Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate cancer is the most common cancer amongst males in developed countries. Surgical removal of the prostate effectively cures the primary disease but the metastatic disease is refractory to most forms of chemotherapy. There is a clinical need to develop novel treatment strategies that exploit the mode of action of both conventional and alternative drugs/medicinal plants. We have been investigating the anti-proliferative and anti-tumor effects of an herbal preparation termed PC-SPES (patent pending, US serial number 08/697, 920) which is a refined powder of eight different medicinal plants. PC-SPES administered as a food supplement caused a dramatic decrease in prostate specific antigen levels in some prostate cancer patients with advanced disease. These preliminary clinical findings laid the foundation for a program to examine the in vitro and in vivo effects of PC-SPES, and identify the active component in this mixture so that a standardized treatment regimen can be formulated. In this communication, we report the anti-tumor effects of PC-SPES incorporated in the diet utilizing a well studied Dunning R3327 rat prostate cancer model. Dietary PC-SPES at levels of 0.05% and 0.025% did not exhibit any toxicity and no significant difference in food intake was noted at the end of six weeks. Dose dependent inhibitory effect of dietary PC-SPES was observed on both tumor incidence (P=0. 01) and rate of tumor growth when tumors were induced in syngeneic Copenhagen rats by intradermal injections of MAT-LyLu cells that are known to metastasize in the lung and lymph nodes. The number of pulmonary metastases in animals on PC-SPES that showed no primary tumor growth had no metastatic lesions in the lung, however, in animals that did not respond to PC-SPES, the number of pulmonary metastases was not significantly different from the non-treated controls. The significant anti-tumor effects of PC-SPES on MAT-LyLu induced tumorigenesis and metastasis in Copenhagen rats, in general refractory to most conventional therapy, suggests a therapeutic benefit of this herbal food supplement and may be a useful adjuvant to conventional therapeutic modalities.
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PMID:Anti-tumor effects of PC-SPES, an herbal formulation in prostate cancer. 1008 19

The steroid hormone 1,25-dihydroxyvitamin D [1,25(OH)2D, also known as calcitriol] is known to inhibit the proliferation and to promote the differentiation of human prostate cancer cells. Additionally, we showed that 1,25(OH)2D markedly inhibits the invasiveness of human prostate cancer cells in vitro (G. G. Schwartz et al., Cancer Epidemiol. Biomark. Prev., 6: 727-732, 1997). These properties support the use of 1,25(OH)2D as differentiation therapy in prostate cancer. However, the use of 1,25(OH)2D in vivo is limited by the risk of hypercalcemia. We therefore compared the effects of 1,25(OH)2D and of EB1089, an analogue of 1,25(OH)2D with reduced calcemic effects, in an in vivo model of androgen-insensitive metastatic prostate cancer, the rat Dunning MAT LyLu prostate cancer model. Tumor growth and metastasis were studied using Copenhagen rats given s.c. injections of MAT LyLu cells. Fifty male rats were divided into five groups of 10 rats each. Four experimental groups received i.p. injections of low and high doses of 1,25(OH)2D and EB1089 (0.5 and 1.0 microg/kg, low and high, respectively). A control group received injections of vehicle only. Tumor volumes were measured three times per week. Rats were weighed weekly. The number of metastases to the lungs and the extent of hypercalcemia were evaluated. Compared with controls, tumor volumes were significantly smaller in all experimental groups. Similarly, the number of lung metastases (number of foci/lung) was reduced markedly by both 1,25(OH)2D and EB1089. Control rats developed 22.7 (+/- 1.98 SE) tumor foci per lung. Rats treated with 1,25(OH)2D and with EB1089 (1.0 microg/kg) developed 10.4 (+/- 2.81) and 7.70 (+/- 1.29) tumor foci, respectively (P < 0.001 and P < 0.0001, respectively; drug versus control). Compared with controls (10.79 +/- 0.1 mg/dl), serum calcium levels were significantly elevated in both 1,25(OH)2D and EB1089-treated rats (P < 0.01). However, EB1089 was significantly less calcemic than 1,25(OH)2D (12.59 +/- 0.21 mg/dl versus 14.47 +/- 0.46 mg/dl; 1.0 microg/kg; P < 0.001). Rats treated with 1,25(OH)2D showed marked weight loss: 20.0 +/- 1.9% and 26.3 +/- 1.7% of their initial weight (low and high doses, respectively, P < 0.001). Weight loss was significantly lower in rats treated with EB1089 at the high dose 8.4 (+/- 2.9) %. Moreover, rats treated with low-dose EB1089 gained 5.2 (+/- 3.7) % of their initial weight. In conclusion, 1,25(OH)2D and EB1089 showed marked and equivalent inhibition of prostate cancer metastasis in vivo. EB1089 was significantly less calcemic than 1,25(OH)2D and did not induce severe weight loss. This is the first report of a vitamin D analogue that significantly inhibits prostate cancer metastasis in vivo and that does so without producing cachexia or unacceptable hypercalcemia.
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PMID:Inhibition of prostate cancer metastasis in vivo: a comparison of 1,23-dihydroxyvitamin D (calcitriol) and EB1089. 1009 Mar 2

