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

The mechanisms by which tumor cells metastasize to bone are not well understood. We have investigated the role of the basement membrane glycoprotein, laminin, in bone metastasis, since antagonists to laminin have been shown to inhibit the formation of lung metastases. We studied the formation of osteolytic metastases caused by a human tumor which is known to cause osteolysis and hypercalcemia in nude mice. We found that tumor-bearing nude mice developed hypercalcemia, cachexia, and characteristic osteolytic lesions throughout the skeleton after injection of this human melanoma cell line (A375) into the left ventricle. When we gave injections to nude mice with A375 cells which had been exposed to C(YIGSR)3-NH2, a laminin-derived synthetic peptide containing three linear sequences of YIGSR with an amino-terminal cysteine which competes with laminin for its receptor, we found a decrease in the formation of detectable osteolytic bone metastases. The tumor cells were incubated with the antagonist and then inoculated into nude mice which were administered the antagonist i.p. Hypercalcemia and cachexia were also decreased in tumor-bearing mice treated with the laminin antagonist. In contrast, laminin itself increased the number of osteolytic bone metastases, as has been shown for other tumor cells. These data suggest that laminin plays a role in the formation of osteolytic bone metastases in this model and that laminin antagonists may be useful in the prevention of bone metastases in some human tumors.
 ...
PMID:A synthetic antagonist to laminin inhibits the formation of osteolytic metastases by human melanoma cells in nude mice. 139 44

We have investigated the adhesive properties and invasiveness of cells of the human ovarian carcinoma line, NIH:OVCAR-3, in vitro. OVCAR-3 cells exhibited a similar rate of adhesion to all substrates tested including laminin, fibronectin, and collagens I and IV. The synthetic peptide YIGSR-NH2, which corresponds to an attachment site in laminin, inhibited the adhesion of the cells to laminin, but not to fibronectin. In contrast, a GRGDS-NH2 peptide blocked adhesion to fibronectin but not to laminin. OVCAR-3 cells invaded and formed branched colonies on Matrigel. Colony formation was retarded by both YIGSR-NH2 and GRGDS-NH2 peptides. Serine protease inhibitors and human recombinant TIMP, the tissue inhibitor of metalloproteases, inhibited ovarian tumor cell invasion while a synthetic collagenase IV inhibitor (SC-44463) had no effect. These studies suggest that metalloproteases other than collagenase IV may be important for the invasive activity of ovarian cancer cells. It is possible that synthetic peptides with antiadhesive cellular activity and certain antiproteases could be used to control the progressive colonization and invasion of peritoneal surfaces by malignant ovarian cancer cells.
Invasion Metastasis 1991
PMID:Effects of synthetic peptides and protease inhibitors on the interaction of a human ovarian cancer cell line (NIH:OVCAR-3) with a reconstituted basement membrane (Matrigel). 191 87

A peptide mitogen for cultured osteoblast-like cells was purified from serum-free conditioned culture medium of a human prostatic cancer cell line, PC-3. Based on amino acid sequencing and estimated molecular weight, this peptide was identified as an NH2-terminal fragment of urokinase-type plasminogen activator (uPA). Recombinant high molecular weight (HMW) uPA and the NH2-terminal growth factor domain (GFD) of uPA, but not low molecular weight (LMW) uPA (lacking the NH2-terminal region) stimulated [3H] thymidine incorporation and proliferation in osteoblast-like cells, and specific, competitive binding sites for HMW, but not LMW, uPA were demonstrable. These studies demonstrate the production of a mitogenic NH2-terminal fragment of uPA by a human prostatic cancer cell line which may be of importance in the pathogenesis of osteoblastic metastases.
 ...
PMID:An amino-terminal fragment of urokinase isolated from a prostate cancer cell line (PC-3) is mitogenic for osteoblast-like cells. 212 13

