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)

A series of 18 ruthenium(III) complexes, structurally related to the selective antimetastatic drug Na[trans-RuCl4(DMSO)Im], and characterized by the presence of sulfoxide and nitrogen-donor ligands were tested on TLX5 lymphoma and some of them on MCa mammary carcinoma to evaluate the dependence of the degree of cytotoxicity and of antimetastatic activity on the chemical properties. In vitro cytotoxicity is present only at high concentrations (> 10(-4) M), depends upon lipophilicity and is markedly affected by the presence of 5% serum or plasma samples in the culture medium. The comparison of the effects on in vitro cytotoxicity with in vivo antitumor and antimetastatic action points out that these compounds reduce metastasis formation by a mechanism unrelated to a direct tumor cell cytotoxicity. If on one hand Na[trans-RuCl4(TMSO)Iq], the compound that shows the most potent in vitro cytotoxic effects, is the least effective against metastases, on the other Na[trans-RuCl4(DMSO)Im], the compound that better reduces metastasis formation, is rather devoid of cytotoxic effects on tumor cells kept in vitro. In particular, Na[trans-RuCl4(DMSO)Im] seems to distinguish between artificially induced metastases and spontaneous metastases and reduces only the former by a cytotoxic mechanism. Out of all the tested compounds, with the exception of Na[trans-RuCl4(DMSO)Ox], Na[trans-RuCl4(DMSO)Im] is confirmed to be the most selective antimetastatic agent of the group.
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PMID:Effects of ruthenium complexes on experimental tumors: irrelevance of cytotoxicity for metastasis inhibition. 769 44

The ruthenium-dimethylsulfoxide complex Na(trans-RuCl4(DMSO)Im] was given i.v. to mice bearing MCa mammary carcinoma and its effects on tumor growth and on healthy host tissues were studied by macroscopic examination of primary tumor growth, by survival time, and by histological analysis using light microscopy and SEM. Either by means of vivo-vivo bioassays or by microscopic examination it appeared that the growth of lung tumors was markedly reduced, whereas the growth of the i.m. primary tumor was much less affected. These effects account for the prolongation of survival time and for the cure rate observed. The favourable effect on survival time was also influenced by the lack of significant cytotoxicity for normal tissues such as lung and kidney epithelia, muscle and liver cells, splenocytes and bone marrow. It thus appears that the selective interaction with tumor cells in the lungs cannot simply be attributed to a selectively higher localization of the compound at this site, nor to a modification of the histological structure of primary tumor. These results highlight the pharmacologic properties of this compound for the control of solid tumor metastases, an effect that was shown to be similarly exerted on advanced tumor metastases.
Clin Exp Metastasis 1994 Mar
PMID:Antimetastatic action and toxicity on healthy tissues of Na[trans-RuCl4(DMSO)Im] in the mouse. 830 32

Metalloproteases are implicated in conferring invasive properties to tumor cells. We show here that treatment of ras-oncogene-transformed rat fibroblasts with dimethylsulfoxide (DMSO) results in a reversible decrease in stromelysin mRNA. Furthermore, stromelysin expression was found to be repressed by DMSO, but not by glucocorticoid hormone, in a fibrosarcoma cell line showing low AP-1 (fos/jun) transcription factor activity. In two fibrosarcoma cell lines which express high levels of stromelysin and low levels of 68 kDa type IV collagenase, the DMSO-induced decrease in stromelysin expression was paralleled by a decreased invasive propensity.
Clin Exp Metastasis 1993 Jan
PMID:Repression of stromelysin metalloprotease expression in rat fibrosarcoma cells by dimethylsulfoxide. 842 9

