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)

Melanin synthesis of B16 mouse melanoma cells was found to be stimulated dose and time dependently by 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3], the hormonal form of vitamin D3. The stimulation of melanogenesis resulted from an increase in the activity of tyrosinase, a key enzyme in melanin synthesis. The minimum dose required for this stimulation was as low as 0.05 ng/ml, or 0.12 nM, a physiological level of plasma 1 alpha,25(OH)2D3. The stimulation by 1 alpha,25(OH)2D3 was specific; other derivatives of vitamin D3 caused no stimulation at a concentration of 500 ng/ml. When the cells were plated on agar plates, the proportion of dark or black colonies was not increased by the exposure to 1 alpha,25(OH)2D3. Furthermore, this compound did not induce melanin synthesis of an amelanotic variant. Thus, its stimulatory effect seemed to be due to stimulation of melanin synthesis of melanotic cells, rather than to conversion of amelanotic clones to melanotic ones. 1 alpha,25(OH)2D3 did not induce intracellular cyclic adenosine 3':5'-monophosphate, while cholera toxin induced cyclic adenosine 3':5'-monophosphate and stimulated melanin synthesis and tyrosinase activity much more than did 1 alpha,25(OH)2D3, suggesting that 1 alpha,25(OH)2D3 stimulates melanin synthesis by a cyclic adenosine 3':5'-monophosphate-independent mechanism. B16 melanoma cells contained specific receptors for 1 alpha,25(OH)2D3. Scatchard plot analysis revealed two types of receptor; the high-affinity receptor had a Kd of 18.3 pM and an Nmax of 10.6 fmol/mg of protein. The specificity of receptor binding was demonstrated by studies showing that, for 50% displacement of 1 alpha,alpha,25(OH)2D3 binding, other derivatives were required at 500 times higher concentrations or more. In contrast to 1 alpha,25(OH)2D3, retinoic acid inhibited melanin synthesis and tyrosinase activity of B16 melanoma cells dose and time dependently. On simultaneous treatment, 1 alpha,25(OH)2D3 and retinoic acid caused mutual interference, and a balance between their respective stimulating and inhibitory effects was obtained at a molar ratio of 10:1; i.e., with 10 nM 1 alpha,25(OH)2D3 and 1 nM retinoic acid.
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PMID:Regulation of melanin synthesis of B16 mouse melanoma cells by 1 alpha, 25-dihydroxyvitamin D3 and retinoic acid. 298 83

To a limited extent, we corroborated a previous report of human neuroblastoma sensitivity to 13-cis-retinoic acid. Seven cultured human neuroblastoma, two primitive neuroectodermal tumor, and one melanoma cell line were exposed to 0.001 to 10.0 microM 13-cis-retinoic acid for six to fourteen days. The neuroblastoma cell line, SK-N-DZ, was the only cell line lysed by all concentrations of 13-cis-retinoic acid. The other cell lines were refractory to concentrations as high as 10 microM. Increased cell process formation was observed in three neuroblastoma, SK-N-SH, SK-N-BE, SK-N-LE, and one melanoma cell line. We conclude that sensitivity to 13-cis-retinoic acid is unevenly distributed among histogenetically similar tumors from different patients.
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PMID:Human neuroblastoma cells and 13-cis-retinoic acid. 298 26