Forty-six patients with the gastrinoma syndrome were divided into 2 categories: 1) benign sporadic gastrinoma (n = 30), and 2) gastrinoma with metastases to liver (n = 16). Thirteen of the 46 patients had multiple endocrine neoplasia type I syndrome. Serum gastrin levels in patients fasted overnight were determined by RIA using antisera directed toward the NH2- and COOH-terminals of heptadecapeptide gastrin (G17) and the NH2-terminus of the triacontatetrapeptide (G34). These results were compared with findings in 50 normal subjects. In the normal subjects, the mean COOH-terminal gastrin-17 level was higher [65 +/- 8 (+/- SEM) pg/ml] than the NH2-terminal gastrin-17 level (11 +/- 0.2 pg/ml) and lower than the NH2-terminal gastrin-34 level (134 +/- 20 pg/ml). The levels of NH2-terminal gastrin-17 were higher in patients with metastatic disease than in those with benign gastrinoma, whereas the COOH-terminal gastrin-17 and the NH2-terminal gastrin-34 levels were similarly high in both groups. The mean ratio of NH2-terminal gastrin-17 to COOH-terminal gastrin-17 was less than 1 in normal subjects (0.22 +/- 0.02) and benign gastrinoma patients (0.2 +/- 0.04), and it was 2.2 +/- 0.41 in the patients with metastatic gastrinoma. An NH2 to COOH gastrin-17 ratio greater than 1 was found in 13 of 16 patients with metastatic gastrinoma, but in none of the patients with benign gastrinoma or normal subjects. Similar results were found in multiple endocrine neoplasia type I patients with benign and metastatic disease. A high NH2 to COOH gastrin-17 ratio is suggestive of metastatic gastrinoma. In 4 patients with metastatic gastrinoma, the NH2 to COOH gastrin-17 ratio fell in parallel with the response to chemotherapy.
 ...
PMID:Evaluation of NH2-terminus gastrins in gastrinoma syndrome. 287 76

In 1941, Huggins and his colleagues discovered that testicular androgens exert a stimulatory effect on prostate cancer growth. Our group has made the key observations that the human adrenals, in addition to the tests, also secrete important amounts of androgens and cancer cells exhibit a marked heterogeneity of androgen sensitivity. In fact, human adrenals secrete large amounts of precursor steroids that are converted into active androgens in peripheral tissues (including the prostate), thus providing 40% to 50% of total androgens in adult men. The action of these androgens remaining after castration can be inhibited in prostatic cancer tissue by administering a pure antiandrogen that also decreases the local concentration of dihydrotestosterone (DHT). The castration levels of serum testosterone left in men after castration have an important stimulatory activity on the growth of androgen-sensitive normal as well as cancer tissues. Cancer cells have markedly different requirements for androgens. Some cell clones can grow in the presence of minimal amounts of androgens, requiring more complete androgen blockade and more potent antiandrogens for inhibiting growth. Among the compounds recommended as antiandrogens, the most unexpected finding is that many of them are devoid of any antiandrogenic activity. In fact, medroxyprogesterone acetate, chlormadinone acetate, and megestrol acetate have androgenic activity, but do not inhibit the peripheral action of DHT in prostatic tissue. These compounds should not be classified as antiandrogens. Cyproterone acetate, on the other hand, is a mixed agonist-antagonist. The only compounds showing pure antiandrogenic activity are Flutamide and its analogues. There is thus a need for a more complete blockade of androgens of both testicular and adrenal origins in order to exert a maximal inhibitory effect on cancer growth. We have therefore performed clinical studies in previously untreated stage D2 and C prostate cancer patients with the combination therapy using the LHRH agonist [D-Trp6, des Gly NH2(10)] LHRH ethylamide and the antiandrogen Flutamide. There was a significant increase in patients with a complete response, as compared with studies limited to the removal or blockade of testicular androgens. There was also a significant decrease in the number of non-responders, an increased duration of positive response, and a decrease in the death rate. This was achieved with minimal or no side effects, thus preserving a good quality of life.
Cancer Metastasis Rev 1987
PMID:Combination therapy in stage C and D prostatic cancer: rationale and five year clinical experience. 332 35

