses, 4 disease stabilizations, 8 progression of disease. Median response duration was 6 months. Notably, 6 of 7 responders but only 1 of 8 patients with disease progression developed leukocytosis during therapy. Therefore, we conclude that continuous low-dose GM-CSF has substantial activity in heavily pretreated patients with either metastatic breast cancer or female genital tract cancer. Achievement of mild leukocytosis seems to be a predictor of response.
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PMID:Continuous low-dose GM-CSF as salvage therapy in refractory recurrent breast or female genital tract carcinoma. 1593 97

Indole-3-carbinol (I3C) is produced by members of the family Cruciferae, and particularly members of the genus Brassica (e.g., cabbage, radishes, cauliflower, broccoli, Brussels sprouts, and daikon). Under acidic conditions, 13C is converted to a series of oligomeric products (among which 3,3'-diindolylmethane is a major component) thought to be responsible for its biological effects in vivo. In vitro, 13C has been shown to suppress the proliferation of various tumor cells including breast cancer, prostate cancer, endometrial cancer, colon cancer, and leukemic cells; induce G1/S arrest of the cell cycle, and induce apoptosis. The cell cycle arrest involves downregulation of cyclin D1, cyclin E, cyclin- dependent kinase (CDK)2, CDK4, and CDK6 and upregulation of p15, p21, and p27. Apoptosis by I3C involves downregulation antiapoptotic gene products, including Bcl-2, Bcl-xL, survivin, inhibitor-of-apoptosis protein (IAP), X chromosome-linked IAP (XIAP), and Fas-associated death domain protein-like interleukin-1-beta-converting enzyme inhibitory protein (FLIP); upregulation of proapoptotic protein Bax; release of micochondrial cytochrome C; and activation of caspase-9 and caspase-3. This agent inhibits the activation of various transcription factors including nuclear factor-kappaB, SP1, estrogen receptor, androgen receptor and nuclear factor-E2-related factor 2 (Nrf2). This indole potentiates the effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) through induction of death receptors and synergises with chemotherapeutic agents through downregulation of P-glycoprotein (P-gp). In vivo, I3C was found to be a potent chemopreventive agent for hormonal-dependent cancers such as breast and cervical cancer. These effects are mediated through its ability to induce apoptosis, inhibit DNA-carcinogen adduct formation, and suppress free-radical production, stimulate 2-hydroxylation of estradiol, inhibit invasion and angiogenesis. Numerous studies have indicated that I3C also has a strong hepatoprotective activity against various carcinogens. Initial clinical trials in women have shown that I3C is a promising agent against breast and cervical cancers.
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PMID:Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. 1608 11

In this study, we have assessed whether referral for primary radiotherapy varied according to hospital size in a region with 1 million inhabitants served by community hospitals. We studied 20178 patients diagnosed with breast, non-small cell lung, prostate, rectal, or endometrial cancer between 1988 and 1999. We used logistic regression analysis, adjusted for age, stage and period of diagnosis. Medium-sized and small hospitals referred breast cancer patients more often (OR=2.2, 95%CI: 2.0-2.5, OR=1.2, 95%CI: 1.1-1.4, respectively), and patients with prostate cancer less often (OR=0.7 (0.5-0.8) and 0.7 (0.6-0.9), respectively). Referral rates for patients with non-small cell lung and rectal cancer showed minor differences according to hospital size, referral for endometrial cancer was somewhat higher for patients from medium-sized hospitals (OR=1.5 (1.0-2.1)). Time trends in variation were shown, but differences according to hospital size only decreased over time for rectal cancer. Despite multidisciplinary oncology meetings and treatment guidelines there were large variations in rates of referral for radiotherapy.
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PMID:Hospital variation in referral for primary radiotherapy in South Netherlands, 1988-1999. 1624 15

17Beta-hydroxysteroid dehydrogenase type 5 (AKR1C3) that is involved in the pre-receptor regulation of androgen and estrogen action in the human is an emerging therapeutic target in the treatment of hormone-dependent forms of cancer, such as prostate cancer, breast cancer and endometrial cancer. To discover novel inhibitors, we tested the effect of a series of cinnamic acids on the reductive activity of the human recombinant AKR1C3. The compounds were evaluated in a spectrophotometric assay using 9,10-phenanthrenequinone as a substrate. The best inhibitor in the series was alpha-methylcinnamic acid (IC50=6.4 microM). Also, unsubstituted cinnamic acid was a good inhibitor of AKR1C3 (IC50=50 microM). Small hydrophobic substituents of the phenyl ring did not alter the activity; however, substitution with polar groups decreased the potency of inhibition. The most active compounds in this series represent promising starting points for further structural modifications in the search for more potent inhibitors of AKR1C3.
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PMID:Cinnamic acids as new inhibitors of 17beta-hydroxysteroid dehydrogenase type 5 (AKR1C3). 1633 32

