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 biological activity of the novel vitamin C derivative, 2-O-alpha-D-glucopyranosyl-L-ascorbic acid (AA-2G), was evaluated in vitro and in vivo. The percutaneous absorption of AA-2G was determined in five Japanese males. The excretion of ascorbic acid (AA) in the subjects administered AA-2G was sustained for a longer period than in the subjects administered ascorbic acid 2-phosphate (AA-2P), which is a conventional vitamin C derivative. An analysis of the distribution of AA in the skin showed that small black specks assumed to be AA were observed in the epidermis even 3 d after applying AA-2G. The melanin synthesis in B16 melanoma cells was inhibited more by AA-2G than by AA-2P, and AA-2G also prevented more UV-induced damage of human skin keratinocytes and fibroblasts than AA-2P did. From these in vivo and in vitro results, it is supposed that the conversion of AA-2G to AA is sustained for a long time compared with that of AA-2P, and that AA-2G is an effective and available compound having vitamin C activity in human subjects.
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PMID:In vitro and in vivo prolonged biological activities of novel vitamin C derivative, 2-O-alpha-D-glucopyranosyl-L-ascorbic acid (AA-2G), in cosmetic fields. 974 56

alpha-Melanocyte stimulating hormone (alpha-MSH) analogs, cyclized through site-specific rhenium (Re) and technetium (Tc) metal coordination, were structurally characterized and analyzed for their abilities to bind alpha-MSH receptors present on melanoma cells and in tumor-bearing mice. Results from receptor-binding assays conducted with B16 F1 murine melanoma cells indicated that receptor-binding affinity was reduced to approximately 1% of its original levels after Re incorporation into the cyclic Cys4,10, D-Phe7-alpha-MSH4-13 analog. Structural analysis of the Re-peptide complex showed that the disulfide bond of the original peptide was replaced by thiolate-metal-thiolate cyclization. A comparison of the metal-bound and metal-free structures indicated that metal complexation dramatically altered the structure of the receptor-binding core sequence. Redesign of the metal binding site resulted in a second-generation Re-peptide complex (ReCCMSH) that displayed a receptor-binding affinity of 2.9 nM, 25-fold higher than the initial Re-alpha-MSH analog. Characterization of the second-generation Re-peptide complex indicated that the peptide was still cyclized through Re coordination, but the structure of the receptor-binding sequence was no longer constrained. The corresponding 99mTc- and 188ReCCMSH complexes were synthesized and shown to be stable in phosphate-buffered saline and to challenges from diethylenetriaminepentaacetic acid (DTPA) and free cysteine. In vivo, the 99mTcCCMSH complex exhibited significant tumor uptake and retention and was effective in imaging melanoma in a murine-tumor model system. Cyclization of alpha-MSH analogs via 99mTc and 188Re yields chemically stable and biologically active molecules with potential melanoma-imaging and therapeutic properties.
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PMID:Design and characterization of alpha-melanotropin peptide analogs cyclized through rhenium and technetium metal coordination. 978 97

In a 31P-NMR spectroscopic study of cultured M2R mouse melanoma cells, we previously demonstrated the acute stimulation of three peaks in the phosphomonoester region of the spectrum by [Ahx4, DPhe7]alpha-melanotropin (concomitant with an increase in cellular adenosine 3',5'-phosphate (cAMP) and a decrease in ATP [Degani, H., DeJordy, J. O. & Salomon, Y. (1991) Proc. Natl Acad. Sci. USA 88, 1506-1510]. Chemical identification of these metabolites was performed in this study using 32P metabolic labeling and polyethyleneimine-cellulose thin layer chromatography in combination with 31P-NMR and 13C-NMR spectroscopic methods. Two of the stimulated signals were identified as P1 and P6 of fructose 1,6-bisphosphate (FruP2) and their mode of regulation by alpha-melanotropin was examined. The FruP2 response to alpha-melanotropin coincided in time and dose with a rise in cAMP and a decrease in levels of ATP, while elevation of cAMP by forskolin alone did not increase FruP2. The stimulatory effect of alpha-melanotropin was not associated with a change in the overall rate of glycolysis, suggesting that FruP2 levels were not rate limiting in this process. The data suggest the presence of a previously unknown response of M2R melanoma cells to alpha-melanotropin, which coincides in time with enhanced cAMP accumulation but is not mediated by cAMP and may relate to the control of FruP2 in a non glycolytic context.
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PMID:Stimulation of fructose 1,6-bisphosphate production in melanoma cells by alpha-melanocyte-stimulating hormone-- 31P/13C-NMR and 32P-labeling studies. 985 93

