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)

Marimastat (BB-2516) is the first matrix metalloproteinase inhibitor to have entered clinical trials in the field of oncology. It has excellent bioavailability and has completed phase I and II trials. Phase I studies involved healthy volunteers who received short courses of marimastat; these were well tolerated. Symptoms experienced by many patients with various malignancies included severe joint and muscle pain which were debilitating in >60% of patients at doses >50 mg bid. These symptoms were reversible on discontinuation of the drug, and their incidence has been decreased by using marimastat 10 mg bid, the dose used in current studies. Phase II studies involved the use of serum tumor markers as surrogate indicators of antitumor activity. Six studies in colorectal, ovarian, and prostate cancer have been completed and pooled analysis has demonstrated a dose-dependent biological effect (as defined by the authors); 58% of patients respond at doses >50 mg bid. Effects on tumor markers were associated with increased survival. Small phase II studies have suggested potential activity in pancreatic and gastric cancer and have demonstrated the safety of combining cytotoxic chemotherapeutic agents with marimastat. Ongoing phase III studies are investigating the effects of marimastat in addition to chemotherapy in the treatment of small cell lung cancer and pancreatic and gastric carcinoma.
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PMID:Marimastat (BB2516): current status of development. 1035 60

The positive impact on survival of traditional chemotherapeutic agents has renewed interest in developing newer cytotoxic agents and orally active compounds with improved therapeutic indices. In addition, new insights into the pathways of human tumorigenesis have led to novel approaches aimed at specific mechanism-based targets. The taxane class, of which paclitaxel was the first member, has the unique ability to promote and stabilize microtubule function directly, thereby inhibiting mitotic progression and inducing apoptotic cell death. Paclitaxel provides treatment benefit in a broad range of solid tumors including breast, ovarian, and lung cancer. The success with paclitaxel stimulated interest in the microtubule as a new therapeutic target. Taxane analogues with improved preclinical efficacy have been identified and are entering clinical trials. The enthusiasm for oral anticancer agents and the therapeutic importance of platinum compounds has led to the development of JM216 (satraplatin), a novel platinum IV coordination complex with oral activity in cisplatin-resistant cell lines, which is now in phase III trials in prostate cancer. Another compound in late development is DPPE, a chemopotentiator that enhances the in vivo antitumor effects of cytotoxic agents such as doxorubicin, cyclophosphamide, and cisplatin. Agents that inhibit topoisomerase I and II have also been of interest. TAS-103 is a dual topoisomerase I and II inhibitor with preclinical efficacy in a broad spectrum of tumors and in multidrug-resistant tumor cell lines. Vaccination strategies represent a rational therapeutic approach in the minimal residual disease or high-risk adjuvant therapy setting. The GMK and MGV vaccines utilizing ganglioside antigens overexpressed on human tumors such as melanoma and small cell lung cancer appear to induce antibody production reliably at tolerable doses and are under further clinical investigation. Inhibition of matrix metalloproteinases (MMPs) is another attractive target for intervention in several aspects of tumor progression. Local production of MMPs with subsequent degradation of the extracellular matrix is implicated in supporting tumor growth, invasion, and angiogenesis. The development of orally active, nontoxic MMP inhibitors is critical since these compounds will likely require chronic administration in conjunction with other therapies. Oncogenes and tumor suppressor genes are appealing targets for therapy since they are thought to be responsible for a significant number of cancers. Mutations in the Ras oncogene occur with great frequency in a number of human cancers including lung, pancreas, and colon cancer. Clinical development of potent and selective inhibitors of farnesyltransferase, the Ras-processing enzyme, is ongoing. These compounds uncouple Ras activity, affect tumor growth, and have demonstrated significant antitumor activity against experimental models of human cancer. The exciting compounds and novel therapeutic approaches currently under investigation by Bristol-Myers Squibb Pharmaceutical Research Institute offer great potential as effective cancer chemotherapy agents for the near future.
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PMID:Promising new developments in cancer chemotherapy. 1035 61

