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)

Estimates of the gain in survival, if all local failures were eliminated, indicate that many more patients could be cured provided the efficacy of treatment of the primary and regional disease were substantially improved. The expected gain in survival is assumed to be the gain in local control, less the loss due to distant metastases and intercurrent disease among the new local control subjects. The observed incidence of DM among local failure patients may be higher than among local control patients; this excess in incidence of DM is assumed to result from metastases established secondary to the persistent or recurring tumor. A powerful argument that higher local control rates would result in more cured patients is the high incidence of long-term survivors after salvage surgery for local failures. Examples of higher survival associated with more effective local therapy are presented from the literature for medulloblastoma, ependymoma, carcinoma of the oral cavity-oropharynx, carcinoma of the urinary bladder, carcinoma of the prostate and carcinoma of the rectum. For Stage I-II cancer of the breast, the reduction of an already low local failure rate by combining surgery and radiation has a very small impact. For tumors, such as, early stage breast cancer, where the possible decrease in local failure is small and the loss due to DM is high, a demonstrable gain in survival is not likely. The potential increase in number of survivors among the U.S. cancer population, if the primary-regional disease were regularly treated successfully, indicates large gains for patients with cancer of the uterine cervix, oral cavity-oropharynx, ovary, colo-rectum, non-oat cell cancer of lung, prostate cancer, and bladder cancer. These provide powerful bases for aggressive investigation of new approaches to improvement of local-regional therapies.
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PMID:Impact of improved local control on survival. 351 48

Since its discovery as a protein associated with the cytoplasmic region of E-cadherin, beta-catenin has been shown to perform two apparently unrelated functions: it has a crucial role in cell-cell adhesion in addition to a signaling role as a component of the Wnt/wg pathway. Wnt/wg signaling results in beta-catenin accumulation and transcriptional activation of specific target genes during development. It is now apparent that deregulation of beta-catenin signaling is an important event in the genesis of a number of malignancies, such as colon cancer, melanoma, hepatocellular carcinoma, ovarian cancer, endometrial cancer, medulloblastoma pilomatricomas, and prostate cancer. beta-catenin mutations appear to be a crucial step in the progression of a subset of these cancers, suggesting an important role in the control of cellular proliferation or cell death. The APC/beta-catenin pathway is highly regulated and includes players such as GSK3-beta, CBP, Groucho, Axin, Conductin, and TCF. c-MYC and cyclin D1 were recently identified as a key transcriptional targets of this pathway and additional targets are likely to emerge. Published 1999 John Wiley & Sons, Inc.
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PMID:beta-catenin signaling and cancer. 1058 Sep 87

In the application of pixel-based intensity-modulated radiation therapy (IMRT) using the step-and-shoot delivery method, one major difficulty is the prolonged delivery time. In this study, we present an integrated IMRT planning system that involves a simple smoothing method to reduce the complexity of the beam profiles. The system consists of three main steps: (a) an inverse planning process based on a least-square dose-based cost function; (b) smoothing of the intensity maps; (c) reoptimization of the segment weights. Step (a) obtains the best plan with the lowest cost value using a simulated annealing optimization algorithm with discrete intensity levels. Step (b) takes the intensity maps obtained from (a) and reduces the complexity of the maps by smoothing the adjacent beamlet intensities. During this process each beamlet is assigned a structure index based on anatomical information. A smoothing update is applied to average adjacent beamlets with the same index. To control the quality of the plan, a predefined clinical protocol is used as an acceptance criterion. The smoothing updates that violate the criterion are rejected. After the smoothing process, the segment weights are reoptimized in step (c) to further improve the plan quality. Three clinical cases were studied using this system: a medulloblastoma, a prostate cancer, and an oropharyngeal carcinoma. While the final plans demonstrate a degradation of the original plan quality, they still meet the plan acceptance criterion. On the other hand, the segment numbers or delivery times are reduced by 40%, 20%, and 20% for the three cases, respectively.
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PMID:A new smoothing procedure to reduce delivery segments for static MLC-based IMRT planning. 1519 5

Activation in transformed cells of normal stem cells' self-renewal pathways might contribute to the survival life cycle of cancer stem cells and promote tumor progression. The BMI-1 oncogene-driven gene expression pathway is essential for the self-renewal of hematopoietic and neural stem cells. We applied a mouse/human comparative translational genomics approach to identify an 11-gene signature that consistently displays a stem cell-resembling expression profile in distant metastatic lesions as revealed by the analysis of metastases and primary tumors from a transgenic mouse model of prostate cancer and cancer patients. To further validate these results, we examined the prognostic power of the 11-gene signature in several independent therapy-outcome sets of clinical samples obtained from 1,153 cancer patients diagnosed with 11 different types of cancer, including 5 epithelial malignancies (prostate, breast, lung, ovarian, and bladder cancers) and 5 nonepithelial malignancies (lymphoma, mesothelioma, medulloblastoma, glioma, and acute myeloid leukemia). Kaplan-Meier analysis demonstrated that a stem cell-like expression profile of the 11-gene signature in primary tumors is a consistent powerful predictor of a short interval to disease recurrence, distant metastasis, and death after therapy in cancer patients diagnosed with 11 distinct types of cancer. These data suggest the presence of a conserved BMI-1-driven pathway, which is similarly engaged in both normal stem cells and a highly malignant subset of human cancers diagnosed in a wide range of organs and uniformly exhibiting a marked propensity toward metastatic dissemination as well as a high probability of unfavorable therapy outcome.
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PMID:Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. 1593 83

