Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of all-trans retinoic acid on metastatic B16 melanoma lung colonization and synthesis and properties of glycosaminoglycans was examined. Injection of tumour cells, pretreated with 10(-6) M-retinoic acid or grown to low density, into the tail vein of syngeneic C57 mice produced significantly fewer pulmonary tumours compared to subconfluent control cells. By cochromatography of glycosaminoglycans isolated from control ([14C]glucosamine-labelled) and 10(-6) M-retinoic acid-treated ([3H]glucosamine-labelled) cells on DEAE ion-exchange columns, differences in elution profiles were detected. Chondroitin sulphates isolated from retinoic acid-treated cells eluted at a lower salt concentration than those from control cells, while retinoic acid-treated cells synthesised heparan sulphates of a higher charge density than heparans from control cultures. These changes were apparent in both medium and trypsin-releasable fractions. Retinoic acid-treated cultures were seeded so that they were of a similar density to control cultures when harvested, as cell density was shown to affect glycosaminoglycan synthesis, the glycosaminoglycans from low-density cultures having similar properties to those isolated from retinoic acid-treated cultures. Retinoic acid treatment also reduced the overall synthesis of glycosaminoglycans while having little effect on the composition or distribution between medium, trypsin-releasable and cell-associated fractions. These observed changes in glycosaminoglycans may, in part, be responsible for retinoic acid-induced inhibition of lung colonization, and reduced adhesion to basement membrane components, which we have previously demonstrated.
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PMID:Retinoic acid-induced inhibition of lung colonization and changes in the synthesis and properties of glycosaminoglycans of metastatic B16 melanoma cells. 251 93

Previous experimental evidence indicates that immunogenicity of mouse tumor cells can be increased by treatment with dacarbazine and other triazene compounds. The present studies have been conducted on the human cell lines H125 (lung cancer), 1246 (melanoma), X3 (EBV-immortalized B cells) subjected to in vitro treatment with 4 (3-methyl-1-triazeno) benzoic acid potassium salt (MTBA). Untreated or drug-treated sublines were tested for susceptibility to allogeneic NK effector cells, either non-stimulated or pretreated with beta-Interferon. In the case of X3 cell line and its MTBA-treated subline the expression of the EBV-associated antigens and the capability of eliciting autologous cytotoxic T lymphocytes (CTL) were also investigated. The results suggest that a modification of membrane antigenic pattern could be induced by MTBA treatment in terms of changes of cell susceptibility to cell-mediated lysis, expression of EBV-related antigens and capability to elicit autologous CTL.
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PMID:Changes of immunological patterns of human cancer cells treated in vitro with a triazene compound. 254 62

Nucleolar antigens p145 and p120 are associated with proliferating cells (Freeman, J.W.; McRorie, D.K.; Busch, R.K.; Gyorkey, P.; Gyorkey, F.; Ross, B.E.; Spohn, W.H.; Busch, H. Cancer Res. 46:3593; 1986 and Freeman, J.W.; Busch, R.K.; Gyorkey, P.; Gyorkey, F.; Ross, B.E.; Busch, H. Cancer Res. 48:1244; 1988) and are not detectable in normal resting cells. Recent immunoelectron microscopic studies (Ochs, R.L.; Reilly, M.T.; Freeman, J.W.; Busch, H. Cancer Res. 48:6523; 1988) suggest that the two antigens have overlapping nucleolar localizations. In this study the nucleolus was physicochemically and biochemically studied to determine whether p145 and p120 were associated with a common nucleolar component. Antigen p145 was associated with 40-80 S ribonucleoprotein particles (RNPs), and the p145 antigen was not detected in HeLa cells following in situ RNAse digestion. P120 was found in a 40-80 S, RNAse resistant complex. Sequential extraction of HeLa nucleoli showed that most of antigen p145 was extractable in 10 mM Tris with 0.2% deoxycholate, whereas p120 was found in a nucleolar residue fraction requiring DNAse and high salt treatment for optimal extraction. Neither antigen p145 nor p120 was detectable in normal resting tissues. Antigen p145 was detected in all proliferating tissues examined, including a variety of malignant tumors (ten of ten), benign tissues including adenomas and hyperplasias (eight of eight), and in normal proliferating cells such as colonic epithelium and spermatogonia of the testes. Antigen p120 was not detected in all tumors, being absent in three of seven lymphomas and in one melanoma examined.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Proliferation-related nucleolar antigens P145 and P120 associated with separate nucleolar elements and differences in tissue distribution. 270 42