Vitamin A inhibits growth and increases the activity of cAMP-dependent protein kinase in B16 mouse melanoma cells. In this report we show that retinoic acid (RA) treatment of intact cells alters their subsequent in vitro protein phosphorylation, but we could not demonstrate any changes in in vivo protein phosphorylation. A 48-h treatment with RA results in a concentration-dependent decrease of protein phosphorylation of a 95K molecular weight (MW) protein in both supernatant and particulate fractions. The phosphorylation of this protein does not appear to be regulated by cAMP. Proteins at 92K and 82K MW in the supernatant fraction are increased in phosphorylation. The former (but not the latter) is regulated by cAMP. In the particulate fraction a variety of proteins 12K-68K MW are increased in phosphorylation, as the cells are treated with increasing amounts of RA. The phosphorylation of most of these proteins is regulated by cAMP. Another inhibitor of B16 cell growth, melanocyte-stimulating hormone (MSH) also alters protein phosphorylation. At short incubation periods (1 h), this hormone stimulates phosphorylation of a number of proteins (17-40K MW), while in longer incubation periods (48 h) phosphorylation is inhibited. All of these phosphorylations appear to be regulated by cAMP. We attempted to repeat these observations using intact-cell phosphorylation with 32PO4. In two experiments we saw small changes in the phosphorylation of proteins. In most experiments, however, we could find no change in the phosphoproteins. Further experiments have led us to question the in vivo phosphorylation, since treatment of the cells with MSH, cholera toxin, or db-cAMP also did not affect intact-cell protein phosphorylation. We have previously documented that under these latter conditions cAMP levels are greatly elevated and cAMP-dependent protein kinase is activated. The in vitro phosphorylation results suggests that in RA-treated cells, kinase activities and/or protein substrate levels are changing. However, the physiological significance of the particular MW phosphoproteins changes we have described must await resolution of the in vivo phosphorylation data.
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PMID:The effect of retinoic acid on protein phosphorylation in mouse melanoma cells. 301 73

Five human melanoma cell lines (C8146C, C8161, C82-7A, C83-2CY and MIRW5) were shown to contain a significant number of melanoma colony-forming units resistant to single-agent treatment by dexamethasone, alpha-interferon and trans-retinoic acid. These biological modifiers were combined with difluoromethylornithine into a low-dose combination using concentrations below pharmacologically achievable levels. The suppression of melanoma colony formation induced by this combination was consistent and significantly higher than that seen with any single agent, colony formation being reduced by an average of 90%. Leaving either DEX or DFMO out of the 4-agent combination resulted in a significant decrease in the observed inhibition. This was also verified by the addition of putrescine which inhibited only the DFMO activity. Median effect analysis of the DFMO + IFN inhibition of C8161 cells demonstrated that the 2 agents interacted synergistically over the entire dose-response curve. Of the high-dose combination-treated melanoma colony-forming units, 97% did not form small growth units; most remained as arrested single cells, but the cells and small growth units could still metabolize tetrazolium stain after the experiment, suggesting that the high-dose combination arrested the growth of the melanoma colony-forming units via a non-cytotoxic mechanism.
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PMID:Difluoromethylornithine enhances inhibition of melanoma cell growth in soft agar by dexamethasone, clone A interferon and retinoic acid. 307 41

The effect of retinoic acid on murine B16 melanoma cell growth, tyrosinase activity and melanin synthesis was investigated. Retinoic acid inhibited the growth of B16F1, B16F10 and B16BL6 melanoma cells, but enhanced melanin synthesis only in the B16F1 cells. The B16F10 and B16BL6 cells exhibited retinoic acid-induced suppression of tyrosinase activity and melanin synthesis, which was most apparent in the B16F10 cell variant. For comparison, Cloudman S91 melanoma cells proved to be particularly sensitive to retinoic acid-induced growth inhibition and stimulation of the expression of their melanotic phenotype. These results suggest considerable heterogeneity in the B16 melanoma with respect to their response to retinoic acid.
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PMID:Different susceptibilities of melanoma cells to retinoic acid-induced changes in melanotic expression. 313 94