During animal development, the Hedgehog (Hh) signal transduction pathway plays critical roles in cell fate determination and tissue patterning. In humans, aberrant Hh signaling has been linked to several genetic disorders and cancers. Binding of Hh to its receptor initiates a signaling cascade, which ultimately results in the activation of the Gli/Ci transcription factors. Suppressor of fused (Su(fu)) is a Gli/Ci-interacting protein, which acts as a negative regulator of Hh signaling in Drosophila and vertebrates. Su(fu) is also implicated as a tumor suppressor as its mutations have been found in medulloblastoma and prostate cancer. Su(fu) is thought to act by preventing the nuclear accumulation of Gli/Ci, however, mechanistic insight into its mode of action has remained elusive. We demonstrate here that Su(fu) prevents the nuclear accumulation of Gli1 and Gli2 through multiple mechanisms. While Su(fu) itself is not subject to CRM1-dependent regulation, Su(fu) sequesters Gli1 in the cytoplasm mostly through a mechanism that depends on the activity of the nuclear export protein CRM1. In contrast, CRM1-mediated export is not required for Su(fu) to sequester Gli2. Furthermore, we show that the N-terminus of Su(fu) is sufficient for Gli inactivation in the absence of cytoplasmic sequestration. Together, these observations reveal that Su(fu) regulates the activity of Gli1 and Gli2 through distinct cytoplasmic and nuclear mechanisms.
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PMID:Negative regulation of Gli1 and Gli2 activator function by Suppressor of fused through multiple mechanisms. 1631 10

In this paper, we will outline the current understanding of cell cycle modulation and induction of apoptosis in cancer cells by natural and synthetic bile acid. Bile acid homeostasis is tightly regulated in health, and their cellular and tissue concentrations are restricted. However, when pathophysiological processes impair their biliary secretion, hepatocytes are exposed to elevated concentrations of bile acids which trigger cell death. In this context, we developed several newly synthesized bile acid derivatives. These synthetic bile acids modulated the cell cycle and induced apoptosis in several human cancer cells similar to natural bile acids. In human breast and prostate cancer cells with different tumor suppressor p53 status, synthetic bile acid-induced growth inhibition and apoptosis were associated with up-regulation of Bax and p21(WAF1/CIP1) via a p53-independent pathway. In Jurkat human T cell leukemia cells, the synthetic bile acids induced apoptosis through caspase activation. In addition to this, the synthetic bile acids induced apoptosis in a JNK dependent manner in SiHa human cervical cancer cells, via induction of Bax and activation of caspases in PC3 prostate cancer cells and induction of G1 phase arrest in the cell cycle in HT29 colon cancer cells. Moreover, they induced apoptosis in four human glioblastoma multiform cell lines (i.e., U-118MG, U-87MG, T98G, and U-373MG) and one human TE671 medulloblastoma cells. In addition to this, a chenodeoxycholic acid derivative, called HS-1200, significantly decreased the growth of TE671 medulloblastoma tumor size and increased life span in non-obese diabetic and severe combined immunodeficient (NOD/SCID) mice. Therefore, these new synthetic bile acids, which are novel apoptosis mediators, might be applicable to the treatment of various human cancer cells.
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PMID:Modulation of the cell cycle and induction of apoptosis in human cancer cells by synthetic bile acids. 1716 73

The developmentally important Hedgehog (Hh) signaling pathway has recently been implicated in several forms of solid cancer. Current drug development programs focus on targeting the protooncogene Smoothened, a key transmembrane pathway member. These drug candidates, albeit promising, do not address the scenario in which pathway activation occurs downstream of Smoothened, as observed in cases of medulloblastoma, glioma, pericytoma, breast cancer, and prostate cancer. A cellular screen for small-molecule antagonists of GLI-mediated transcription, which constitutes the final step in the Hh pathway, revealed two molecules that are able to selectively inhibit GLI-mediated gene transactivation. We provide genetic evidence of downstream pathway blockade by these compounds and demonstrate the ineffectiveness of upstream antagonists such as cyclopamine in such situations. Mechanistically, both inhibitors act in the nucleus to block GLI function, and one of them interferes with GLI1 DNA binding in living cells. Importantly, the discovered compounds efficiently inhibited in vitro tumor cell proliferation in a GLI-dependent manner and successfully blocked cell growth in an in vivo xenograft model using human prostate cancer cells harboring downstream activation of the Hh pathway.
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PMID:Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. 1749 66

