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)

Needle biopsies of normal, benign hyperplastic, neoplastic and metastatic prostatic tissues were used to study the uptake of 3H testosterone by these tissues and their ability to convert testosterone to dihydrotestosterone. Histological quantification is important because stroma is active in both of these areas of biochemical activity. The 3H testosterone uptake by the tissues is relatively similar but benign prostatic hyperplasia and normal tissue consistently convert more testosterone to dihydrotestosterone than do neoplastic tissues. The least active in this regard are pure biopsies of neoplastic cells obtained from nodal metastases, suggesting extensive loss or repression of 5-alpha-reductase activity. Further, this defect is present in neoplastic tissues even if the patient has had an orchiectomy and/or received hormonal therapy. It is not known whether testosterone may substitute for dihydrotestosterone in the neoplastic nucleus. Our studies indicate that animal models that yield data on suppresion of 5-alpha-reductase activity by certain agents may have limited relevance to the tissues of human prostatic carcinoma.
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PMID:In vitro uptake of 3H testosterone and its conversion to dihydrotestosterone by prostatic carcinoma and other tissues. 6 62

A total of 28 untreated patients with asymptomatic, stage D prostate cancer was randomized in a double-blinded fashion to receive finasteride (10 mg. per day), a 5 alpha-reductase inhibitor or placebo. Patients were evaluated at 3-week intervals by rectal examination, and serum prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) levels, and at 6-week intervals by bone scan and transrectal ultrasound determinations of prostatic volume. Patients stopped the medication at week 6 at the discretion of the investigator when PSA levels increased from baseline. After 12 weeks all patients were reevaluated. Of the patients 13 received finasteride and 15 received placebo. The 2 groups did not differ statistically with respect to patient age, initial PSA and PAP level, or the extent of metastases on initial bone scan. A statistically significant decrease in the median percentage change from baseline in PSA at weeks 3 and 6 occurred in the finasteride group compared to the placebo group (-22.9% versus -2.9% and -15.1% versus +11.7%, respectively, p less than 0.05). Finasteride had no effect upon PAP, serum testosterone, prostatic volume or appearance of bone scans. A decrease in serum PSA in the finasteride treatment group suggests that finasteride exerts a minor effect in patients with prostate cancer. This effect does not approach that seen with medical or surgical castration yet because of the potency preserving feature and the lack of toxicity finasteride may warrant further study in the treatment of prostate cancer.
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PMID:Multicenter, randomized, double-blind, placebo controlled study to investigate the effect of finasteride (MK-906) on stage D prostate cancer. 138 74

Flow cytometry of 20 prostate cancer specimens was carried out and the percentage DNA content in each phase of the cell cycle was correlated to the 5 alpha-reductase activity of the tumour. A group of 20 hyperplastic specimens was also entered into this study as control. Tumours were divided into 3 groups on the basis of their 5 alpha-reductase activity. This classification made it possible to identify a group of tumours of which none formed metastases (diploid tumours with 5 alpha-reductase activity greater than 20 pmol/mg protein/30 min and with less than 10% of the cells undergoing mitosis) and a second group of which 78% had metastasised at the time of presentation (diploid tumours with 5 alpha-reductase activity less than 10 pmol/mg protein/30 min and with more than 15% of the cells undergoing mitosis). DNA content within each of the 5 alpha-reductase groups appeared also to correlate with the histological grade of the cancer but no relationship was established with the stage of the disease. Our results suggest that a multi factorial discriminant combining DNA ploidy and 5 alpha-reductase measurements offers a good prognostic index for the assessment of disease progression in prostate cancer and that this might form the basis of a new approach to the treatment of this disease.
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PMID:Flow cytometric analysis of cellular DNA in human prostate cancer: relationship to 5 alpha-reductase activity of the tissue. 247 58