Membrane type 1-matrix metalloproteinase (MT1-MMP) is a known activator of latent MMP-2 (pro-MMP-2), and increased MMP-2 expression has been associated with tumor aggressiveness in prostate cancer. However, expression of MT1-MMP in human prostate tissue has not been described. We investigated the expression and immunolocalization of MT1-MMP and MMP-2 in the epithelial components of benign prostate epithelium, high-grade prostatic intraepithelial neoplasia (HGPIN), and prostate cancer. Tissue sections from the peripheral zone of 50 prostates (radical prostatectomy specimens) were chosen based on their containing benign glands, HGPIN, and prostate cancer glands. All 50 sections were immunostained for MT1-MMP and MMP-2 and were evaluated for staining pattern, uniformity, and intensity. Western blotting and gelatin zymography were done to confirm expression of MT1-MMP and activity of MMP-2, respectively. Comparisons were made between benign epithelium, HGPIN, and cancer. In benign glands, basal cells (BCs) uniformly stained intensely for MT1-MMP, whereas secretory cells (SCs) were rarely positive (P < 0.0001). Conversely in HGPIN, SCs showed consistent cytoplasmic staining (P < 0.0001). In cancer cells, staining was heterogeneous and varied from no staining to very intense staining in select glands. MMP-2 in normal tissue stained both BCs and the apical region of SCs, whereas in HGPIN, staining was observed in the SC in a predominantly cytoplasmic pattern. Similar to MT1-MMP, staining in cancer tissue for MMP-2 was heterogeneous; however, there was a significant association between the pattern of MMP-2 and MT1-MMP staining within the epithelial components of the cancer glands in individual specimens (P < 0.001). Finally, MMP-2 and MT1-MMP were confirmed to be expressed in the prostate tissues by gelatin zymography and Western blotting. In conclusion, we found that consistent changes in localization and intracellular distribution of MMP-2 and MT1-MMP were associated with the transition from benign prostate epithelium to HGPIN, suggesting that regulation of these enzymes is altered during the earliest stages of prostate cancer.
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PMID:Membrane type 1-matrix metalloproteinase (MT1-MMP) and MMP-2 immunolocalization in human prostate: change in cellular localization associated with high-grade prostatic intraepithelial neoplasia. 1063 47

Bone metastases are often associated with osteolysis and subsequent pathological fractures. To determine if metastatic human cancer cells can directly degrade non-mineralized and mineralized bone, we used prostate PC3 adenocarcinoma cell lines, which were originally established from skeletal metastases. We show that PC3 cells and their conditioned medium degraded non-mineralized, osteoid-like radiolabelled extracellular matrices from human Saos2 and U2OS osteoblast-like cells. These cells also directly degraded mineralized bone by inducing (45)Ca release from rat fetal calvariae and forming resorption pits on bone slices, an effect increased by transforming growth factor-beta(1). A role for matrix metalloproteinases in degradation was shown by: (1) stimulation by the phorbol ester TPA of PC3-induced matrix degradation and release of matrix metalloproteinase activity; (2) abrogation of matrix degradation by 1,10-phenanthroline, a metalloproteinase inhibitor, and (3) degradation of purified type I collagen by PC3 cells and their conditioned medium. We demonstrate that human prostate cancer cells can directly degrade bone-related matrices and that matrix metalloproteinases have a role in this process.
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PMID:Human metastatic prostate PC3 cell lines degrade bone using matrix metalloproteinases. 1072 74

Previous work suggested that antiangiogenic activity may be a novel mechanism contributing to the cancer chemopreventive activity of selenium (Se). Because methylselenol has been implicated as an in vivo active chemopreventive Se metabolite, experiments were conducted to test the hypothesis that this metabolite pool might inhibit the expression of matrix metalloproteinase-2 (MMP-2) by vascular endothelial cells and of vascular endothelial growth factor (VEGF) by cancer epithelial cells, two proteins critical for angiogenesis and its regulation. In human umbilical vein endothelial cells (HUVECs), zymographic analyses showed that short-term exposure to methylseleninic acid (MSeA) and methylselenocyanate (MSeCN), both immediate methylselenol precursors, decreased the MMP-2 gelatinolytic activity in a concentration-dependent manner. In contrast, Se forms that enter the hydrogen selenide pool lacked any inhibitory effect. The methyl Se inhibitory effect on MMP-2 was cell dependent because direct incubation with Se compounds in the test tube did not result in its inactivation. Immunoblot and enzyme-linked immunosorbent assay analyses showed that a decrease of the MMP-2 protein level largely accounted for the methyl Se-induced reduction of gelatinolytic activity. The effect of MSeA on MMP-2 expression occurred within 0.5 h of exposure and preceded MSeA-induced reduction of the phosphorylation level of mitogen-activated protein kinases (MAPKs) 1 and 2 (approximately 3 h) and endothelial apoptosis (approximately 25 h). In addition to these biochemical effects in monolayer culture, MSeA and MSeCN exposure decreased HUVEC viability and cell retraction in a three-dimensional context of capillary tubes formed on Matrigel, whereas comparable or higher concentrations of selenite failed to exert such effects. In human prostate cancer (DU145) and breast cancer (MCF-7 and MDA-MB-468) cell lines, exposure to MSeA but not to selenite led to a rapid and sustained decrease of cellular (lysate) and secreted (conditioned medium) VEGF protein levels irrespective of the serum level (serum-free medium vs. 10% fetal bovine serum) in which Se treatments were carried out. The concentration of MSeA required for suppressing VEGF expression was much lower than that needed for apoptosis induction. Taken together, the data support the hypothesis that the monomethyl Se pool is a proximal Se for inhibiting the expression of MMP-2 and VEGF and of angiogenesis. The data also indicate that the methyl Se-specific inhibitory effects on these proteins are rapid and primary actions, preceding or independent of inhibitory effects on mitogenic signaling at the level of MAPK1/2 and on cell growth and survival.
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PMID:Monomethyl selenium--specific inhibition of MMP-2 and VEGF expression: implications for angiogenic switch regulation. 1117 Feb 62