An extract of a tumour metastases from a human medullary thyroid carcinoma contained a high concentration (at least 2.9 nmol/g wet weight) of the immunoregulatory peptide, thymosin-beta 4. The peptide was isolated as a mixture of two components with free and blocked NH2-terminal amino acid residues, the latter form predominating (approximately 98% of the total). The primary structure of the peptide was established by automated Edman degradation after cleavage with cyanogen bromide. The amino acid sequence of human thymosin-beta 4 was identical to thymosin-beta 4 previously isolated from calf thymus. Further studies are warranted to determine whether thymosin-beta 4 production is a useful marker for thyroid and other tumours.
 ...
PMID:Isolation and structural characterization of thymosin-beta 4 from a human medullary thyroid carcinoma. 341 Dec 80

The molecular species of gastrin in the circulation and in tumor extracts were studied in two groups of patients: (1) with benign gastrinoma and (2) with gastrinoma with liver metastases. Radioimmunoassays (RIAs) and immunoaffinity chromatography for the amino (NH2)- and amidated COOH-terminus of gastrin-17 (antiserum G17) and the NH2-terminus of gastrin-34 (antiserum G34) were employed. In both benign and metastatic tumors the molecular forms of gastrin in boiling water extracts measured by the gastrin-17 NH2- and COOH-terminal assays were similar. In addition to a molecular component resembling the amidated gastrin-17, there were also significant amounts of larger molecular weight (mol. wt.) forms. The larger mol. wt. forms absorbed by the NH2-terminus of G17 antiserum corresponded to the COOH-terminus-extended forms of gastrin-17. Furthermore, larger mol. wt. gastrins immunopurified by antiserum to the NH2-terminus of gastrin-34 corresponded to gastrin-34 extended molecules. Sera of patients with liver metastases had higher concentrations of the NH2-terminal of gastrin-17 whereas sera of patients with benign gastrinoma contained predominantly gastrins detected by the COOH-terminal assay. These results suggest that: (a) there are differences in the molecular pattern of gastrin in the circulation of patients with benign and metastatic gastrinomas; (b) gastrins which are fully processed with carboxy-terminal amidation predominate in the circulation of patients with benign gastrinoma; and (c) gastrins containing the gastrin-17 and COOH-terminally extended gastrin-17 and gastrin-34 precursor molecules occur in high concentration in the circulation of gastrinoma patients with metastases to the liver.
 ...
PMID:Identification of gastrin molecular variants in gastrinoma syndrome. 355 1

Thrombospondin induces the migration of human melanoma and carcinoma cells. Using a modified Boyden chamber assay, tumor cells migrated to a gradient of soluble thrombospondin (chemotaxis). Checkerboard analysis indicated that directional migration was induced 27-fold greater than stimulation of random motility. Tumor cells also migrated in a dose-dependent manner to a gradient of substratum-bound thrombospondin (haptotaxis). A series of human melanoma and carcinoma cells were compared for their relative motility stimulation by thrombospondin haptotaxis vs. chemotaxis. Some cell lines exhibited a stronger haptotactic response compared to their chemotactic response while other lines exhibited little or no migration response to thrombospondin. Human A2058 melanoma cells which exhibit a strong haptotactic and chemotactic response to thrombospondin were used to study the structural domains of thrombospondin required for the response. Monoclonal antibody C6.7, which binds to the COOH-terminal region of thrombospondin, inhibited haptotaxis in a dose-dependent optimal manner. C6.7 had no significant effect on thrombospondin chemotaxis. In contrast, monoclonal antibody A2.5, heparin, and fucoidan, which bind to the NH2-terminal heparin-binding domain of thrombospondin, inhibited thrombospondin chemotaxis but not haptotaxis. Monoclonal antibody A6.1 directed against the internal core region of thrombospondin had no significant effect on haptotaxis or chemotaxis. Synthetic peptides GRGDS (50 micrograms/ml), but not GRGES, blocked tumor cell haptotaxis on fibronectin, but had minimal effect on thrombospondin or laminin haptotaxis. The 140-kD fragment of thrombospondin lacking the heparin-binding amino-terminal region retained the property to fully mediate haptotaxis but not chemotaxis. When the COOH region of the 140-kD fragment, containing the C6.7-binding site, was cleaved off, the resulting 120-kD fragment (which retains the RGDA sequence) failed to induce haptotaxis. Separate structural domains of thrombospondin are therefore required for tumor cell haptotaxis vs. chemotaxis. This may have implications during hematogenous cancer metastases formation.
 ...
PMID:Thrombospondin-induced tumor cell migration: haptotaxis and chemotaxis are mediated by different molecular domains. 368 Mar 88

