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)

Androgen-receptor (AR) gene mutations have been found in clinical prostate cancer, both prior to hormonal therapy and in hormone-refractory disease that persists despite androgen-ablative therapy. Thus, mutations that are present in late-stage disease might arise prior to therapy rather than as a result of therapy. A common feature of mutations in untreated prostate cancer and in hormone-refractory prostate cancer is that the AR retains activity as a ligand-dependent transcription factor. Some AR mutations in prostate cancer show broadened ligand specificity, such that the transcription-factor activity of the AR can be stimulated not just by dihydrotestosterone (DHT) but also by estradiol and other androgen metabolites that have a low affinity for the AR. The activation of mutant AR by estrogen and weak androgens could confer on prostate cancer cells an ability to survive testicular androgen ablation by allowing activation of the AR by adrenal androgens or exogenous estrogen. Such mutations might confer an advantage even prior to androgen ablation, since prostate cancer has lower levels of 5 alpha-reductase and, therefore, of DHT, than normal. Thus, AR mutations that occur prior to therapy may characterize a more aggressive disease. A large percentage of tumors appear to have no AR gene mutation. In tumors without an AR gene mutation, AR function might be affected via other mechanisms (e.g., AR gene amplification, which could increase the amount of AR activity at a given DHT level). Importantly, the apparent absence of AR gene mutations in the majority of earlystage tumors indicates that the role of androgen in the development of clinical prostate cancer is mediated predominantly by a normal AR gene. There are actually multiple alleles of the normal AR gene; these allelic variants differ in glutamine and glycine repeat length in the transactivation domain of the protein, and they may differ in signal-transducing activity. The glutamine and glycine repeat length may thereby modulate the effect of androgen on tumor-cell proliferation that occurs during clonal expansion.
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PMID:Androgen-receptor gene structure and function in prostate cancer. 891 73

Androgen ablation prior to radical prostatectomy currently is under investigation with the goal of improving cancer control in patients with clinically treated localized prostate cancer. Results of several randomized studies have shown a significant pathologic downstaging and a decrease in the rate of positive surgical margins using neoadjuvant therapy in stage B cancers. Despite theoretic advantages, neoadjuvant therapy may have side effects and is associated with costs. Until long-term results of biologic and clinical failure rates are available, this approach should be considered investigational.
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PMID:The role of neoadjuvant androgen deprivation prior to radical prostatectomy. 894 12

Prostate cancer represents a heterogeneous disease entity with varying degrees of behavior, aggressiveness, patterns of metastasis, and response to therapy. Progressive metastatic prostate cancer is associated with a formidable array of morbidity that ultimately contributes to death of the patient. Thus far, there has been no convincing evidence to support routine use of non-hormonal chemotherapeutic agents or combinations over symptomatic treatment only. Furthermore, no single compound or combination has shown a dramatic improvement in conventional quality of life parameters over symptomatic treatment only. Androgen ablation remains the primary systemic therapeutic modality for this disease, yet the intense delineation of mechanisms involved in tumor cell metastasis has lead to new therapeutic strategies, ranging from cytotoxic to cytostatic, including immunomodulators. Among those strategies currently being studied are granulocyte-macrophage colony-stimulating factor-transduced prostate cancer vaccines, differentiation therapy, gene therapy, inducers of apoptosis, antimetastatic agents, angiogenesis inhibitors, radiation therapy (local and systemic), and systemic approaches targeted at prostate cancer morbidity. The difficult issue is which agents should be developed and how should we best assess the response using standard and newly identified endpoints. Certainly, the future of advanced prostate cancer therapy will undergo dramatic changes as a result of the continued interaction between the laboratory and the clinic.
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PMID:Prostate cancer treatment strategies based on tumor-specific biological principles: future directions. 899 87

We report two cases of intracranial metastatic adenocarcinoma of the prostate that presented with visual disturbance. The two patients had no prior history of prostate cancer and both underwent invasive neurosurgical procedures. Progressive neurological decline mandated craniotomy in one patient and the other patient underwent transphenoidal surgery for biopsy. Androgen deprivation therapy was instituted postoperatively for both patients when prostate cancer was determined to be the source of the metastatic lesions.
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PMID:Intracranial metastatic adenocarcinoma of the prostate presenting as visual disturbance. 917 Feb 27