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

Prostate cancer cells contain specific receptors (VDR) for la,25-dihydroxyvitamin D (1alpha,25(OH)2D), which is known to inhibit the proliferation and invasiveness of these cells. These findings support the use of 1alph,25(OH)2D for prostate cancer therapy. However, because 1alpha,25(OH)2D can cause hypercalcemia, analogs of 1alpha,25(OH)2D that are less calcemic but which exhibit potent antiproliferative activity would be attractive as therapeutic agents. We studied four vitamin D compounds: 25-hydroxyvitaminD3 [25(OH)D3], which is converted to 1alpha,25(OH)2D3 in prostate cells, and three analogs of 1alpha,25(OH)2D3: EB1089, 19-nor-1alpha,25(OH)2D2 and hexafluoro-1alpha,25(OH)2D3 (F6-1alpha,25(OH)2D3). 19-nor-1alpha,25(OH)2D2 has been shown to be less calcemic than 1alpha,25(OH)2D3 in clinical trials. F6-1alpha,25(OH)2D3 has been shown to be 100-fold more active than 1alpha,25(OH)2D3 and to be longer-lasting in inhibiting keratinocyte proliferation in vitro. EB1089 has been shown to be less calcemic than 1alpha,25(OH)2D3 in rats implanted with Leydig cell tumors. For 25(OH)D3, 19-nor-1alpha,25(OH)2D2 and F6-1alpha,25(OH)2D3, we studied the in vitro effects and compared their activity to 1alpha,25(OH)2D3 on cellular proliferation by 3H-thymidine incorporation assay. In addition, we studied transactivation of the VDR in the presence of 25(OH)D3 and 19-nor-1alpha,25(OH)2D2 in prostate cells. For EB1089, we compared its inhibition of prostate cancer metastasis to that induced by 1alpha,25(OH)2D3 in vivo in the rat Dunning MAT LyLu prostate cancer model. We found that 1alpha,25(OH)2D3 and 19-nor-1alpha,25(OH)2D2 caused similar dose-dependent inhibition in 3H-thymidine incorporation into DNA in prostate cells and behaved similarly in the CAT reporter gene transactivation assay in PC-3/VDR cells. F6-1alpha,25(OH)2D3 is 10- to 50-fold more active than 1alpha,25(OH)2D3 in 3H-thymidine incorporation into DNA in the primary cultured prostate cells. Likewise, 25(OH)D3 had comparable antiproliferative activity to la,25(OH)2D3. In the rat model, tumor volumes and the number of metastases in the lungs were significantly reduced by both 1alpha,25(OH)2D3 (10.4 +/- 2.81 tumor foci) and EB1089 (7.7+/-1.29 tumor foci) compared to controls (22.7 +/- 1.98 tumor foci). Although serum calcium levels were significantly elevated in both 1alph,25(OH)2D3- and EB1089-treated rats, EB1089 was significantly less calcemic than 1alpha,25(OH)2D3 (12.59+/-0.21 mg/dl versus 14.47+/-.46 mg/dL; 1 microg/kg; p < 0.001). In conclusion, our data indicate that 25(OH)D3 and the three 1alpha,25(OH)2D analogs represent two different solutions to the problem of hypercalcemia associated with vitamin D-based prostate cancer therapies: 25(OH)D3 requires the presence of 25-hydroxyvitaminD-1alpha-hydroxylase, whereas 19-nor-1alpha,25(OH)2D2, F6-1alpha,25(OH)2D3 and EB1089 do not. These compounds may be good candidates for human clinical trials in prostate cancer.
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PMID:Evaluation of vitamin D analogs as therapeutic agents for prostate cancer. 1289 29