Two large-scale, phase III cancer prevention trials, the Breast Cancer Prevention Trial (BCPT) of tamoxifen and Prostate Cancer Prevention Trial (PCPT) of finasteride, concluded with strikingly positive and simultaneously problematic results: reduced cancer risks but a major adverse finding with each agent that prevented its widespread use in the community. For most moderate-risk people, such as those studied in the BCPT and PCPT, the benefit of reduced breast or prostate cancer does not outweigh the major risk of tamoxifen (endometrial cancer in the BCPT) or apparent risk of finasteride (high-grade prostate cancer in the PCPT). Promising interventions with biologically active substances are likely to have adverse, perhaps unforeseen effects, especially with long-term preventive use. Acceptance of such agents will depend heavily on the level of cancer risk of the target population. This article outlines research in molecularly identified high-risk oral intraepithelial neoplasia that creates the clinical opportunity for optimizing the risk-benefit ratio of agents to prevent oral cancer. Two other major research efforts focused on improving preventive agent risk-benefit ratios are molecular-targeted research designed to target away from known adverse signaling pathways and multidisciplinary research based on the PCPT that will develop comprehensive models of prostate cancer risk (especially of aggressive prostate cancer) and pharmacoecogenetic models for identifying high-risk men most likely to benefit from (and not be harmed by) finasteride or similar (5alpha-reductase inhibiting) agents. Defining and targeting high-risk populations, developing molecular-targeted approaches, and developing accurate pharmacoecogenetic models promise to reduce the risk of chemoprevention and ultimately to reduce the risk and burden of major cancers.
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PMID:Reducing the "risk" of chemoprevention: defining and targeting high risk--2005 AACR Cancer Research and Prevention Foundation Award Lecture. 1654 Jun 34

In 1998, the concept of breast cancer prevention became a reality with the approval of tamoxifen to reduce the risk of developing breast cancer in women at increased risk for the disease. This approval was based on decades of research on selective estrogen receptor modulators providing an understanding of the role of the estrogen receptor in breast cell growth, and an appreciation of the carcinogenic process. Although results from the Breast Cancer Prevention Trial demonstrated a 49% reduction in breast cancer in women at increased risk, there were associated toxicities related to the estrogenic effects of tamoxifen; that is, deep vein thrombosis, pulmonary embolism, and endometrial cancer. In an effort to improve its benefit-risk profile, tamoxifen is now being compared with raloxifene, a selective estrogen receptor modulator approved for the treatment and prevention of osteoporosis. This equivalency prevention Study of Tamoxifen and Raloxifene completed accrual of 19 747 high-risk postmenopausal women in November 2004. Meanwhile, another class of estrogen-directed drugs, the aromatase inhibitors, have shown efficacy in breast cancer adjuvant trials, spawning a number of prevention trials that have recently been initiated. As with breast cancer the hormonal contribution to prostate carcinogenesis was the basis for the Prostate Cancer Prevention Trial which showed that finasteride, an androgen antagonist, reduces the incidence of prostate cancer compared to placebo.
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PMID:Hormonal interventions to prevent hormonal cancers: breast and prostate cancers. 1741 94

In the present study, self-reported health care utilization of cancer survivors is compared with those of an age- and gender-matched normative population and predictors of health care utilization are identified. A population-based, cross-sectional survey among 1893 long-term survivors of endometrial and prostate cancer and malignant lymphomas (Hodgkin's and non-Hodgkin's) diagnosed between 1989 and 1998 was conducted using the cancer registry of the Comprehensive Cancer Centre South. Cancer survivors visited their general practitioner somewhat more often compared to the age and gender-matched general Dutch population but this effect was not always statistically significant. In addition, they visited their medical specialist significantly more often. Survivors only sporadically (0-3%) visited or required a dietician, sexologist, oncology nurse, pastor, creative therapy or recovery program. Contact with a psychologist, physiotherapist and other cancer survivors took place somewhat more often. Patients visited a medical specialist less often if they were diagnosed with endometrial cancer (OR = 0.2; 95% CI = 0.1-0.5), if they were diagnosed between 10-15 years ago (OR = 0.6; 95% CI = 0.1-0.5) and if they were not married or divorced (OR = 0.5; 95% CI = 0.3-0.9). Contact with a psychologist was related to having a university or college degree (OR = 3.6; 95% CI = 1.3-9.4). Cancer survivors visited their specialist more often compared to the normative population. Changes in health care, such as less administrative work for the specialist and more efficiency, are probably necessary in order to cope adequately with the increasing demand on the system.
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PMID:Increased health care utilization among long-term cancer survivors compared to the average Dutch population: a population-based study. 1741 82

Breast cancer is a hormone-dependent cancer like prostate cancer and endometrial cancer. Estrogen plays important roles in the development and progression of breast cancer. Endocrine therapy is the treatment of choice for estrogen receptor- and/or progesterone receptor-positive breast cancer. Endocrine therapy has been used for several purposes, including chemoprevention, preoperative treatment, postoperative adjuvant treatment and treatment for recurrent diseases. A large number of clinical trials have provided evidence showing the clinical benefits of various endocrine therapies for the treatment of breast cancer. The current status and recent advances in endocrine therapy for breast cancer are reviewed based on the results of current clinical trials. Future perspectives of endocrine therapy are also discussed.
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PMID:Current clinical trials of endocrine therapy for breast cancer. 1748 7


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