Toward the goal of developing an optical imaging contrast agent that will enable surgeons to intraoperatively distinguish cancer foci from adjacent normal tissue, we developed a chlorotoxin:Cy5.5 (CTX:Cy5.5) bioconjugate that emits near-IR fluorescent signal. The probe delineates malignant glioma, medulloblastoma, prostate cancer, intestinal cancer, and sarcoma from adjacent non-neoplastic tissue in mouse models. Metastatic cancer foci as small as a few hundred cells were detected in lymph channels. Specific binding to cancer cells is facilitated by matrix metalloproteinase-2 (MMP-2) as evidenced by reduction of CTX:Cy5.5 binding in vitro and in vivo by a pharmacologic blocker of MMP-2 and induction of CTX:Cy5.5 binding in MCF-7 cells following transfection with a plasmid encoding MMP-2. Mouse studies revealed that CTX:Cy5.5 has favorable biodistribution and toxicity profiles. These studies show that CTX:Cy5.5 has the potential to fundamentally improve intraoperative detection and resection of malignancies.
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PMID:Tumor paint: a chlorotoxin:Cy5.5 bioconjugate for intraoperative visualization of cancer foci. 1763 99

The Francis H. Burr Proton Therapy Center has a 230 MeV cyclotron from which proton beams are directed to two isocentric gantries, a stereotactic intracranial beam line, and an eye line. Because of improved physical dose distribution, proton radiotherapy allows dose escalation to improve local tumor control in anatomic sites and histologies where local control is suboptimal with photons. The improved dose localization also reduces normal-tissue doses with an anticipated reduction in acute and late toxicity. Clinical treatment protocols, developed to exploit the dosimetric advantages of protons over photons, have been grouped into two broad categories. In the first, dose is escalated for anatomic sites where local control with conventional radiation doses has been suboptimal. In the second, normal-tissue sparing with protons is designed to minimize acute and late toxicity. Treatment of patients on clinical research protocols has been encouraged. Patient treatments began on the first gantry in November 2001; on the eye line in April 2002; on the second gantry in May 2002; and on the stereotactic intracranial line in August 2006. The facility currently treats 60 patients per day, including up to six children daily under anesthesia. Dose-escalation studies have been completed for early stage prostate cancer (in conjunction with Loma Linda University) and sarcomas of the cervical spine/base of skull and thoracolumbosacral spine. Protocols are in progress or development for carcinoma of the nasopharynx, paranasal sinus carcinoma, non-small-cell lung carcinoma, locally advanced carcinoma of the prostate, hepatocellular carcinoma, and pancreatic cancer. Studies evaluating the use of protons for morbidity reduction include protocols for craniospinal irradiation in conjunction with systemic chemotherapy for medulloblastoma, retinoblastoma, pediatric rhabdomyosarcoma, other pediatric sarcomas, and accelerated, hypofractionated partial breast irradiation for T1N0 breast carcinomas. For pediatric patients, protons have also been accepted as an alternative to photons for children enrolled in Children's Oncology Group (COG) protocols. Treatment of patients on these studies has often required the development of new treatment techniques (i.e., matching abutting fields for craniospinal irradiation), respiratory gating, and development of appropriate clinical infrastructure support (i.e., increase in availability of pediatric anesthesia) to allow appropriate treatment. In addition, a clinical research infrastructure for protocol development and data management is required. Results to date indicate that proton radiation therapy offers several potential treatment advantages to patients that can be studied in the setting of clinical trials. Patients' willingness to enter these clinical trials seems to be quite high; accrual to selected studies has been favorable.
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PMID:Clinical proton radiation therapy research at the Francis H. Burr Proton Therapy Center. 1766 54

The neurotrophin receptors TrkA (NGF receptor) and TrkC (NT-3 receptor) have been shown to be important in staging disease and predicting progression and drug response for various neoplasias such as neuroblastoma, medulloblastoma and prostate cancer. Less is known about the role of the p75 neurotrophin receptor in cancer, but it influences metastatic potential in glioblastoma. To determine the effect of each neurotrophin receptor or co-receptor expression in tumorigenesis, we examined PC12 pheochromocytomas. PC12 wild type (TrkA(+), p75(++)) were compared to three PC12-derived cell lines expressing varying levels of TrkA or TrkC and/or p75. Growth rates, tumorigenic potential ex vivo and in vivo, and chemotherapeutic drug response profiles differed depending on the neurotrophin receptor phenotype. The ability of neurotrophins to rescue cells from doxorubicin or cisplatin induced cell death also varied depending on phenotype. Thus, unique neurotrophin receptor tumor profiles may determine tumor aggressiveness and chemoresistance. This work may help to develop tailored therapies for specific tumor phenotypes by combining traditional chemotherapy with neurotrophin receptor modulators.
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PMID:Differential roles of Trk and p75 neurotrophin receptors in tumorigenesis and chemoresistance ex vivo and in vivo. 1970 34


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