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)

Bisphosphonates (BPs) are potent inhibitors of osteoclast-mediated bone resorption, and it is well accepted that tumor cells in bone, especially breast cancer and myeloma cells, can stimulate osteoclast formation and activity leading to the release of growth factors or cytokines, which will further stimulate cancer cells' growth and their secretion of osteolytic factors. BPs are now the standard treatment for cancer hypercalcemia, for which a dose of 90 mg of pamidronate or 1500 mg of clodronate is recommended; the former compound is more potent and has a longer lasting effect. Repeated pamidronate infusions exert clinically relevant analgesic effects in more than half of patients with metastatic bone pain. Recent data suggest that non-responding patients should perhaps be treated with higher doses. The optimal dose actually remains to be defined, especially as it is thought that it is probably a function of the disease stage. Regular pamidronate infusions can also achieve a partial objective response according to conventional UICC criteria and they can almost double the objective response rate to chemotherapy. Lifelong administration of oral clodronate to patients with breast cancer metastatic to bone reduces the frequency of morbid skeletal events by more than one-fourth. Two double-blind randomized placebo-controlled trials comparing monthly 90 mg pamidronate infusions to placebo infusions for 1-2 years in addition to hormone or chemotherapy in patients with at least one lytic bone metastasis have shown that the mean skeletal morbidity rate could be reduced by 30-40%. The results obtained with intravenous BPs are generally viewed as better than those obtained with oral clodronate. However, preference can be given to the oral route when BPs are started early in the process of metastatic bone disease in a patient receiving hormone therapy. According to the recently published ASCO guidelines, pamidronate 90 mg i.v. delivered over 2 h every 3-4 weeks can be recommended in patients with metastatic breast cancer who have imaging evidence of lytic destruction of bone and who are concurrently receiving systemic therapy with hormonal therapy or chemotherapy. Furthermore, the ASCO Panel considered it "reasonable" to start i.v. BPs in women with localized pain whose bone scans were abnormal and plain radiographs normal, but not when an abnormal bone scan is asymptomatic. The pertinence of these criteria is discussed below. Because BPs are providing supportive care, reducing the rate of skeletal morbidity but evidently not abolishing it, the criteria for stopping their administration have to be different from those used for classic antineoplastic drugs, and they should not be stopped when metastatic bone disease is progressing. However, criteria to determine whether and for how long an individual patient benefits from their administration are lacking. New biochemical markers of bone resorption might help identify those patients continuing to benefit from therapy. Even better results have been achieved in patients with multiple myeloma, and the general consensus is that BPs should be started as soon as the diagnosis of lytic disease is made in myeloma patients. On the other hand, data are scanty in prostate cancer, but large-scale trials with potent BPs are ongoing or planned in such patients. Similar results to those achieved with pamidronate have been obtained with monthly 6-mg infusions of the newer BP ibandronate in patients with breast cancer metastatic to bone. The tolerance of ibandronate could be better, and the drug has the potential to be administered as a 15- to 30-min infusion. Zoledronate can also be administered safely as a 15-min 4-mg infusion, and large scale phase III trials have just been completed. These newer BPs will simplify the current therapeutic schemes and improve the cost-effectiveness ratio; they also have the potential to improve the therapeutic efficacy, at least in patients with an aggressive osteolytic disease or when given as adjuvant therapy. For that matter, initial data with clodronate indicate that they have the potential to prevent the development of bone metastases, but the use of BPs in the adjuvant setting must still be viewed as experimental.
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PMID:Bisphosphonates for cancer patients: why, how, and when? 1213 23