Five ionic cyclopentadienyltitanium (IV) derivatives were investigated for their activity against fluid Ehrlich ascites tumor. Four compounds were built up by the intact bis(cyclopentadienyl)titanium(IV) ("titanocene") unit, forming the cationic moiety together with two covalently bound ligands, with certain anions being bonded via electrostatic forces: the acetonitrile complex [(C5H5)2TiCl(NCCH3)]+[FeC14]- (I), the 2'2'-bipyridyl derivative [(C5H5)2Ti(bipy)]2+[CF3SO3]2 (II), the o-phenanthroline complex [(C5H5)2Ti(phen)]2+[CF3SO3]2 (III), and the N-methyl-o-aminothiophenolate derivative [(C5H5)2Ti[o-S(NACH3)C6H4]]+I- (IV). Another ionic cyclopentadienyltitanium derivative investigated was the five-coordinate bis(dithiolene) chelate (C5H5)Ti(1,2,4-S2C6H3CH3)2]-N(C2H5)4)+ (V), the cyclopentadienyltitanium moiety representing the anionic part of the complex salt. All complexes were ionic, salt-like compounds, distinguished by good water solubility. Whereas complexes I, III, and V, given at optimal dose levels, effected maximal cure rates of only 70%-80%, all animals were cured after receiving complexes II and IV at dose ranges of 200-220 and 240-300 mg/kg, respectively. The antitumor activity of complex I was confirmed against solid experimental tumor systems B16 melanoma, colon 38 carcinoma, and Lewis lung carcinosarcoma. Because of their improved solubility in water and pronounced antitumor activity (especially that of II and IV against fluid Ehrlich ascites tumor), ionic cyclopentadienyl titanium complexes are considered to be an interesting new type of antitumor agent.
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PMID:Ionic titanocene complexes: a new type of antitumor agent. 272 Aug 88

Xenotransplanted human melanoma was investigated by measuring the increase in tumour volume and in final tumour weight (macroscopical parameters) and histomorphological parameters of cell proliferation: Mitotic index (MI) and autoradiographic [3H]thymidine labelling index (LI). A total of 87 tumours, derived from a human melanoma metastasis and a primary nodular melanoma respectively, were analysed by these methods in two series. Topical treatment of the tumours with azelaic acid cream resulted in a statistically significant reduction in the increase in tumour volume and, in the first series, in a clear decrease in final tumour weight and in the MI, as compared with controls. The LI was decreased only in the superficial region of the tumours, i.e. at the site of treatment. Subtumoral injection of azelaic acid (disodium salt solution) was the second route of local therapy. It was followed by a significant reduction in the increase in tumour volume, of final tumour weight (first series) and in the MI. The average LI was clearly smaller than in the controls, especially at the tumour base, which was the site of injection (local effect). Systemic (intravenous) injection of azelaic acid (same concentration of the disodium salt solution) had no negative effect on the increase in tumour volume or final tumour weight, but was followed by a clear reduction of the MI. The average LI of this group was significantly smaller than in the controls as well. This effect was most impressive in the perivascular regions of large and small vessels, which fact can be interpreted as a sort of local effect via the blood stream after systemic application of azelaic acid.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Topographical analysis of proliferation ([3H]thymidine labelling index and mitotic index) as compared with tumour growth and tumour weight in xenotransplanted melanoma. Changes due to local and systemic application of azelaic acid. 277 15

The mechanism of action of NSC 368390 (DUP-785, 6-fluoro-2-(2'-fluoro-1, 1'-biphenyl-4-yl)-3-methyl-4-quinoline carboxylic acid sodium salt) was studied using three different approaches. First, we studied growth inhibition by DUP-785 in L1210 leukemia cells and M5 melanoma cells. The concentrations causing 50% growth inhibition after 48 hr of culture were 5.8 and 0.6 microM, respectively. DUP-785 had to be present continuously throughout culture. Growth inhibition by 25 microM DUP-785 could be prevented by addition of 1 mM uridine or orotic acid to cultures of these cell lines; in M5 cells cytidine was also able to prevent growth inhibition. Dihydro-orotic acid (DHO) and carbamyl-aspartate were not able to prevent growth inhibition by DUP-785. Second, we studied accumulation of orotic acid and of orotidine induced by incubation with 1 microM pyrazofurin, an inhibitor of the orotate phosphoribosyl-transferase-orotidine-monophosphate decarboxylase complex. Addition of DUP-785 to the culture medium prevented the orotic acid accumulation. Furthermore, DUP-785 prevented accumulation of H14CO3- into orotic acid of pyrazofurin-treated L1210 cells. Third, we measured the effect of DUP-785 on DHO-dehydrogenase (DHO-DH), since the results indicated that this enzyme was affected by DUP-785. DHO-DH was assayed in isolated rat liver mitochondria. The Km for L-DHO was about 12 microM. DUP-785 appeared to be a potent inhibitor of DHO-DH with an apparent Ki of about 0.1 microM and an apparent Ki' of about 0.8 microM. The mode of inhibition appeared to be linear mixed type. After exposure of L1210 cells to 25 microM DUP-785 for 2 hr DHO-DH was almost completely inhibited. After suspension in fresh medium without drug, DHO-DH activity was recovered to about 60% after 24 hr. In conclusion, DUP-785 is a potent inhibitor of pyrimidine de novo biosynthesis, by inhibition of the mitochondrial enzyme DHO-DH.
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PMID:Inhibition of pyrimidine de novo synthesis by DUP-785 (NSC 368390). 282 96