Tetracyclines (TCs) and their non-antimicrobial analogs (CMTs) have therapeutic potential to inhibit tissue destructive disease processes, such as cancer invasion and metastasis, by inhibiting certain matrix metalloproteinases. Enhanced matrix metalloproteinase-2 (MMP-2; gelatinase A) activity has been correlated to cancer invasiveness, and membrane type MMP (MT1-MMP) expressed by tumor cells is involved in localizing and activating pro-MMP-2, a pathway believed to mediate cancer induced tissue breakdown. CMT-3 (6-demethyl, 6-deoxy, 4-dedimethylamino TC) has been shown to experimentally suppress prostate cancer, colon adenocarcinoma and melanoma invasiveness in cell culture and to inhibit tumor growth and metastasis in vivo and was used in the current in vitro study. Confluent MT1-MMP transfected COS-1 cells were harvested, washed thoroughly, subjected to N(2) cavitation and cell membrane enriched fractions were isolated by sequential centrifugations. This MT1-MMP preparation exhibited (i) pro-MMP-2 activating activity as shown by molecular weight shift of this gelatinase from 72 kDa to 62 kDa using gelatin zymography, and (ii) the ability to degrade both [(3)H-methyl] gelatin and casein at 37 degrees C. Adding CMT-3 at final concentrations of 5--20microM inhibited MT1-MMP gelatinolytic and caseinolytic activity, blocked MT1-MMP activation of pro-MMP-2, and decreased invasiveness (using the Matrigel system) of HT-1080 fibrosarcoma cells. The inhibition of MT1-MMP by CMT-3 may partially explain the inhibition of cancer cell -mediated tissue breakdown and invasiveness by this non-antimicrobial tetracycline analog.
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PMID:CMT-3, a non-antimicrobial tetracycline (TC), inhibits MT1-MMP activity: relevance to cancer. 1117 80

Prostate cancer is the most frequently diagnosed malignancy in the Western world and changes in the ratio of testosterone and estrogens with advancing age is one of the potential risk factors in the development of this disease. However, the molecular mechanisms associated with hormone imbalance in prostate carcinogenesis are poorly understood. In this study we induced a high incidence of prostate hyperplasia, dysplasia and adenocarcinoma in the Noble rat using a combination of testosterone and estradiol-17beta. Using this animal model, we studied the gene expression profile during sex hormone-induced prostate carcinogenesis using a cDNA array technique; the results were further confirmed by RT-PCR, western blotting and immunohistochemical analyses. We found up-regulation of TRPM-2 (testosterone-repressed prostatic message-2), MMP-7 (matrix metalloproteinase-7) and Id-1 (inhibitor of differentiation or DNA binding) during development of sex hormone-induced prostate cancer. Increased expression of TRPM-2 and MMP-7 was observed in both premalignant and malignant tissues after sex hormone treatment, indicating their role in the early stages of hormone response and prostate cancer development. In contrast, Id-1 was expressed at relatively low levels in all premalignant samples but increased in malignant cells, suggesting its potential roles as a biomarker for prostate cancer cells. Furthermore, expression of Id-1 appeared to be stronger in poorly differentiated lesions than in well-differentiated carcinomas, suggesting that the levels of Id-1 expression may be correlated with the malignancy of tumors. Our results provide the first evidence of up-regulation of TRPM-2, MMP-7 and Id-1 during sex hormone-induced prostate carcinogenesis and strongly suggest their association with the development of prostate cancer.
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PMID:Up-regulation of TRPM-2, MMP-7 and ID-1 during sex hormone-induced prostate carcinogenesis in the Noble rat. 1137 6