In this study we provide evidence that the low expression of IGF-1R at the cell surface of estrogen-independent breast cancer cells is due to a low rate of de novo synthesis of dolichyl phosphate. The analyses were performed on the estrogen receptor-negative breast cancer cell line MDA231 and, in comparison, the melanoma cell line SK-MEL-2, which expresses a high number of plasma membrane-bound IGF-1R. Whereas the MDA231 cells had little or no surface expression of IGF-1R, they expressed functional (i.e., ligand-binding) intracellular receptors. By measuring the incorporation of [3H]mevalonate into dolichyl phosphate, we could demonstrate that the rate of dolichyl phosphate synthesis was considerably lower in MDA231 cells than in SK-MEL-2 cells. Furthermore, N-linked glycosylation of the alpha-subunit of IGF-1R was 8-fold higher in the melanoma cells. Following addition of dolichyl phosphate to MDA231 cells, N-linked glycosylation of IGF-1R was drastically increased, which in turn was correlated to a substantial translocation of IGF-1R to the plasma membrane, as assayed by IGF-1 binding analysis and by Western blotting of plasma membrane proteins. The dolichyl phosphate-stimulated receptors were proven to be biochemically active since they exhibited autophosphorylation. Under normal conditions MDA231 cells, expressing very few IGF-1R at the cell surface, were not growth-arrested by an antibody (alphaIR-3) blocking the binding of IGF-1 to IGF-1R. However, after treatment with dolichyl phosphate, leading to a high cell surface expression of IGF-1R, alphaIR-3 efficiently blocked MDA231 cell growth. Taken together with the fact that the breast cancer cells produce IGF-1 and exhibit intracellular binding, our data suggest that the level of de novo -synthesized dolichyl phosphate may be critical for whether the cells will use an intracellular or an extracellular autocrine IGF-1 pathway.
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PMID:Expression of the insulin-like growth factor 1 receptor (IGF-1R) in breast cancer cells: evidence for a regulatory role of dolichyl phosphate in the transition from an intracellular to an extracellular IGF-1 pathway. 1033 89

Fetal calf serum (FCS) and 1-oleoyl lysophosphatidic acid (LPA) were previously found to be potent inducers of invasion (transcellular migration) in an in vitro system. A novel LPA, composed of cyclic phosphate and cyclopropane-containing hexadecanoic acid (PHYLPA), first isolated from myxoamoebae of Physarum polycephalum, and its synthetic derivatives (cLPA) were tested for their ability to inhibit tumor cell invasion and metastasis. Amoung these, Pal-cLPA, which has a palmitoyl moiety, was most potent in inhibiting invasion, with 93.8% inhibition at the concentration of 25 microM. Invasion in vitro by mouse melanoma cells (B16), human pancreatic adenocarcinoma cells (PSN-1), human lung cancer cells (OC-10) and human fibrosarcoma cells (HT-1080) was also inhibited by Pal-cLPA. The stimulation of MMI cells with LPA triggered F-actin formation, which was impaired by the addition of Pal-cLPA at invasion-inhibitory concentration. Pal-cLPA induced a rapid increase in adenosine 3',5'-cyclic monophosphate (cAMP) concentration in MMI cells. The addition of dibutyryl cAMP significantly abrogated LPA-induced invasion by MM1 cells and actin polymerization in the cells. The inhibition of MM1 cell invasion by Pal-cLPA may be ascribed to an increased level of cAMP. Pal-cLPA also suppressed invasion in vitro by MM1 cells induced by FCS dose dependently, without affecting proliferation. It also suppressed the pulmonary metastasis of B16 mouse melanoma cells injected into the tail vein of C57BL/6 mice. Thus, Pal-cLPA is effective in inhibiting invasion and metastasis of a variety of tumor cells.
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PMID:Inhibition of tumor invasion and metastasis by a novel lysophosphatidic acid (cyclic LPA). 1036 39