Activities of a cathepsin B-like cysteine proteinase have previously been observed to correlate with the malignancy of several animal and human tumors. Plasma membrane fractions of some of these tumors have been found to be enriched in cathepsin B-like activity. We have determined the subcellular distribution of this enzyme and three additional lysosomal hydrolases (cathepsin H, beta-hexosaminidase, and beta-glucuronidase) in normal murine liver and six metastatic variants of the B16 melanoma. The tissues were fractionated initially by differential centrifugation followed by Percoll density gradient centrifugation of the light mitochondrial fraction. Two fractions were obtained: an L-2 fraction enriched in all four lysosomal hydrolases; and an L-1 fraction enriched in a marker enzyme for the plasma membrane. Cathepsin B-like and beta-hexosaminidase activities, but not the other hydrolase activities, were also found to be enriched in the L-1 fractions of the metastatic B16 tumors. We explored the nature of the association of the cathepsin B-like activity with the plasma membrane using fractions from the spontaneously metastatic B16 amelanotic melanoma. Activity could not be dissociated from the plasma membrane fraction by washing with a physiological salt solution suggesting that it was not adsorbed to this fraction nonspecifically, nor could it be displaced by mannose 6-phosphate or other sugars which compete for binding to the known lysosomal receptors. High salt concentrations, low concentrations of the mild detergent saponin, mild acidification, or phosphatidylinositol-specific phospholipase C did not elute the cathepsin B-like activity. However, activity was eluted by exposure to 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate, a detergent used in the purification of integral membrane proteins. The B16 amelanotic melanoma plasma membrane-associated cathepsin B-like activity had a slightly higher pH optimum and was resistant to inactivation by neutral pH and to inhibition by three low molecular weight inhibitors of cysteine proteinases. The Ki values for inhibition by leupeptin and stefin A were 20-fold higher. The presence of a cathepsin B-like cysteine proteinase at the surface of metastatic tumor cells, particularly in a form which can retain activity at physiological pH and retain activity in the presence of extracellular proteinase inhibitors, may contribute to the focal dissolution of the extracellular matrix observed at sites of contact with invading tumor cells.
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PMID:Properties of a plasma membrane-associated cathepsin B-like cysteine proteinase in metastatic B16 melanoma variants. 282 39

A novel antitumor compound, N-beta-dimethyl-aminoethyl 9-carboxy-5-hydroxy-10-methoxybenzo[a]-phenazine-6-carboxamide sodium salt (NC-190) was evaluated for its antitumor activity in experimental murine tumor systems. In the initial studies with P388 leukemia (i.p.-i.p.), NC-190 led to an increase of greater than 200% in life span (ILS), and 75% of the mice were alive on day 30, when the optimal dose (50 mg/kg, days 1-5) was given. Additionally, the compound had significant activities against i.p. inoculated mouse L1210 leukemia, B16 melanoma, M5076 reticulum cell sarcoma, sarcoma 180, mouse hepatoma MH134, and rat Yoshida sarcoma and Yoshida ascites hepatoma AH130. The optimal dose resulted in a greater than 280% ILS with a 30-day survival of 50% in mice with L1210 leukemia (100 mg/kg, days 1-5), a 156% ILS in mice with B16 melanoma (50 mg/kg, days 1-5), a 98% ILS with a 90-day survival of 25% in mice with M5076 reticulum cell sarcoma (25 mg/kg, days 1, 5, 9, and 13), a greater than 300% ILS with a 60-day survival of 50% in mice with sarcoma 180 (50 mg/kg, days 3-10), a 148% ILS with a 60-day survival of 25% in mice with MH134 (25 mg/kg, days 1-5), a 129% ILS with a 60-day survival of 12.5% in rats with Yoshida sarcoma (12.5 mg/kg, day 3-10), and a greater than 161% ILS with a 60-day survival of 50% in rats with AH130 (6.3 mg/kg, days 3-10). In the experiments with s.c. inoculated tumors, NC-190 not only inhibited tumor growth, but also increased the life span of mice with Lewis lung carcinoma or B16 melanoma. The 60-day survivors accounted for 60% and 30% in mice with Lewis lung carcinoma and B16 melanoma, respectively. The compound significantly inhibited the spontaneous lung metastasis of Lewis lung carcinoma by more than 90% when eight daily i.v. injections were given. NC-190 was active by the i.p., s.c., and i.v. routes. Five consecutive daily i.p. doses (days 1-5) were more effective than a single dose (day 1), two doses (days 1 and 5), or three doses (days 1, 5, and 9). NC-190 warrants further study as a potential antineoplastic agent against human neoplasms, as it has a broad spectrum of antitumor activity and inhibits metastasis.
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PMID:In vivo activity on murine tumors of a novel antitumor compound, N-beta-dimethylaminoethyl 9-carboxy-5-hydroxy-10-methoxybenzo[a]phenazine-6-carboxamide sodium salt (NC-190). 292 70