The ability of difluoromethylornithine (DFMO), a specific polyamine synthesis inhibitor, to interact with various biological modifiers to inhibit the colony-forming growth of human melanoma cells was determined by using the median effect principle to computer model the strength of two agent interactions. Either alpha- or gamma-IFN (interferon) in combination with DFMO resulted in a synergistic inhibition on human melanoma colony formation. For human melanoma cells which were not resistant to 13-cis RA (retinoic acid), an additive suppression on colony formation was obtained with the retinoid-DFMO combination. Dexamethasone (DEX) interacted with DFMO to yield a synergistic reduction in melanoma colony number on glucocorticoid sensitive cells and no growth enhancement with DFMO on glucocorticoid resistant melanoma lines. Human melanoma cells displayed differential long-term growth sensitivity to DFMO treatment. C8146C human melanoma cells were terminally growth-inhibited by a 96 h exposure to DFMO, in a manner which was concentration and time dependent. The proliferation of C82-7A melanoma cells was inhibited by 95% in presence of DFMO, but upon removal of DFMO the cells regained their ability to proliferate and form colonies. The simultaneous addition of DEX plus alpha-IFN plus 13-cis-RA with DFMO caused most of the human melanoma cells in these lines to become permanently growth arrested. Pre-treatment with DEX plus alpha-IFN plus 13-cis RA, but without DFMO, did not have any long term effect on the ability of melanoma cells to recover and proliferate in soft agar.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Median effect and long term recovery analysis of biological modifier interactions with difluoromethylornithine on the proliferation of human melanoma cells. 314 16

The purpose of the experiments was to establish whether individual cells of a tumor cell population, or clonal lines derived from its express the differentiated phenotype, or respond heterogeneously following treatment with inducers of differentiation or with cytostatic drugs. The human cell lines used in this study were: HL-60 promyelocytic leukemia, K562 erythroleukemia, BHM-97 and A2058 melanoma, and A-1, A-2, A-4 and A-6 clones of A2058 line. Inducers of differentiation were phorbol myristate acetate (PMA), dimethylsulfoxide (DMSO) and retinoic acid (RA); cytostatics: adriamycin (ADM), 5-fluorouracil (5-FU), dacarbazine (DTIC), cis-platin (platidiam, PD) and arabinosyl cytosine (ara-C). Expression of the differentiated phenotype was shown by cell attachment (HL-60), hemoglobin production (K562), dendrit formation (A2058, BHM-97). Individual cells expressed the differentiated phenotype heterogeneously in all types of cell populations. Clone A-4 was the most, and clone A-6 the least sensitive to PMA. The drug sensitivity of the clones was different and drug-dependent. It is concluded that induction of differentiation as another approach to therapy of cancer, similar to anticancer drug therapy, also implies disadvantages due to population heterogeneity. Combinations of cytostatics with differentiation inducers might result in improved therapeutic effects.
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PMID:Heterogeneity of the response to inducers of differentiation and to cytostatics of tumor cell populations. 323 68

The effects of 2-hydroxyethyl retinamide, N-(4-hydroxy-phenyl) all-trans-retinamide, and 13-cis-retinoic acid on the growth and metastasis of a malignant hamster melanoma cell line HM1-F5 was determined in a double blind study using 4- to 5-week-old male NIH Swiss and BALB/c derived athymic nu/nu mice. Mice were fed retinoids (0.75 and 1.0 or 1.5 mmol/kg diet) or a placebo diet ad libitum beginning on the day of s.c. inoculation of 5 x 10(5) HM1-5 cells. Tumor incidence, latency, and growth rate were similar in both strains of mice. All placebo-treated mice had lung metastasis on the day of autopsy, although the total number of metastases was lower in NIH Swiss derived athymic mice. While mean tumor incidence and latency were not significantly altered by any retinoid treatment, tumor growth rate (volume) and final tumor weight were inhibited (P less than 0.05) by 0.75 mmol/kg 13-cis retinoic acid and 1.5 mmol/kg N-(4-hydroxyphenyl) all-trans-retinamide. In contrast, at 1.0 or 1.5 mmol/kg diet, 2-hydroxyethyl retinamide had no significant effect on tumor growth rate. 13-cis retinoic acid, 0.75 mmol/kg, 2-hydroxyethyl, 1.0 mmol/kg, and N-(4-hydroxyphenyl), 1.0 mmol/kg significantly reduced the mean number of metastatic lesions in NIH Swiss derived mice, but N-(4-hydroxyphenyl) all-trans-retinamide also reduced metastatic incidence while 2-hydroxyethyl retinamide and 13-cis retinoic acid had no effect. A concentration of 1.5 mmol/kg diet of 2-hydroxyethyl and N-(4-hydroxyphenyl) all-trans-retinamide significantly reduced the overall number of gross lung metastases in BALB/c and Swiss mice, and mean number of metastases in Swiss mice. Analysis of correlation indicated that the inhibitory effect of high-dose N-(4-hydroxyphenyl) and 2-hydroxyethyl retinamide on metastasis was not associated with (independent of) any inhibitory effect on primary tumor invasiveness or growth rate. Our observations suggest that agents such as retinoids have an antimetastatic potential.
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PMID:Influence of retinoids on growth and metastasis of hamster melanoma in athymic mice. 334 19