Estrogens occurring naturally in the body are metabolized to catecholestrogens (2- and 4-hydroxyestradiol) by the cytochrome P450 enzymes. 2-Hydroxy catecholestrogens are further metabolized by catechol-O-methyltransferase to 2-methoxyestradiol, which is known to be protective against tumor formation. 2-Methoxyestradiol exhibits potent apoptotic activity against rapidly growing tumor cells. It also possesses antiangiogenic activity through a direct apoptotic effect on endothelial cells. Other molecular mechanisms, including microtubule stabilization by inhibition of the colchicine-binding site, have been reported. The exact mechanism of action of 2-methoxyestradiol is still unclear, but it has been shown to be effective in preventing tumor growth in a variety of cell lines. 2-Methoxyestradiol also possesses cardioprotective activity by inhibiting vascular smooth muscle cell growth in arteries. It has a lower binding affinity for estrogen receptor alpha compared with that of estradiol, and its affinity for estrogen receptor beta is even lower than that of estrogen receptor alpha, thus it has minimal estrogenic activity. 2-Methoxyestradiol is distinct because of its inability to engage estrogen receptors as an agonist, and its unique antiproliferative and apoptotic activities are mediated independently of estrogen receptors alpha and beta. A phase I clinical trial of 2-methoxyestradiol 200, 400, 600, 800, and 1,000 mg/day in 15 patients with breast cancer showed significant reduction in bone pain and analgesic intake in some patients, with no significant adverse effects. Another phase I study of 2-methoxyestradiol 200-1,000 mg/day in combination with docetaxel 35 mg/m2/week for 4-6 weeks performed in 15 patients with advanced refractory metastatic breast cancer showed no serious drug-related adverse effects. A phase II randomized, double-blind trial of 2-methoxyestradiol 400 and 1,200 mg/day in 33 patients with hormone-refractory prostate cancer showed that it was well tolerated and showed prostate specific antigen stabilizations and declines. We have started a phase I clinical trial to explore dosages greater than 1,000 mg/day.
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PMID:2-Methoxyestradiol, a promising anticancer agent. 1258 5

Recently cancer susceptibility syndromes have been characterized that suggest possible genetic linkages between breast cancer and prostate cancer within families. Despite these connections, male breast cancer and prostate cancer in an individual man has rarely been reported. The clinical features of 10 patients with both of these cancers are described here. One hundred sixty-one patients with male breast cancer were seen at the Dana-Farber Cancer Institute and Massachusetts General Hospital between 1977 and 2000. Of these, 10 were identified who also had prostate cancer. A retrospective review of records from these 10 patients was performed. Breast cancer preceded prostate cancer in eight of these men. The mean age of diagnosis of breast cancer was 65.7 years (range 47-72 years). Twenty percent had nodal involvement at diagnosis and two patients ultimately developed evidence of metastatic disease. The mean age of diagnosis of prostate cancer was 68.0 years (range 51-76 years) with a median prostate-specific antigen (PSA) level at diagnosis of 6 ng/ml (range 1.8-47.5 ng/ml). Seven patients had a family history of female breast cancer in a first-degree relative, while one had a family history of prostate cancer. At a median follow-up of 6.5 years from initial cancer diagnosis, one patient had died of metastatic breast cancer and another had died of metastatic prostate cancer. The clinical features and course of the breast cancers diagnosed in this series do not appear significantly different from those described for the general population of male breast cancer patients. In addition, these men do not appear to develop prostate cancer at an earlier age or more aggressive stage than the general population.
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PMID:Male patients with diagnoses of both breast cancer and prostate cancer. 1275 29

Monoclonal antibodies are used to detect serum antigens associated with specific malignancies. These tumor markers are most useful for monitoring response to therapy and detecting early relapse. With the exception of prostate-specific antigen (PSA), tumor markers do not have sufficient sensitivity or specificity for use in screening. Cancer antigen (CA) 27.29 most frequently is used to follow response to therapy in patients with metastatic breast cancer. Carcinoembryonic antigen is used to detect relapse of colorectal cancer, and CA 19-9 may be helpful in establishing the nature of pancreatic masses. CA 125 is useful for evaluating pelvic masses in postmenopausal women, monitoring response to therapy in women with ovarian cancer, and detecting recurrence of this malignancy. Alpha-fetoprotein (AFP), a marker for hepatocellular carcinoma, sometimes is used to screen highly selected populations and to assess hepatic masses in patients at particular risk for developing hepatic malignancy. Testing for the beta subunit of human chorionic gonadotropin (beta-hCG) is an integral part of the diagnosis and management of gestational trophoblastic disease. Combined AFP and beta-hCG testing is an essential adjunct in the evaluation and treatment of nonseminomatous germ cell tumors, and in monitoring the response to therapy. AFP and beta-hCG also may be useful in evaluating potential origins of poorly differentiated metastatic cancer. PSA is used to screen for prostate cancer, detect recurrence of the malignancy, and evaluate specific syndromes of adenocarcinoma of unknown primary.
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PMID:Serum tumor markers. 1452 94