Androgen ablation is frequently used in conjunction with radiotherapy in the treatment of high-risk prostate cancer. Androgen ablation-induced cell kinetic changes could result in sub-additive (increased quiescence) or supra-additive (reduction in repopulation) interactions with radiotherapy. The cell kinetic changes were studied in R3327-G Dunning rat prostate tumors grown in vivo using double thymidine analogue labeling and flow cytometry, the terminal deoxynucleotidyl transferase-mediated nick end labeling assay for apoptosis, and measurements of tumor cell numbers. Tumors grown in intact and castrate male rats were continuously labeled for various periods of time with chlorodeoxyuridine and pulse-labeled with iododeoxyuridine 8 h before tumor removal. Androgen ablation resulted in a maximal reduction in labeling index (10 to 1.6%) and an increase in potential doubling time (Tpot; 6-42 days) within 3 days, which was related to a reduction in growth fraction (65% to <10%). In contrast, the length of S-phase was minimally altered (19 to 23 h). The response to androgen ablation involved little apoptosis and no necrosis, and Tpot was approximately the same as the tumor volume doubling time. Hence, the increase in Tpot was mainly the result of a shift to quiescence, and this shift occurred with minimal cell loss. Because quiescence is usually associated with radioresistance, these cell kinetic changes suggest that a sub-additive interaction may occur for some prostate cancers when androgen ablation and irradiation are given together.
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PMID:Quiescence in R3327-G rat prostate tumors after androgen ablation. 919 31

Human glandular kallikrein (hK2) protein, like prostate-specific antigen (PSA), is produced mainly in prostatic epithelium. It may be useful as a new diagnostic indicator for prostate cancer. Recently, a number of hK2-specific monoclonal antibodies have been developed that enable us to detect hK2 protein in human prostate tissue, seminal fluid, and sera. Whether hK2 can be expressed, like PSA, in nonprostatic cells is not known. In this study, we have characterized the presence of hK2 in an androgen-responsive breast cancer cell line T47-D at both the protein and mRNA levels with an immunoassay, Western blot analysis, Northern blot analysis, and the reverse transcription-PCR. Using a sensitive immunoassay with monoclonal antibodies to hK2, we found that T47-D cells could be induced with androgens, mineralocorticoids, glucocorticoids, and progestins to produce significantly more hK2 than PSA. Estrogens failed to mimic the effect of the other steroids, blocking instead the stimulatory effect of androgens. Androgen induction of hK2 in T47-D cells was dose dependent. More interestingly, we found that the hK2 in androgen-induced T47-D cell spent media appears to be the pro-form of hK2 rather than mature hK2. Our study demonstrates that hK2, a serine protease thought to be found only in prostate-related tissues and fluids, is also produced in a breast cancer cell line T47-D after steroid stimulation. This finding suggests that hK2 may have a potential role in breast cancer as well as prostatic cancer and will be the impetus for further studies of hK2 distribution and function.
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PMID:Expression of human prostate-specific glandular kallikrein protein (hK2) in the breast cancer cell line T47-D. 920 72

Androgen ablation therapy is the treatment of choice for the palliation of patients with advanced prostate cancer. In addition to palliation, maximal androgen ablation (MAA), with a combination of medical or surgical castration and an antiandrogen, has been shown to increase the survival of patients with metastatic prostate cancer in at least three large well-conducted trials. A subgroup analysis of these trials has suggested that patients, particularly those with low volumes of metastatic disease, fared much better when treated with MAA than with castration alone. This observation has prompted many clinicians to begin androgen ablation earlier in men with advanced but not necessarily metastatic prostate cancer, thus exposing them to prolonged periods of androgen ablation and its side effects. These include impotence, loss of libido, loss of muscle mass, malaise, and psychological disturbances. In order to offer the putative advantages of early hormone therapy but to mitigate its side effects a number of innovative methods of androgen ablation are under investigation. These include 'sequential androgen blockade' and 'intermittent androgen suppression'. Sequential androgen blockade uses a 5 alpha-reductase inhibitor to reduce the conversion of testosterone to dihydrotestosterone in conjunction with an antiandrogen or androgen-receptor blocker to prevent residual androgen from reaching the androgen receptor. Circulating testosterone levels are not reduced thus minimizing side effects. Intermittent androgen suppression uses combined therapy to rapidly reduce serum testosterone and induce tumor regression. From time to time treatment is stopped and androgen concentrations rise. This method reduces the total time of exposure to castrate levels of androgen and, although prostate-specific antigen levels rise during the second phase of therapy suggesting tumor growth, proponents of this cycling method suggest that this should prolong the time to androgen independence of the tumor. Early results with both methods suggest that the time to progression is long and side effects are minimized as compared to MAA. Large scale trials will be needed to determine the exact risks and benefits of these novel methods of androgen ablation.
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PMID:Innovative approaches to the hormonal treatment of advanced prostate cancer. 926 90