Indole-3-carbinol (I3C), a compound present as glucobracissin in cruciferous vegetables has anticancer activities which is in line with some of the epidemiological evidence that suggests a beneficial effect of consumption of cruciferous vegetables on cancer incidence and progression. The precise target of indole-3-carbinol has not been determined. We examined the effect of I3C on prostate cancer in a well-defined R3327 model using Copenhagen rats and the transplantable cell line, MAT-LyLu. This cell line derived from a tumor in Copenhagen rats is androgen independent and metastasizes to the lung and lymph nodes. Tumors were induced in Copenhagen rats by injecting MAT-LyLu subcutaneously and the animals treated with I3C that was administered either intraperitoneally or intravenously, in order to achieve maximal systemic exposure. This was a departure from the traditional chemopreventive route of indole-3-carbinol where the compound was incorporated in the diet. Our results indicate that I3C inhibited the incidence, growth and metastases of MAT-LyLu cells and both i.p. and i.v. injections of I3C were equally effective. Statistical analysis (Kaplan-Meier curves) clearly indicates a tumor-free and overall survival benefit as a result of treatment with I3C. These studies show for the first time that I3C in an injectible form has anti-prostate cancer activity.
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PMID:Anti-carcinogenic and anti-metastatic properties of indole-3-carbinol in prostate cancer. 1558 7

Bone metastases occur frequently in patients with advanced breast or prostate cancer. Bone metastases can be predominantly osteolytic, osteoblastic or mixed. Studies with animal models allow advances in understanding the molecular basis for bone metastases and provide new targets for therapy. Several animal models have been developed in rat with different pathophysiologies; they required injection or implantation of neoplastic cells into orthotopic locations, bones or the left ventricle of the heart. Several specific strains of rat have an increased incidence of spontaneous tumors. Carcinomas can be induced by either chemicals or physical agents. However, the most used and convenient way to induce bone metastases is a syngeneic transmission. MAT-Ly-Lu cells have been used in several models using Copenhagen rats to induce osteoblastic bone lesions. PA-III cells derived from Pollard tumors can also produce a combination of osteolytic and osteoblastic reactions at the site of transplantation. Osteolytic bone lesions can be obtained with an injection of Walker cells. The use of 13762 or c-SST2 cells allows also leads to osteolysis. Human xenografts can only be used in nude animals. It is essential to validate and correctly interpret the lesions in several models of bone metastasis. No animal model is sufficient by itself to represent the clinical findings observed in humans. The use of models developed in different species should be more predictive and bring a beam of arguments for a better knowledge of pathophysiological and therapeutic mechanisms.
Clin Exp Metastasis 2005
PMID:Rat models of bone metastases. 1667 Sep 64

The glycolytic phenotype is a widespread phenomenon in solid cancer forms, including breast cancer. Dichloroacetate (DCA) has recently been proposed as a novel and relatively non-toxic anti-cancer agent that can reverse the glycolytic phenotype in cancer cells through the inhibition of pyruvate dehydrogenase kinase. We have examined the effect of DCA against breast cancer cells, including in a highly metastatic in vivo model. The growth of several breast cancer cell lines was found to be inhibited by DCA in vitro. Further examination of 13762 MAT rat mammary adenocarcinoma cells found that reversal of the glycolytic phenotype by DCA correlated with the inhibition of proliferation without any increase in cell death. This was despite a small but significant increase in caspase 3/7 activity, which may sensitize cancer cells to other apoptotic triggers. In vivo, DCA caused a 58% reduction in the number of lung metastases observed macroscopically after injection of 13762 MAT cells into the tail vein of rats (P = 0.0001, n > or = 9 per group). These results demonstrate that DCA has anti-proliferative properties in addition to pro-apoptotic properties, and can be effective against highly metastatic disease in vivo, highlighting its potential for clinical use.
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PMID:Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. 1954 30