An HLA class II-positive melanoma cell line, DU-Mel 17, was treated with three compounds known to induce differentiation in various cell lines. Neither retinoic acid nor dibutyryl cAMP altered levels of DR alpha mRNA, but 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) significantly decreased the level of DR alpha mRNA 48 h after treatment. Optimal effect of the hormone on DR alpha mRNA was reached by 72 h. DU-Mel 17 cells were responsive to 1,25(OH)2D3 in a dose-dependent manner, and a reduction in DR alpha mRNA was seen at concentrations as low as 5 x 10(-13) M. The action of 1,25(OH)2D3 on DR alpha mRNA levels was dependent on protein synthesis as evidenced by inhibition of its effect upon addition of cycloheximide. Both DR and DQ protein levels on the surface of DU-Mel 17 were beginning to decline by 72 h after 1,25(OH)2D3 treatment, and by 96 h these proteins were decreased by 65%. 1,25(OH)2D3 was not capable of altering expression of class II molecules on three different class II-positive B lymphoblastoid cell lines, although one of these lines was shown to express the receptor for 1,25(OH)2D3. These findings are important because 1) there is no known physiologic regulator that actively down-regulates class II molecules that are present in and/or on cells, 2) levels of mRNA derived from a very limited number of genes are known to be altered by 1,25(OH)2D3, and 3) they support the contention that 1,25(OH)2D3 may alter the differentiation state of these cells and the activity of the normal counterpart of these cells in an immune response.
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PMID:1,25-Dihydroxyvitamin D3 decreases expression of HLA class II molecules in a melanoma cell line. 337 95

Previous studies have demonstrated the ability of retinoic acid (RA) to inhibit the growth of two spontaneous murine melanoma cell lines (B16-F1 and S91-C2) and to augment both sialyltransferase activity and the sialylation of an Mr 160,000 cell-surface glycoprotein. The present study examined the effects of RA on an ultraviolet irradiation-induced murine melanoma cell line K-1735P. Like the two spontaneous melanomas, the uv-induced melanoma exhibited susceptibility to the growth-inhibitory action of RA. Both the anchorage-dependent and the anchorage-independent growths of the K-1735P cells were suppressed by RA, with IC50 values of 5 X 10(-9) and 3 X 10(-12) M, respectively. Sialyltransferase activity in both S91-C2 and K-1735P cells treated with 10(-6) or 10(-5) M RA increased two- and three-fold, respectively, as compared with untreated cells. In contrast, cell-surface sialo- and galactoglycoproteins, revealed by labeling with periodate and tritiated borohydrate or with neuraminidase, galactose oxidase, and tritiated borohydrate, respectively, varied between the S91-C2 and the K-1735P cells, and each cell line's modulation by RA was also distinct. These findings suggest that although RA can increase the activity of sialyltransferase in different melanoma cells, this increased activity may, in turn, result in an increased sialylation of distinct cell-surface glycoproteins.
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PMID:Enhancement of sialyltransferase in two melanoma cell lines that are growth-inhibited by retinoic acid results in increased sialylation of different cell-surface glycoproteins. 339 Dec 45


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