Prostate cancer carries significant morbidity and mortality, but its outcome is difficult to predict in the individual. Androgen ablation delays progression in men, but hormone resistance soon develops and much basic science research has focused on how prostate cancer 'escapes' hormonal control. Stem cell models of prostate development and homeostasis have been proposed, but have not yet been fully characterized. Some androgen-regulated signalling pathways and abnormalities that affect them have been defined recently. It is apparent that locally produced growth factors, often regulated by androgens, exert an effect both physiologically and pathologically and these too will be discussed.
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PMID:Basic science aspects of prostate cancer. 929 78

Our laboratory has developed two cellular models of human prostate cancer progression. The LNCaP prostate cancer progression model is based upon the well-known cellular interaction between human prostate or bone stromal cells and LNCaP cells in vivo. The marginally tumorigenic LNCaP cells acquired tumorigenic and metastatic potential upon cellular interaction with either prostate or bone fibroblasts. A subline termed C4-2 was observed to grow readily in castrated animals and acquired metastatic potential spreading from the primary tumor site to the lymph node, the seminal vesicles, and the axial skeleton, resulting in an intense osteoblastic reaction. The second model is ARCaP, where prostate cancer cells derived from the ascites fluid of a man with metastatic disease exhibited an Androgen- and estrogen-Repressed Prostate Cancer cell growth and tumor formation in either a hormone-deficient or a castrated environment. However, the growth of either the tumor cells in vitro or the tumors in vivo was suppressed by both estrogen and androgen. While the tumor cells expressed low levels of androgen receptor and prostate-specific antigen (PSA), they were highly metastatic when inoculated orthotopically. Distant metastases to a number of organs were detected, including the liver, lung, kidney, and bone. We have employed a human prostate cancer progression model as a system to study the efficacy of gene therapy. Results of the study show that whereas universal promoters, such as Cytomegalovirus (CMV) and Rous Sarcoma Virus (RSV) promoter-driven tumor suppressors (e.g. p53, p21, and p16), were effective in inhibiting prostate tumor growth, the advantages of driving the expression of therapeutic toxic genes using a tissue-specific promoter prostate-specific antigen (PSA) and a tumor--but not tissue-specific promoter, osteocalcin (OC), are preferred. In the case of the PSA promoter, we can achieve cell-kill in PSA-producing human prostate cancer cells. To circumvent the supporting role of bone stroma for prostate cancer epithelial growth, we have recently developed a novel concept where the expression of therapeutic toxic genes is driven by a tumor--but not a tissue-specific OC promoter. Osteocalcin-thymidine kinase (OC-TK) was found to efficiently eradicate the growth of osteosarcoma, prostate, and brain tumors both in vitro and in vivo. We observed that androgen-independent human prostate cancer cells lines expressed OC-TK at higher levels than androgen-dependent human prostate cancer cell lines. We have obtained data to suggest that Ad-OC-TK plus a pro-drug acyclovir (ACV) may be used as an effective therapy to treat prostate cancer bone metastasis in models where the growth of androgen-independent PC-3 and C4-2 tumors in the bone has occurred.
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PMID:Human prostate cancer progression models and therapeutic intervention. 943 28

It is generally accepted that early human prostate cancers reveal higher androgen dependency than do advanced ones. In the present study, we examined whether the animal model of prostate cancer has already lost androgen dependency at the early stages of carcinogenesis. At experimental week 46, androgen deprivation was induced in rats and the incidences of atypical hyperplasia and cancer were examined in the ventral, dorsolateral prostate, coagulating glands, and seminal vesicles. Androgen deprivation significantly lowered the incidence of atypical hyperplasia in all four organs. As for the incidence of cancer, no significant differences were observed in the coagulating glands and seminal vesicles. Regarding atypical hyperplasia, androgen deprivation significantly decreased the proliferative cell nuclear antigen labeling index in the coagulating gland and seminal vesicles. The presence of cancer was also decreased in the coagulating gland but not in the seminal vesicles. With control group specimens, more intense staining of androgen receptor was observed in atypical hyperplasias than in cancers. Compared with the atypical hyperplasias, the cancers revealed low androgen dependency at the early stages of carcinogenesis. The cancers in the seminal vesicles also revealed higher androgen independency than did those in the coagulating gland.
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PMID:Carcinogenesis in accessory sex organs of rats induced by 3,2'-dimethyl-4-aminobiphenyl: response to androgen deprivation. 945 Jun 33


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