HER-2 has been implicated in the oncogenesis of human prostate cancer (CaP) and is the target of a new treatment for metastatic breast cancer using the humanised monoclonal antibody (MAb) trastuzumab (Herceptin). In this study, a novel alpha-particle emitting [213Bi]Herceptin construct, which targets the HER-2 extracellular domain on CaP cells, was prepared and evaluated in vitro. We used immunocytochemistry, flow cytometry and Western blot analysis to examine the expression of HER-2 in a panel of established human CaP cell lines, used the MTS assay to evaluate the cytotoxicity of 213Bi-Herceptin on these cell lines and the TUNEL assay to document apoptosis. The results indicate that LNCaP-LN3 cells express high levels of HER-2 protein, in contrast, DU 145 cells express low to medium levels, and PC-3 cells express an undetectable level of HER-2 protein. 213Bi-Herceptin was specifically cytotoxic to LNCaP-LN3 cells in a concentration-dependent fashion, cause the cells to undergo apoptosis, whereas DU 145 showed an HER-2 level-dependent response to 213Bi-Herceptin cytotoxicity. In contrast, PC-3 cells were resistant to 213Bi-Herceptin-induced cytotoxicity. The 213Bi-Herceptin induced apoptosis in LNCaP-LN3 cells could be inhibited by incubation with unlabeled Herceptin. Our results suggest that 213Bi-Herceptin alpha-conjugate might be a promising new agent for the treatment of preangiogenic cancer cell clusters or micro-metastases with high levels of HER-2 expression.
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PMID:Cytotoxicity of human prostate cancer cell lines in vitro and induction of apoptosis using 213Bi-Herceptin alpha-conjugate. 1503 48

Metastatic bone disease constitutes a major clinical problem. Skeletal complications are common and lead to significant morbidity, and patients live with metastatic bone disease for several years, increasing the prevalence of this problem. Effective management aims to reduce the incidence of skeletal complications and relieve symptoms, such as severe bone pain, which adversely affect patient mobility and quality of life. This article describes and discusses strategies for managing metastatic bone disease, with particularly emphasis on the role of the bisphosphonate ibandronate. Two case histories show the long-term efficacy and tolerability of oral ibandronate in the treatment of metastatic breast cancer. The third case history illustrates the benefits of rapid pain relief from an intensive, high-dose regimen of intravenous ibandronate in metastatic prostate cancer.
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PMID:Managing metastatic bone disease: three case studies. 1549 Mar 82

Tumor metastasis is the most common cause of death in cancer patients. Here, we show that two, fully synthetic migrastatin analogues, core macroketone and core macrolactam, are potent inhibitors of metastasis in a murine breast tumor model. Administration of these readily accessible compounds nearly completely inhibits lung metastasis of highly metastatic mammary carcinoma cells. Treatment of tumor cells with core macroketone and core macrolactam blocks Rac activation, lamellipodia formation, and cell migration, suggesting that these chemical compounds interfere with the invasion step of the metastatic process. These compounds also inhibit the migration of human metastatic breast cancer cells, prostate cancer cells, and colon cancer cells but not normal mammary-gland epithelial cells, fibroblasts, and leukocytes. These data demonstrate that the macroketone and macrolactam core structures are specific small-molecule inhibitors of tumor metastasis. These compounds or their analogues could potentially be used in cancer-therapy strategies.
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PMID:Synthetic analogues of migrastatin that inhibit mammary tumor metastasis in mice. 1572 85