Chemoattractants expressed at bony sites and pelvic lymph nodes are thought to promote the preferential metastasis of human prostate tumor cells to these organs. Epidermal growth factor (EGF) is a potent chemoattractant for several human metastatic prostate tumor cell lines, including the TSU-pr1 cell line, and EGF has been localized to the stroma of both bony sites and pelvic lymph nodes in humans. Hence, we investigated whether the TSU-pr1 cell line expresses a functional EGF receptor (EGFR), which when antagonized reduces EGF-mediated chemomigration of this cell line. In this context, the EGFR immunoprecipitated from cell lysates of TSU-pr1 cells comigrated with the EGFR from A431 cells at a molecular weight of 170 kD. Addition of human EGF (hEGF) to the TSU-pr1 cells for 5 min stimulated the dose-dependent biphasic phosphorylation of the EGFR, with maximal stimulation of EGFR phosphorylation occurring at 2 ng/ml hEGF. In addition, treatment of hEGF-stimulated (2 ng/ml) TSU-pr1 cells with 0.5 microgram/ml anti-hEGF monoclonal antibody or 100 nM staurosporine inhibited EGFR phosphorylation. Conversely, as negative controls, treatment of hEGF-stimulated (2 ng/ml) TSU-pr1 cells with K252a or dimethyl sulfoxide (DMSO) vehicle did not inhibit EGFR phosphorylation. TSU-pr1 cells were stimulated to migration in 4 hr across Boyden chambers in response to 10 ng/ml hEGF. Treatment of the TSU-pr1 cells with anti-hEGFR monoclonal antibody inhibited in a dose-dependent manner the chemomigration of the TSU-pr1 cells across Boyden chambers. Similarly, treatment of the TSU-pr1 cells with staurosporine inhibited in a dose-dependent manner the chemomigration of the TSU-pr1 cells across Boyden chambers. These results demonstrate that antagonists of hEGF-mediated hEGFR phosphorylation also antagonize chemomigration of the TSU-pr1 cells across Boyden chambers, suggesting that antagonists of the EGFR in prostate cancer may be useful in the treatment of metastatic disease.
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PMID:Inhibition of chemomigration of a human prostatic carcinoma cell (TSU-pr1) line by inhibition of epidermal growth factor receptor function. 860 99

Imidazolium trans-imidazoledimethylsulphoxidetetrachlororuthenate ImH[trans-RuCl4(DMSO)Im] (NAMI-A), a ruthenium compound that replaces Na+ with ImH+ in the molecule of Na[trans-RuCl4(DMSO)Im] (NAMI), was studied for the anti-metastasis effects in models of solid metastasizing tumours of the mouse. NAMI-A, given i.p. at 35 mg/kg/day for six consecutive days, a dose equimolar to that of NAMI, to mice bearing Lewis lung carcinoma and MCa mammary carcinoma, markedly reduces lung metastasis weight by 80-90%, with an effect equal or even superior to that of NAMI, depending on the experimental system adopted. Correspondingly, NAMI-A increases the content of connective tissue in the tumour matrix, around blood vessels, and in the tumour capsule, augments the percentage of tumour cells in G2/M phase and reduces the amount of CD45+ cells infiltrating the tumour parenchyma. The effects of the same doses on spleen lymphocytes correspond to an increase of CD8+ subset without any change of the distribution of cells in G0/G1, S and G2/M phases. The study shows that NAMI-A behaves similarly to NAMI on the several parameters examined in comparison experiments and therefore we suggest to credit NAMI-A with all the biological actions already described for NAMI during the last 3 years. The replacement of Na+ with ImH+ therefore, besides the better chemical stability of the molecule, confers to [trans-RuCl4(DMSO)Im]- a closer similarity with a true drug to be used in humans, and suggests this molecule for future studies of preclinical toxicology and phase I and II clinical trials.
Clin Exp Metastasis 1998 May
PMID:Pharmacological control of lung metastases of solid tumours by a novel ruthenium complex. 962 16

