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 use of megestrol acetate in treatment of malignancy (endometrial carcinoma, ovarian cancer, prostate cancer, breast cancer, renal cell carcinoma, malignant melanoma), endometrial hyperplasia, benign prostatic hypertrophy, contraception, anorexia, cachexia and weight loss is reviewed, concluding with a toxicity profile. Megestrol acetate was introduced in 1971 for treatment of endometrial carcinoma. Megestrol acetate is probably effective in proportion to the number of cytoplasmic progesterone receptors, but it has not been tested in a Phase III trial. For ovarian cancer it has been reported to be effective in 1 trail at doses of 800 mg/day. Prostate cancer, although difficult to assess, responds to megestrol acetate at doses of 120 mg/day because of its suppression of gonadotropins, its inhibition of 5alpha-reductase and its binding to the dihydrotestosterone receptor. Megestrol acetate permits a lower dose of diethylstilbestrol, and thus lower toxicity. There is apparently a dose-response between megestrol acetate and breast cancer, along with a response dependent on the number and type of estrogen and progestin receptors. Responses are better in postmenopausal women, and additive with other agents such as tamoxifen and mitomycin C. The medium duration of effect is 6-8 months. It has no effect on renal cancer or malignant melanoma. Megestrol acetate can be considered as an effective medical alternative to surgery for endometrial hyperplasia or benign prostatic hypertrophy. As a contraceptive in inhibits sperm transport rather than ovulation, but also causes irregular bleeding. Megestrol acetate has few side effects, and has the advantage of stimulating appetite and weight gain, a benefit in cancer patients.
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PMID:Megestrol acetate: clinical experience. 247 90

The human melanoma cell line M21 can be induced to differentiate into oligodendrocyte-like cells with concommitant cessation of cell division. Cytosine-arabinoside, 5-aza-2'-deoxycytidine, hydroxyurea, aphidicolin, and phorbol-12-myristate-13-acetate were found to be potent differentiation inducers. We have analyzed the changes of methylation of DNA cytosines that occur after treatment of M21 cells with these compounds. Although DNA methylation levels remain unchanged in the presence of aphidicolin and phorbol ester, 5-aza-2'-deoxycytidine-induced differentiation of these cells results in a 40% DNA demethylation. On the other hand, hydroxyurea and cytosine-arabinoside treatment causes DNA hypermethylation, which, in the case of the cytidine analogue is of only transient nature. These results show that the differentiation of human melanoma cells can be accompanied by variable changes of DNA methylation levels. In another set of experiments, the DNA methylation levels have been analyzed during cytosine-arabinoside-induced differentiation of human K562 erythroleukemia cells. In this system, a transient DNA demethylation precedes the establishment of the differentiated phenotype. Since DNA replication is inhibited, this demethylation cannot be explained by inhibition of the maintenance activity of DNA methyltransferase, but is more likely caused by an active excision of 5-methylcytosine from DNA.
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PMID:The DNA methylation system in proliferating and differentiated cells. 247 29

A sulfated polysaccharide-peptidoglycan complex, DS-4152, isolated from the culture supernatant of an Arthrobacter species inhibited angiogenesis and tumor growth and enhanced the antiangiogenic activity of 11 steroid hormones by 2 to 100 times. In the presence of cortisone acetate or tetrahydro S, DS-4152 suppressed chick chorioallantoic membrane angiogenesis and murine tumor M5076 cell-induced s.c. angiogenesis. The antitumor effects of DS-4152 administered in combination with a steroid whose dose level did not affect tumor growth were examined. DS-4152 significantly inhibited the growth of s.c.-implanted B16 melanoma in combination with cortisone acetate. DS-4152 plus tetrahydro S inhibited the growth of s.c. solid tumors and prolonged the survival time of mice bearing highly metastasizing M5076. The body weight increase was not affected by any administration. On the other hand, the survival of mice with ascitic M5076 tumors was not affected by the combination of DS-4152 plus tetrahydro S. The antiangiogenic activity of DS-4152 was more potent than that of heparin. Furthermore, DS-4152 is an angiogenesis inhibitor by itself, without steroid hormones. Successive s.c. treatment with heparin caused hemorrhagic death, but with DS-4152, suppressed tumor growth without reducing body weight.
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PMID:Antitumor effects of an antiangiogenic polysaccharide from an Arthrobacter species with or without a steroid. 247 71