The evaluation of the biological status of cancer patients should not be limited only to investigation of immune reactivity, but should also include analysis of the endocrine condition, namely concerning those hormones which have appeared to be tumor growth factors, such as prolactin (PRL) for breast and prostate carcinomas. This statement is justified by the fact that the evidence of abnormally high serum concentrations of PRL has been proven to be associated with poor prognosis in breast and prostate cancer patients. Moreover, since hyperprolactinemia negatively influences the efficacy of anticancer therapies in breast cancer, it could be fundamental to achieve a normalization of PRL levels by long-acting dopaminergic agents, such as cabergoline. On this basis, a study was planned to evaluate the effect of cabergoline on PRL levels in hyperprolactinemic metastatic breast cancer subjects. The study included 20 hyperprolactinemic metastatic breast cancer subjects, who were randomized to receive no therapy or cabergoline at 0.5 mg/week orally for 4 consecutive weeks. Cabergoline therapy induced a normalization in all patients, whereas no spontaneous normalization of PRL levels occured in the control group. These results show that a weekly oral administration of the long-acting dopaminergic agent cabergoline is a well tolerated and effective treatment of metastatic breast cancer-related hyperprolactinemia. The possible prognostic impact of PRL normalization needs to be established by successive studies.
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PMID:Biological response modifiers of cancer-related neuroendocrine disorders: efficacy of the long-term dopaminergic agonist cabergoline in the treatment of breast cancer-induced hyperprolactinemia. 1578 95

Docetaxel is a semisynthetic taxane, a class of anticancer agents that bind to beta tubulin, thereby stabilising microtubules and inducing cell-cycle arrest and apoptosis. Docetaxel was first approved for the treatment of anthracycline-refractory metastatic breast cancer in the mid-1990s. Since then, several randomised trials have reported improved time-to-progression, overall survival, or both in metastatic breast cancer treated with single-agent docetaxel or docetaxel-based combination regimens. Data from two adjuvant trials have shown a survival benefit with the addition of docetaxel to standard anthracycline-based regimens in patients with high-risk early breast cancer. In four randomised studies, docetaxel improved survival in locally advanced or metastatic non-small-cell lung cancer. Moreover, two trials have shown that docetaxel combined with estramustine or corticosteroids improves survival in metastatic androgen-independent prostate cancer. Here, we review major randomised phase III trials with docetaxel in the treatment of solid malignant disease.
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PMID:Docetaxel for treatment of solid tumours: a systematic review of clinical data. 1581 18

The anti-cancer agent docetaxel is approved for the treatment of patients with locally advanced or metastatic breast cancer, non-small cell lung cancer (NSCLC) and for the treatment of androgen-independent prostate cancer. At the recommended dose of 60-100 mg/m2 given every 3 weeks, severe neutropenia is the dose-limiting toxicity and a major concern especially when treating patients at high-risk from myelotoxic complications. A less toxic schedule, involving weekly docetaxel administration was developed for patients with poor performance status, multiple comorbidities, poor haematological reserves or those who were heavily pre-treated, elderly or patients for whom palliation is the focus of treatment. Recent randomised trials allow a comparison of efficacy and toxicity between weekly and 3-weekly treatments. Efficacy appears to be similar for the two schedules regardless of the disease while weekly docetaxel is significantly less myelotoxic. However, this benefit comes at the cost of cumulative increases in hyperlacrimation, skin- and nail-toxicity and negatively affects quality of life. Currently, 3-weekly docetaxel remains the standard schedule for treatment, whereas the weekly schedule offers a possibility of treatment individualisation for those patients where the risk of myelosuppression is considered unacceptable.
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PMID:Docetaxel administration schedule: from fever to tears? A review of randomised studies. 1591 Dec 34


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