Tumor-stromal interactions have been suggested to be a critical factor in both tumor invasion and tumor metastasis. Here, we examined the role of tumor-stromal interactions using co-cultures of prostate cancer (PC) cells derived from primary and metastatic tumors with primary or immortalized stromal (fibroblast and smooth muscle) cells and their effect on matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) expression. Co-cultures of PC and stromal cells showed enhanced levels of pro-MMP-9 and reduced levels of TIMP-1 and TIMP-2. Whereas enhanced expression of pro-MMP-9 occurred in PC cells, the TIMPs were down-regulated in stromal cells. Induction of pro-MMP-9 and reduction of TIMP expression did not require cell-cell contact and were mediated by a soluble factor(s) present in the conditioned medium of the effector cell. Collagen I is a potent inducer of pro-MMP-9 in PC cells. Consistently, preliminary characterization of the soluble factor in the fibroblast conditioned medium revealed m.w. of approximately 100 to 250 kDa, and its effect on pro-MMP-9 expression was partly inhibited by an anti-alpha2 integrin antibody, a major collagen I receptor. Expression of pro-MMP-9 protein and mRNA was also induced in metastatic PC-3 cells grown in human fetal bone implants in SCID mice. Together, these findings demonstrate the importance of tumor-stromal interactions in the regulation of MMP and TIMP expression and their potential role in PC progression.
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PMID:Differential regulation of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 expression in co-cultures of prostate cancer and stromal cells. 1147 54

Antibiotic forms of tetracycline exhibit antitumor activity in some tumor models. However, their low in vivo efficacy and associated morbidity limit their long-term application in cancer therapy. This report appraises the efficacy of doxycycline (DC) and non-antimicrobial, chemically modified tetracyclines (CMTs) against prostate cancer. Both DC and several CMTs inhibited prostate tumor cell proliferation in vitro. Some of the CMTs were significantly more potent than DC. One of the CMTs, 6-deoxy, 6-demethyl, 4-de-dimethylamino tetracycline (CMT-3, COL-3), was the most potent inhibitor (50% inhibition dose [GI(50)] < or = 5.0 ,microg/ml). Exposure of tumor cells to CMT-3 induced both apoptosis and necrosis. Mitochondrial depolarization and increased levels of reactive hydroxyl radicals were also observed in cells treated with CMT-3. Cell cycle arrest at the G(0)/G(1) compartment was observed in CMT-3- and DC-treated cells. DC and CMTs also inhibited the invasive potential of the tumor cells in vitro, from 10% (CMT-6) to >90% (CMT-3). CMT-3 and DC decreased matrix metalloproteinase (MMP)-2, tissue inhibitor of MMP (TIMP)-1 and TIMP-2 secretion in treated cultures and inhibited activity of secreted MMPs, CMT-3 was a stronger inhibitor. Daily oral gavage of DC and CMT-3 inhibited tumor growth and metastasis in the Dunning MAT LyLu rat prostate tumor. Decreases in tumor growth (27-35%) and lung metastases were observed (28.9 +/- 15.4 sites/animal [CMT-3-treated] versus 43.6 +/- 18.8 sites/animal [DC-treated] versus 59.5 +/- 13.9 [control]; p < 0.01]. A delay in tumor growth (27 +/- 9.3%, p < 0.05), reduction in metastases (58 +/- 8%) and decrease in tumor incidences (55 +/- 9%, CMT-3-treated) were also observed, when rats were predosed for 7 days. No significant drug-induced morbidity was observed in any of the animals. These results, along with a recently concluded clinical trial, suggest a potential use of CMT-3 as an oral, nontoxic drug to treat metastatic prostate and other cancers.
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PMID:Inhibition of cell proliferation, invasion, tumor growth and metastasis by an oral non-antimicrobial tetracycline analog (COL-3) in a metastatic prostate cancer model. 1185 23

Neuroendocrine differentiation and subsequent excretion of neuropeptides have been demonstrated to be associated with progression of human prostate cancer. Among neuropeptides found to exist in the prostate, bombesin/gastrin-releasing peptide has been shown to upregulate matrix metalloproteinase-9 (MMP-9) in human prostate cancer cell lines. Expression levels of bombesin, MMP-9, and neuron-specific enolase were examined by immunohistochemistry in 41 cases of clinically organ-confined prostate cancers including 9 with microscopic lymph node metastases. Twenty-seven (64%) of the 41 radical prostatectomy specimens were positive for both MMP-9 and bombesin. Expression of these molecules was observed in almost the same population of the cancer cells. The remaining 14 cases were negative for both MMP-9 and bombesin. High-grade tumors (Gleason sum > or = 7) were more likely to express MMP-9 and bombesin (21/24:88%) than low-grade tumors (Gleason sum > or = 6) (7/17:41%). In eight of the nine cases with pathological lymph node metastases, expression of MMP-9 and bombesin was also noted in metastatic sites. Neuron-specific enolase was positive in 16 cases (39%) and not always associated with the expression of bombesin. Expression of bombesin and expression of MMP-9 are common in human prostate cancers and may be related to an aggressive phenotype.
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PMID:Expression of matrix metalloproteinase-9 and bombesin/gastrin-releasing peptide in human prostate cancers and their lymph node metastases. 1219 49


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