Tumour cells can efficiently respond to numerous factors affecting their motility. However, the role of substrata topography in the regulation of cancer cell motility has been quantitatively studied in only a few cases. We demonstrated that human (DU-145) and rat (MAT-LyLu and AT-2) prostate cancer cells are efficiently contact guided by underlying normal cells when invading surrounding tissues and forming metastases. Prostate cancer cells moving on the surface of fibroblasts displayed significantly greater cell displacement than those moving on plastic substrata. This effect was correlated with the polarization (contact guidance) and increased speed of cell movements. We subsequently verified the hypothesis that the observed contact guidance of prostate cancer cells migrating on the surface of fibroblasts results from their reaction to the microtopography of normal cells. The responses of cells to multiple grooved substrata of a size corresponding to the dimensions of a compact monolayer culture of human skin fibroblasts were studied, and the migration of prostate cancer cells appeared to be efficiently affected by topographical features of the substratum. In contrast to random movement under control conditions, all investigated prostate cancer cell lines grown on patterned substrata migrated mainly along artificial grooves and covered, as a result of contact guidance, a longer distance than cells on plain substrata. Moreover, the reaction to microtopography was correlated with the metastatic activity of prostate cancer cells. In conclusion, our results show that grooved substrata have a substantial effect on prostate cancer migration. Since all types of tissue show some kind of patterning and alignment, topographic factors may be crucial for the effective migration of prostate cancer cells during the metastatic process.
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PMID:Topographical control of prostate cancer cell migration. 2147 14

Metastasis of cancer to the skeleton represents a debilitating turning point in the lives of patients. Skeletal metastasis leads to moderate to severe ongoing pain along with bone remodeling that can result in fracture, events that dramatically diminish quality of life. Interleukin-6 (IL-6) levels are elevated in patients with metastatic breast cancer and are associated with a lower survival rate. We therefore determined the consequences of inhibition of IL-6 signaling using a novel small molecule antagonist, TB-2-081, on bone integrity, tumor progression, and pain in a rodent model of breast cancer. Rat MAT B III mammary adenocarcinoma cells were injected and sealed within the tibia of female Fischer rats. Growth of these cells within the rat tibia elicited increased IL-6 levels both within the bone exudate and in the plasma, produced ongoing pain and evoked hypersensitivity, and bone fracture that was observed by approximately day 12. Systemic TB-2-081 delivered by subcutaneous osmotic minipumps starting at tumor implantation prevented tumor-induced ongoing bone pain and evoked hypersensitivity without altering tumor growth. Remarkably, TB-2-081 infusion significantly reduced osteolytic and osteoblastic bone remodeling and time to fracture likely by decreasing osteoclastogenesis and associated increase in bone resorption. These findings indicate that blockade of IL-6 signaling may represent a viable, disease-modifying strategy to prevent tumor-induced bone remodeling allowing for stabilization of bone and decreased fractures as well as diminished ongoing pain that may improve quality of life of patients with skeletal metastases. Notably, anti-IL-6 antibodies are clinically available allowing for rapid testing of these possibilities in humans.
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PMID:Disease modifying actions of interleukin-6 blockade in a rat model of bone cancer pain. 2930 Feb 79

Treatment of patients with lung metastases remains a major challenge. A possible target for therapies is the inhibition of vascularization of metastases. We examined the vascularisation process of lung metastasis in six different preclinical models and found that the tumours incorporated the pre-existing alveolar capillaries (i.e. vessel co-option). During the initial phase of vessel co-option, the incorporated capillaries were still sheathed by pneumocytes, but these incorporated vessels subsequently underwent different fates dependent on the model. In five of the models examined (B16, HT1080, HT25, C26 and MAT-B-III), the tumour cells gradually stripped the pneumocytes from the vessels. These dissected pneumocytes underwent fragmentation, but the incorporated microvessels survived. In the sixth model (C38), the tumour cells failed to invade the alveolar walls. Instead, they induced the development of vascularised desmoplastic tissue columns. In conclusion, our data show that lung metastases can vascularise by co-opting the pulmonary microvasculature.
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PMID:[Mechanism of tumour vascularisation in experimental lung metastases]. 3218 66


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