Synvinolin (MK-733), a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMG-CoA reductase) depressing de novo synthesis of cholesterol, was given to BN472 tumor cells in culture medium, 2 days prior to i.v. injection of the cells into syngeneic rats. Another group of rats received cells cultured under the same conditions but without synvinolin. Two different types of culture medium were used, a 'complete' medium (Hybridoma) and a medium (RPMI 1640) to which 1 per cent of fetal calf serum (FCS) was added. Tumor cells cultured in the presence of synvinolin showed significantly lower cholesterol values than untreated cells. Tumor cells treated with synvinolin had a decreased ability to form metastatic nodules when compared with control cells. The results supply further evidence for the suggestion that cholesterol modulates the ability of mononuclear cells to eliminate tumor cells, although it cannot be excluded that alteration of cell growth plays an important role as well.
Clin Exp Metastasis
PMID:Modulation of metastatic ability by inhibition of cholesterol synthesis. 275 4

LM fibroblasts grown in a chemically-defined, serum-free medium readily incorporated choline or one of three analogues of choline, namely N,N-dimethylethanolamine, N-monomethylethanolamine, or ethanolamine into membrane phospholipids. The effect of these phospholipid manipulations in vitro on tumor growth and metastasis was examined in nude mice. Serum and choline-fed cells most frequently metastasized (74% and 68%, respectively), while frequency of lung metastasis was 46%, 42% and 17% in mice injected with cells fed with dimethylethanolamine, monomethylethanolamine, and ethanolamine, respectively. Metastases from cells cultured with serum, choline or dimethylethanolamine, but not from monomethylethanolamine or ethanolamine, were extensive and highly invasive. The specific activity of the (Na+ + K+)-ATPase but not of 5'-nucleotidase was significantly decreased in local tumor plasma membranes from choline analogue-fed cells as compared to tumor plasma membranes from choline-fed cells. When compared to the choline-fed tumor cells, the specific activities of three mitochondrial enzymes, namely NADH dependent, rotenone insensitive NADH-dependent, and rotenone sensitive NADH-dependent cytochrome-c reductase, were significantly increased in the choline analogue-supplemented cells. The arachidonic acid content of phosphatidylcholine in plasma membranes, microsomes, and mitochondria was significantly decreased in tumor membranes from choline analogue-fed cells as compared to tumor membranes from choline-fed cells. As compared to local tumor plasma membranes, the lung metastasis plasma membranes had elevated (Na+ + K+)-ATPase specific activity, phospholipid oleic and arachidonic acid content, and fluidity. In contrast, the 5'-nucleotidase specific activity, the content of cholesterol, phospholipid, and phosphatidylethanolamine were decreased in lung metastasis plasma membranes. In summary, membrane alterations of LM tumor cells in vitro (1) were not completely reversed in vivo, and (2) affected metastatic ability.
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PMID:Local and metastatic tumor growth and membrane properties of LM fibroblasts in athymic (nude) mice. 283 81

Activities of several steroid metabolizing enzymes (steroid sulfate-sulfatase, 17 beta-hydroxysteroid dehydrogenase, 5 alpha-reductase, and 3 alpha beta-hydroxysteroid dehydrogenase) as well as total tissue content and subcellular distribution (nuclear-extranuclear) of several androgen precursors, active androgens, and androgen deactivation products (DHEA sulfate, DHEA, 5-androstenediol, 4-androstenedione, testosterone, DHT, and 3 alpha-androstanediol) were quantified in primary tumors and lymph node metastases of human prostatic cancer obtained from patients without previous endocrine manipulation. Primary tumors were compared to benign parts of the same prostates, and the metastases were compared to their primary tumors. All enzymes and steroids found in benign prostatic tissues could also be detected in the malignant tissues. Even the capacity to accumulate active androgens in the nuclei was found to be unchanged in nearly all of the samples. Lower activities of hormone-dependent enzymes were observed in the cancers, suggesting a less efficient utilization of hormonal stimuli. Most striking changes found in the malignant tissues were a subtotal loss of 5 alpha-reductase activity and a metabolic shift to testosterone, which was more pronounced in samples from metastatic disease as compared to samples from non-metastatic disease. In conclusion, primary tumors and metastases of prostatic cancers not treated by endocrine manipulations retain their androgen receptor system and possess the same capacity to metabolize adrenal androgen precursors along the pathway to DHT as benign prostatic tissue. Consequently, they should be able to use at least androstenedione for production of active androgens directly in the target tissue.
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PMID:Androgens, adrenal androgen precursors, and their metabolism in untreated primary tumors and lymph node metastases of human prostatic cancer. 285 35