A malignant hamster melanoma cell line HM-1 derived from the heterogenous malignant hamster melanoma MM1 contains a specific, high affinity binding protein for estrogens. Partial purification of the binding protein with ammonium sulfate (40% saturation) increased mean binding content (3.1 +/- 1.2 (SD) fmol/mg protein) 15-fold without any change in affinity (10(10) M-1). The binding protein sedimented at 8-9S on 10-30% low salt sucrose gradients and 9-10S in the presence of 20 mM molybdate ion. Addition of 0.4 M KCl shifted the 8S peak to 4S. Binding was specific, saturable, and indicative of a single class of high affinity sites over a concentration range of 0.01-10.0 nM [3H]estradiol. Estradiol produced a dose related inhibition of HM-1 growth in vitro without altering the growth of an additional line (HM-2) which did not bind estrogen. The antiestrogen tamoxifen (10(-7) M) also significantly inhibited HM-1 melanoma growth in vitro, which was reversed by the addition of estradiol (10(-9) M). HM-1 xenografts grew faster in female BALB/c-nu/nu mice than male mice while there was no sex difference in HM-2 growth. Pharmacological doses of estradiol and the antiestrogen nafoxidine significantly inhibited HM-1 growth without altering tumor incidence or latency. Our observations suggest that HM-1 cell lines bind estrogens specifically and with high affinity and that hamster melanoma cells positive for this binding protein respond to estrogen.
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PMID:Inhibition of hamster melanoma growth by estrogen. 309 10

Nuclear estrogen binding was characterized in HM-1, a malignant hamster melanoma cell line transplanted into male and female athymic mice following acute, subchronic, and chronic injection of estradiol. Nuclear binding was saturable, of high affinity (10(10) M-1) and readily soluble in low salt buffer. Saturation analyses revealed that [3H]estradiol in excess of 5.0 nM apparently bound to a second class of lower affinity (10(9) M-1), higher capacity cytosol sites. Enzyme-linked immunoassay with a specific monoclonal antibody (H222 Sp gamma) directed against the human estrogen receptor protein was in excellent agreement (r = 0.93) with values obtained using hydroxyapatite to separate bound from free ligand. Nuclear estrogen receptor content in HM-1 cells was increased maximally 1 h after acute s.c. injection of a low dose (0.1 microgram) of estradiol. The increase in nuclear receptor content was accompanied by an apparent rapid reduction in cytosol binding. Subchronic (3 days) and chronic exposure (35 days) to estradiol also produced a significant, dose-related increase in tumor nuclear estrogen receptor content. Cytosol binding for progestin was low (less than or equal to 2 fmol) to absent in HM-1 xenografts not exposed to estradiol. Subchronic and chronic exposure to estradiol induced a dose-related, specific, high affinity (10(9) M-1) cytosol binding protein for progestin(s) in HM-1 xenografts carried in male and female athymic mice. In contrast, progestin binding to nuclear receptor was not increased in estrogen-primed animals, nor did acute injection of progesterone (100 micrograms s.c.) increase the amount of saturable, high affinity (10(9) M-1) nuclear progestin receptor in control or estradiol-primed athymic mice. In contrast to the induction of progestin binding, tyrosinase activity was not altered by a similar exposure to estradiol when assayed at a saturating concentration of tyrosine. These observations suggest that the estrogen receptor in HM-1 cells may be functional but that pigmentary changes observed in mammals following chronic exposure to estradiol may not be mediated by a direct effect on the rate limiting enzyme of melanin synthesis.
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PMID:Effects of estradiol on estrogen receptor, progesterone receptor, and tyrosinase in hamster melanoma transplanted into athymic mice. 313 19


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