Treatment with an LHRH agonist (HOE-766) alone causes an almost complete blockage of testicular testosterone formation in rat and man. In order to neutralize androgens of adrenal origin, a pure antiandrogen (RU-23908) was given in combination with the LHRH agonist in the rat. At doses where each drug has no or minimal effect alone, prostate and seminal vesicle weight were reduced to 9 and 15% of control after 5 months of combined treatment, respectively. Among the species studied, man is the most sensitive to the inhibitory effect of treatment with LHRH agonists on testicular steroidogenesis. Near castration levels of serum testosterone and 5 alpha-dihydrotestosterone are obtained within 1-2 weeks of daily subcutaneous administration of the LHRH agonist [D-Ser(tbu)6, des-Gly-NH2(10)]LHRH ethylamide (HOE-766) in adult men with cancer of prostate. The decrease in serum androgen levels is accompanied by objective remission of the cancer in approximately 75% of cases. In a preliminary study where the LHRH agonist was administered in combination with the pure antiandrogen RU-23908, it was shown that the antiandrogen does not interfere with the LHRH-induced inhibition of serum androgen levels. The ease of application of this new form of hormonal therapy should permit its use at early stages of the disease and thus reduce the development of metastases and androgen-resistant cell clones.
 ...
PMID:New hormonal therapy in prostate cancer: combined use of a pure antiandrogen and an LHRH agonist. 641 78

Twenty-two patients with advanced prostatic carcinoma were subjected either to orchiectomy (group I, n = 5) or to chronic administration of a gonadotropin releasing hormone agonistic analogue D, Ser (TBU)6, des Gly-NH2(10) LHRH nonapeptide (HOE 766) (group 2, n = 17). Plasma testosterone was similar in both groups prior to treatment (group 1: 636 +/- 129.29, group 2: 580.85 +/- 37.57; X +/- SE). The levels attained in group I were significantly lower (P less than .05) than those of group 2 through eight weeks of follow-up but were similar by the third month. Prostatic size (cm2) as estimated by transabdominal ultrasonography did not differ between the two groups prior to treatment (group 1: 23.6 +/- 3.35, group 2: 21.4 +/- 1.97; X +/- SE). Both therapies resulted in a decrease of prostatic size that was significantly more pronounced (P less than .05) in group I compared with group 2 by the first and third month; by the six month, there was no statistical difference in the prostatic size attained with either therapeutic modality. Persistent suppression of prostatic size was documented in all patients of group 2 chronically (up to 24 months) treated with HOE 766 even when there was evidence of uninhibited or progressive bony metastases. The above data 1) indicate the efficacy of the HOE 766 in inducing medical castration and prostatic shrinkage in advanced carcinoma of the prostate, 2) document the usefulness of transabdominal ultrasound in the follow-up of such patients, and 3) suggest a relationship between the rapidity of tumor shrinkage and Leydig cell suppression.
 ...
PMID:Transabdominal ultrasonography in the evaluation of patients with advanced prostatic carcinoma: effects of castration and of chronic administration of a gonadotropin releasing hormone agonistic analogue. 641 31


1 2 3 4 5 6 Next >>