Lysosomal enzymes were elevated about two-fold in primary s.c. Lewis lung carcinoma as compared with metastatic nodules in the lung. In a time course experiment, a general two-fold elevation of acid phosphatase and several glycosidases was observed in the primary tumor between the 14th and 17th postimplant day following s.c. inoculation of Lewis lung carcinoma. This increase in hydrolytic enzyme activity was not due to necrosis in the primary tumor since a comparison of enzyme activities in the nonnecrotic and necrotic areas demonstrated much higher activities in the nonnecrotic areas. No increases in lysosomal enzyme activity were observed with time in Sarcoma 180, a tumor which does not metastasize. There was no change with time in primary Lewis lung tumor lactate dehydrogenase activity while a 7-fold increase in serum lactate dehydrogenase activity was observed in tumor-bearing mice. Mitochondrial succinate-2-(p-iodophenyl)-3-(p-nitrophenyl)-5-phenyltetrazolium reductase levels fell in the primary Lewis lung tumor as the tumor size increased. A positive correlation was observed between the time of the elevations of tumor lysosomal enzymes in Lewis lung carcinoma and the appearance of micro- and macrometastatic lesions in the lungs. The mechanisms accounting for the increased intratumoral lysosomal enzymes are unknown, but they may be related to macrophage infiltration or other tumor-host interactions which may facilitate the dissemination of tumor cells.
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PMID:Elevation of lysosomal enzymes in primary Lewis lung tumor correlated with the initiation of metastasis. 742 42

Lovastatin (LST) is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme that regulates the biosynthesis of cholesterol. This drug is used clinically to treat patients with hypercholesterolemia. Numerous studies have also suggested an important, if not essential, role of the cholesterol biosynthetic pathway to cell growth and proliferation. In fact, recent studies demonstrating the inhibitory effects of LST on various tumor cells have drawn much attention. We now describe a novel action of LST that inhibited experimental lung metastasis of the highly metastatic B16F10 mouse melanoma in nude mice. Further, when used in in vitro studies, LST pretreatment of B16F10 cells resulted in inhibition of attachment, motility, and invasion, which are key steps in the dynamic sequence of events that comprise the metastatic cascade. Our studies also suggested that the antimetastatic effect of LST on B16F10 cells is probably not mediated by a growth inhibitory action. We submit that these observations identify an antimetastatic agent with potentially useful clinical application.
Invasion Metastasis 1993
PMID:Metastasis of B16F10 mouse melanoma inhibited by lovastatin, an inhibitor of cholesterol biosynthesis. 786 Feb 24

Adrenal androgens contribute 40% of total androgens in adult men. The inactive precursor steroids dehydroepiandrosterone (DHEA) and DHEA-sulfate are secreted in large amounts by the adrenals and reach the prostate and other peripheral target tissues, where they are transformed into the potent androgen dihydrotestosterone (DHT). We have cloned and sequenced the cDNAs and/or genes which encode the enzymes responsible for the transformation of DHEA into DHT, namely 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase, 17 beta-hydroxysteroid dehydrogenase and 5 alpha-reductase. Blockade of DHT synthesized by these enzymes, with a pure antiandrogen of the class of flutamide, prolongs life in advanced prostate cancer, the effect being much more important when a small number of metastases is present. Most importantly, 3-month combination therapy reduces cancer-positive margins at radical prostatectomy, from 38.5% in control patients to only 13% in those who received combination therapy. Combined with an efficient strategy for detection of early-stage prostate cancer, the present approach could offer the possibility of a cure to more than 80% of prostate cancer patients, compared with the present situation where a cure can be offered to less than 20% of patients, since the first diagnosis of prostate cancer is usually made at a late stage of the disease.
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PMID:Intracrinology: the basis for the rational design of endocrine therapy at all stages of prostate cancer. 826 32