Deaminoneuraminic acid (KDN, 2-keto-3-deoxy-D-glycero-D-galacto-nononic acid) is a member of the family of sialic acids in which an acylamino group at the C-5 position of N-acylneuraminic acid (Neu5Acyl) is replaced by a hydroxyl group. It has recently been shown that KDN is synthesized de novo from its precursor, mannose (Man), in trout testis (Angata, T., Nakata, D., Matsuda, T., Kitajima, K., and Troy, F. A. (1999) J. Biol. Chem. 274, in press). In this study, we examined the effect of extracellular free Man on biosynthesis of KDN in mouse melanoma B16 and African green monkey kidney COS-7 cell lines. The following new findings are reported. First, the levels of free and bound forms of KDN increased when the cells were cultured in the presence of 20 mM Man. The level of intracellular free KDN in COS-7 and B16 cells increased 47- and 66-fold respectively, compared with the levels in control cells. Second, the elevated expression of free KDN was proportional to the intracellular concentration of free Man. Third, KDN 9-phosphate (KDN-9-P) synthase, which condenses Man 6-phosphate and phosphoenolpyruvate (PEP), forming KDN-9-P, was detected in cell lysates from both cell lines. Fourth, the de novo synthesis of KDN in both cell lines in the Man-rich media was unaffected by the addition of N-acetylmannosamine (ManNAc), the hexosamine precursor for synthesis of N-acetylneuraminic acid (Neu5Ac). These results show that KDN is synthesized using free Man as its hexose precursor in these mammalian cells. Thus, the KDN biosynthetic pathway utilizes enzymes distinct, at least in part, from those involved in Neu5Ac biosynthesis. This is the first report showing that in vivo synthesis of KDN can be manipulated by growing cells in the presence of Man. This now provides a useful method to study the metabolism and function of the KDN glycotope.
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PMID:Elevated expression of free deaminoneuraminic acid in mammalian cells cultured in mannose-rich media. 1042 85

A group of 3'-O-butanoyl, 5'-O-butanoyl, and 3',5'-di-O-butanoyl esters of 5-fluoro-2'-deoxyuridine (FDU), and 2',5-difluoro-2'-deoxyuridine (DFDU), 3'-O-retinoyl, and 3',5'-di-O-retinoyl esters of FDU, and 5'-O-bis(2,2,2-trichloroethyl)phosphoryl-FDU and its 3'-O-butanoyl ester, was synthesized. These compounds were designed to act as double prodrugs that would serve as a depot to release two active drugs that act through different mechanisms. Thus, a nucleotide derivative of FDU or DFDU could act as a competitive inhibitor for thymidylate synthase, whereas retinoic acid and butyric acid would be expected to induce cell differentiation. The in vitro anticancer activities for these prodrugs were determined against a panel of nine tumor types (leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate, breast) that encompassed about 60 human tumor cell lines. Structure-activity relationships indicate that O-butanoyl esters of FDU are approximately equipotent to FDU, the O-butanoyl esters of DFDU are less active than FDU, and the retinoyl and bis(2,2,2-trichloroethyl)phosphate derivatives of FDU exhibit comparable activity to FDU. In addition to their cytotoxic effect, 3'-O-retinoyl-FDU (12) and 3'-O-butanoyl-5'-O-bis(2,2,2-trichloroethyl)phosphoryl-FD U (16) also induced in vitro cell differentiation of promyelocytic leukemia HL60 cells. These combined cytotoxic and cell differentiation effects exhibited by 12 and 16 produced greater morphological drug-induced granulation and neutrophil vacuolation, and more cell apoptosis, than observed upon exposure to either retinoic acid or sodium butanoate. Dose-escalation studies in mice showed that 12 or 16 did not induce any acute or chronic toxicity, change in plasma clinical chemistry parameters, or gross histapathological changes at 60 days following an initial dosage regimen of 0.013 mmol/kg i.p. for 7-consecutive days. The in vivo growth delay response of murine mammary EMT6 solid tumors suggests that 3'-O-retinoyl-FDU (12) delays tumor growth relative to the other prodrugs investigated, sodium butyrate, retinoic acid, FDU, or a combination of retinoic acid and FDU. These preliminary results suggest that 3'-O-retinoyl-FDU (12) warrants further in vivo investigation to determine its tissue biodistribution and pharmacokinetic parameters that would be of value in assessing its potential usefulness as an anticancer prodrug.
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PMID:Synthesis and biological evaluation of butanoate, retinoate, and bis(2,2,2-trichloroethyl)phosphate derivatives of 5-fluoro-2'-deoxyuridine and 2',5-difluoro-2'-deoxyuridine as potential dual action anticancer prodrugs. 1048 39

Cytostatin, which is isolated from a microbial cultured broth as a low molecular weight inhibitor of cell adhesion to extracellular matrix (ECM), has anti-metastatic activity against B16 melanoma cells in vivo. In this study, we examined a target of cytostatin inhibiting cell adhesion to ECM. Cytostatin inhibited tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin upon B16 cell adhesion to fibronectin. While the amount of FAK was not affected by cytostatin, electrophoretically slow-migrating paxillin appeared. Alkaline phosphatase treatment diminished cytostatin-induced slow-migrating paxillin. Furthermore, cytostatin increased intracellular serine/threonine-phosphorylated proteins and was found to be a selective inhibitor of protein phosphatase 2A (PP2A). Cytostatin inhibited PP2A with an IC(50) of 0.09 microgram/ml in a non-competitive manner against a substrate, p-nitrophenyl phosphate, but it had no apparent effect on other protein phosphatases including PP1, PP2B and alkaline phosphatase even at 100 microgram/ml. On the contrary, dephosphocytostatin, a cytostatin analogue, without inhibitory effect on PP2A did not affect B16 cell adhesion including FAK and paxillin. These results indicate that cytostatin inhibits cell adhesion through modification of focal contact proteins such as paxillin by inhibiting a PP2A type protein serine/threonine phosphatase. This is the first report that describes a drug with anti-metastatic ability that inhibits PP2A selectively.
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PMID:Cytostatin, an inhibitor of cell adhesion to extracellular matrix, selectively inhibits protein phosphatase 2A. 1055 74