NAMI-A (imidazolium trans-imidazoledimethylsulfoxidetetrachlororuthenate, ImH[trans-RuCl4(DMSO)Im]) is a new ruthenium compound active against lung metastasis of solid metastasizing tumors. We have tested this compound in mice with Lewis lung carcinoma or MCa mammary carcinoma in order to compare the effects on primary tumor and lung metastases with possible alterations of cell cycle distribution of tumor cells. We have also investigated whether there were unequal tissue accumulations of the compound itself at different dose levels ranging from 17.5 to 70 mg/kg/day given for six consecutive days. NAMI-A caused a reduction of metastasis weight larger than that of metastasis number; we explain this finding as the capacity of NAMI-A to selectively interfere with the growth of metastases already settled in the lungs. However, this specificity is not simply related to a larger concentration of NAMI-A in the lungs than in other tissues. Following i.p. treatment, NAMI-A rapidly disappeared from the peritoneal cavity; its low blood concentration may be caused by rapid renal clearance. These data provide further evidence for a selective anti-metastasis effect of the ruthenium complex NAMI-A. The reduction of lung metastasis is followed by a significant prolongation of the host's life-time expectancy, indicating a therapeutic benefit of NAMI-A on lung metastases from solid tumors.
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PMID:Reduction of lung metastasis by ImH[trans-RuCl4(DMSO)Im]: mechanism of the selective action investigated on mouse tumors. 1019 56

Although the loss of sulfomucins was known as an indicator of carcinogenesis and malignant progression of colonic epithelia, it was not known whether the loss was directly related to the malignant behavior of colon carcinoma cells. We have studied the biological properties of LS174T human colon carcinoma cells before and after suppression of sulfomucin production. Incorporation of [35S]-sulfate into high molecular weight mucins decreased after carcinoma cell treatment with 1.5% dimethylsulfoxide (DMSO) for 8 days. The amounts of sulfomucin determined using a sulfomucin-specific monoclonal antibody (mAb 91.9H), in Western blot and flowcytometric analyses, also decreased. In addition, the levels of MUC2 and MUC5B mucin gene expression measured by RT-PCR were reduced after DMSO-treatment, whereas the levels of MUC1, MUC5AC, and MUC6 mucin gene expression were not. The DMSO-treated cells were tested in vitro and in vivo for their properties. Differences were not detected in their anchorage-independent growth, anchorage-dependent growth, E-selectin-dependent cell adhesion or sensitivity to interleukin (IL)-2-activated lymphocyte cytolysis. When untreated or DMSO-treated LS174T cells were injected intrasplenically into nude mice, the treated cells lacking certain cell surface sulfomucins formed fewer metastatic colonies in the liver. These results suggest that the loss of sulfomucins by colonic epithelial cells during progression is not directly related to the enhanced malignant behavior.
Clin Exp Metastasis 1999 Mar
PMID:Malignant and other properties of human colon carcinoma cells after suppression of sulfomucin production in vitro. 1041 Nov