Tumors derived from the colonic epithelium exhibit cholesterol metabolism which is clearly different from that in fibroblasts, hepatocytes, adrenals, and ovaries. In hepatocytes and fibroblasts MEV inhibition of the rate limiting step in cholesterol synthesis HMG Co A reductase can be overcome by the uptake of LDL. Colon cancer cells however do not overcome MEV inhibition by LDL uptake but rather exhibit further growth suppression Mevinolin (Mevacor), a drug used to lower serum cholesterol levels has the advantage of accumulating in the liver to approximately 95% with the first pass. A small but variable percentage of non-sterol precursors may escape inhibition and be utilized for other pathways in the isoprenylation of certain proteins, among them members of the ras family. Mutated ras, an oncogene, is found in 40-50% of colon tumors and the expression of a functional gene product is dependent on isoprenylation for anchorage to the tumor cell membrane. d-Limonene, a relatively non-toxic monoterpene found in orange skin oil, selectively inhibits isoprenylation and also accumulates to some extent in the liver. It was hypothesized that the differences in mevalonate metabolism between hepatocytes and colon tumor cells could provide a chemotherapeutic advantage in which MEV and/or d-limonene could effectively inhibit cholesterol synthesis and post-translational modification of proteins with non-sterol cholesterol precursors in colon tumor derived hepatic metastases and thus inhibit their growth. Since each drug affects aspects of mevalonate synthesis at different points, the effects of the combination of their agents on inhibiting tumor metastases was investigated to ascertain if these could be additive. In tissue culture, MEV and d-limonene significantly inhibited the growth of CT-26, a murine transplantable colon tumor. Cholesterol synthesis assessed in these cells indicated that in lipid deficient media the following additions-25-hydroxycholesterol, and LDL significantly reduced cholesterol synthesis. Conversely, perillyl alcohol increased cholesterol synthesis 2.5 fold. In cells cultured in FBS based medium, which have an FBS control, MEV treatment reduced cholesterol synthesis to 65% of control. Perillyl alcohol increased synthesis 1.4 fold and when given in conjunction with MEV, it abolished the effects of this inhibitor. In isoprenylation studies of 14C-mevalonate incorporation into proteins, MEV impaired isoprenylation by restricting synthesis of mevalonate derived intermediates. Results of CT-26 treatment with perillyl alcohol are inconsistent with its putative role as a protein isoprenylation inhibitor. The combination of these agents indicates an additive action which requires additional investigation to elucidate their mechanism(s). Dietary MEV and d-limonene were evaluated alone and in combination for their chemotherapeutic potential in a hepatic "metastasis" model. Using splenic colonization in which CT-26 was implanted into the spleen and ultimately seeded the liver, each of these compounds were found to inhibit the growth of resultant tumors both alone and in combination by approximately 80% versus controls at 35 days post-implantation. Assessment of HMGCoA reductase in liver and tumor indicated that these agents were effective in reaching these target sites. The findings to date indicate that while d-limonene and MEV may differentially affect the same pathway, and their individual actions may appear antagonistic in vitro, their overall action individually or together, appears promising as a chemotherapeutic modality for the possible management of hepatic metastases from colon cancer.
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PMID:Effects of monoterpenes and mevinolin on murine colon tumor CT-26 in vitro and its hepatic "metastases" in vivo. 888 30


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