The invasion of human fibrosarcoma HT-1080 cells through Matrigel was shown to be inhibited by pretreatment with ascorbic acid (Asc) or its four derivatives, such as Asc-6-O-palmitate (Asc6Plm), Asc-2-O-phosphate (Asc2P), Asc-2-O-phosphate-6-O-palmitate (Asc2P6Plm), and Asc-5,6-benzylidene (Asc5,6Bz) of non-cytotoxic concentrations for 1 or 18 hr. Two lipophilic derivatives such as Asc6Plm and Asc2P6Plm exerted an invasiveness-inhibitory activity more markedly with 1-hr pretreatment, being a more practical index in terms of the plasma half-life, than Asc, Asc5,6Bz or Asc2P being less lipophilic. Considerably less cytotoxicity (a > 3.3-fold higher IC50 for 1-hr pretreatment) of Asc2P6Plm sufficiently compensated a slightly lower invasiveness-inhibitory activity (a < 1.8-fold higher EC50) as compared with Asc6Plm. Pulmonary metastasis of mouse melanoma B16BL6 cells injected into the tail vein was also inhibited by intravenous administration with Asc2P6Plm dose-dependently. Thus Asc2P6Plm, a lipophilicity-hydrophilicity balanced molecule protectively blockd in the autooxidation-prone moiety, is anticipated as a potent anti-metastatic agent via inhibition of tumor invasion.
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PMID:Anti-metastatic effect of an autooxidation-resistant and lipophilic ascorbic acid derivative through inhibition of tumor invasion. 1076 42

We have reported the synthesis of a series of anthracycline analog prodrugs that give rise to intensely cytotoxic metabolites in the presence of carboxylate esterases and beta-glucuronidases. We now report structurally related prodrugs that are converted to similar potent metabolites in the presence of beta-galactosidases. The prototypical compound, N-[(4"RS)-4"-ethoxy-4"(1'"-O-beta-D-galactopyranosyl)butyl]daunorubicin, 8a, was prepared by reductive condensation of daunomycin with 1-O-[(1'RS)-1'-ethoxy-4'-oxobutyl]-2, 3, 4, 6-tetra-O-acetyl-beta-D-galactopyranoside in the presence of sodium cyanoborohydride, followed by deacetylation of the galactoside moiety with sodium methoxide. A related prodrug (8b) with enhanced lipophilicity (the 4'-hexoxy analog of 8a) and 8c (the propyldaunomycin analog of 8a) were prepared for comparative studies. 8a and 8b were isolated after chromatography on silica as a mixture of 4'R and 4'S diastereomers; 8c, on the other hand, was resolved into its component 3' diastereomers, 8c(R) and 8c(S). 8a, 8c(R) and 8c(S) showed no evidence of decomposition when incubated at 37 degrees C in 0.05 M phosphate buffer, pH 7.4, for 2 weeks; 8b, under the same conditions, was degraded with a half-life of 49 h. In the presence of two units of Escherichia coli beta-galactosidase per pmol of substrate, the half-lives of 8a, 8b, 8c(R) and 8c(S) were 1.98, 1.06, 3.5 and 2.4 h, respectively. HPLC analysis of the incubation mixtures showed that 8a and 8b gave rise to a single, chromatographically identical metabolite. 8c(R) and 8c(S) also gave rise to a single, identical metabolite. 8a and 8b were nearly one million-fold more toxic to human A375 melanoma cells in culture in the presence of E. coli beta-galactosidase than in the absence of the enzyme. The activation products of 8c(R) and 8c(S) were approximately 1000-fold less potent. These beta-galactoside prodrugs have chemotherapeutic potential for use in conjunction with tissue-targeting strategies such as antibody-directed enzyme prodrug therapy (ADEPT) and gene-directed enzyme prodrug therapy (GDEPT).
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PMID:Intensely cytotoxic anthracycline prodrugs: galactosides. 1083 72


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