The prognosis of patients with metastasised follicular thyroid carcinoma (FTC) is limited, necessitating the search for new treatment options. Beneficial effects of retinoids have been suggested in thyroid cancer and the present study was performed to investigate the effects of retinoic acid (RA) on important determinants of metastatic behaviour in FTC: the disengagement of tumour cells from the primary tumour and the degradation of extracellular matrix, focusing on the role of the plasmin activation system and the integrin and E-cadherin families of attachment molecules. Three FTC cell lines were studied: FTC-133, derived from the primary tumour; and FTC-236 and FTC-238, derived from metastases. FTC cell lines were cultured with 0.1, 1 and 10 microM 13-cis-RA or with the solvent DMSO for 1 and 5 days. Extracellular matrix degradation by these cell lines was studied by assessing the 48-h release of radioactivity from (35)S-methionine labelled extracellular matrix proteins synthesised by the MC3T3 cell line coated onto plastic. The involvement of constituents of the plasmin activation system was investigated by semi-quantitative RT-PCR and zymography. Attachment to extracellular matrix was studied by determining the number of adhering FTC cells to extracellular matrix coated onto plastic, 3 h after seeding. The involvement of attachment molecules was studied by RT-PCR with primers for integrin subclasses and E-cadherin and immunofluorescence for E-cadherin. Five days culturing with 10 microM RA reduced the degradation of extracellular matrix significantly in all cell lines: FTC-133 by 35%, FTC-236 by 74% and FTC-238 by 31%. Zymography revealed diminished activity of urokinase type plasminogen activator (uPA) in FTC-236 and FTC-238, but not in FTC-133 cultured with RA. mRNA expression of the uPA receptor was diminished in FTC-236. In the attachment assay, 10 microM RA for 5 days increased the number of adherent cells to extracellular matrix significantly by 91% in FTC-133, 64% in FTC-236 and 87% in FTC-238. No effects of RA on integrin or E-cadherin mRNA expression were observed. Immunofluorescence, however, revealed enhanced organisation of E-cadherin along the cell membrane by RA treatment. In conclusion, the present study demonstrates beneficial effects of RA on important determinants of metastatic behaviour in FTC cell lines, e.g. decreased degradation of extracellular matrix which may in part be explained by effects on the plasmin activation system and enhanced attachment to extracellular matrix. These findings may add to the explanations for beneficial effects of retinoids in thyroid cancer.
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PMID:Beneficial effects of retinoic acid on extracellular matrix degradation and attachment behaviour in follicular thyroid carcinoma cell lines. 1105 36

NAMI-A is a novel ruthenium complex with selective activity against metastases currently in Phase I clinical trials in The Netherlands. The photostability of this new agent in solid state and in solution has been investigated utilizing a stability-indicating reversed-phase high performance liquid chromatographic (HPLC) assay and ultraviolet/visible (UV/VIS) light spectrophotometry. In solid state, NAMI-A proved to be photostable. In solution, however, the compound degraded rapidly, in a pH-independent manner in the pH range of 2-5. At alkaline pH, the degradation rate was higher than at acidic pH. The type of buffer species had little influence. NAMI-A concentration was inversely related to the photostability. Addition of photostabilizers (5% DMSO, 2% benzyl alcohol, 0.001% curcumin) marginally increased the half-life. NAMI-A's photostability in solution was influenced to the greatest extent by addition of an alcohol, with the least polar solvent system (50% propylene glycol) providing the most stable medium. Based on the presented results, it is recommended to store NAMI-A solutions in the dark.
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PMID:Photostability profiles of the experimental antimetastatic ruthenium complex NAMI-A. 1240 19

The effects of the treatment of tumor cells of MCa mammary carcinoma and TLX5 lymphoma with the ruthenium complex Na[trans-RuCl(4) (DMSO)lm] for several transplant generations were studied on tumor growth and metastases formation. On TLX5 lymphoma cells, treatment was performed in vitro prior to in vivo inoculation of tumor cells in intact or immunesuppressed mice. Either considering tumor take and growth or its capacity to invade the brain of the inoculated hosts, Na[trans-RuCl(4)(DMSO)lm] did not induce any significant modification. Conversely, in mice with MCa mammary carcinoma, the in vivo treatment of tumor cells in immunesuppressed hosts caused a progressive increase of DNA activity and, starting from the 4th transplant generation, a significantly increased susceptibility of lung metastasis formation to a further treatment in intact mice. These data seem to suggest that Na[trans-RuCl(4)(DMSO)Im] does not induce chemical xenogenization of tumor cells nor its repeated treatment induces resistance in tumor cells. Conversely, it appears that Na[trans-RuCl(4)(DMSO)lm] may select a tumor cell population which maintains its capacity to metastasise to the lung but with enhanced sensitivity to the antimetastatic properties of this compound.
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PMID:Reduction of Lung Metastases by Na[trans-RuCl(4)(DMSO)Im] is not Coupled With the Induction of Chemical Xenogenization. 1847 98


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