We studied the mode of action of the synthetic peptide CKS-17, which is a heptadecapeptide homologous to a highly conserved region of the immunosuppressive retroviral envelope protein p15E, as well as to envelope proteins of the human T cell leukemia virus I and II. Previous studies have established that CKS-17 conjugated to BSA (CKS-17-BSA) inhibited IL-1-mediated tumor toxicity in melanoma cells and proliferation in murine Th clones. We examined the effects of CKS-17-BSA on IL-1 action. CKS-17-BSA did not bind to IL-1, nor did it affect the number of IL-1 receptors, their binding affinity, or their ability to internalize IL-1. However, CKS-17-BSA inhibited production of IL-2 by murine thymoma cells treated with IL-1 or with 12-O-tetradecanoyl phorbol-13 acetate. The potent protein kinase C inhibitor, H7, also inhibited IL-1-mediated responses, while HA1004, a weak inhibitor of protein kinase C, did not. Protein kinase C activity in the cytosolic fraction prepared from thymoma cells was found to be inhibited by CKS-17-BSA in a dose-dependent manner. All of these findings are consistent with the idea that CKS-17-BSA inhibits IL-1-mediated responses by interfering with signal transduction through a protein kinase C pathway.
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PMID:Synthetic peptide corresponding to a conserved domain of the retroviral protein p15E blocks IL-1-mediated signal transduction. 252 28

We have examined the effects of a biologically active tumor promoting phorbol ester (phorbol 12-myristate, 13-acetate (PMA] which activates protein kinase C (PKC) on melanotropin receptor function and cell growth in the M2R mouse melanoma cell clone. Treatment of M2R cells with PMA resulted in a significant loss of beta-MSH binding. The effect was both time- and concentration-dependent. The inhibition of beta-MSH binding resulted from a decrease (greater than 85%) in active membranal receptors available on the external cell surface and not from either enhanced internalization or change in the binding affinity. Agonist-stimulated cyclic AMP accumulation was profoundly increased in a non-selective manner following short-term incubation (3 h) with PMA. This effect was completely reversed during long-term (72-96 h) incubation with the tumor promoting agent. Long-term culturing of M2R cells with PMA resulted in enhanced (+50%) proliferation of the melanoma cells. This enhancement was blocked by the addition of agents which stimulate the production of cAMP. Hence, phorbol esters are powerful growth promoters in transformed melanocytes and our findings indicate that the effects of melanotropins are selectively impaired during the process of growth promotion.
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PMID:Phorbol ester impairs melanotropin receptor function and stimulates growth of cultured M2R melanoma cells. 254 Sep 97

The relationship between tight junctional resistance of a tissue and its penetration by metastatic cells was examined in vitro using LLC-PK1 cells, an epithelial cell line derived from pig kidney, and B16-F10 cells, a murine melanoma cell line metastatic in syngeneic C57BL/6 mice. When grown to confluence on 8.0-microns pore size polycarbonate filters, LLC-PK1 cells formed tight junctions between adjacent cells which offered an electrical resistance to a nondestructive 20-mu ampere alternating current passed across the cell layer. B16-F10 cells seeded on top of an LLC-PK1 epithelial layer with a measured transepithelial resistance of approximately 300 omega x cm2 were unable to penetrate the epithelial barrier. The tumor-promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) lowered the electrical resistance of the epithelial layer by 80% and simultaneously opened the epithelial barrier to penetration by metastatic cells.
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PMID:Effect of tight junctional resistance on penetration of LLC-PK1 epithelial cell layers by metastatic B16-F10 melanoma cells. 258 51

The mechanism of human interleukin (IL)-1 beta-mediated cytolysis was studied in a human melanoma cell line, A375.6. Purified recombinant human IL-1 beta produced 50% cytocidal activity at 50 pg/ml. A variety of compounds were tested for their ability to interfere with A375.6 lysis. Compounds were added simultaneously with IL-1 beta (100 pg/ml), and tumor cytolysis was measured after 72 hr of culture by release of 125I from DNA of A375.6 cells labeled with [125I]-dUrd. A variety of anti-inflammatory/immunosuppressive agents (including auranofin, chloroquine, cyclosporin A, d-penicillamine) and several cyclooxygenase/lipoxygenase inhibitors (AA-861, BW755c, and indomethacin) lacked protective activity. Similarly, phospholipase inhibitors (mepacrine and 4-bromophenacyl bromide), putrescine, inhibitors of lysosomal activity (chloroquine and NH4Cl), calcium channel blockers (nifedipine and verapamil), calmodulin inhibitors (W-7 and calmidazolium), and inhibitors of ADP ribosylation (nicotinamide and 3-aminobenzamide) were inactive. In contrast, corticosteroids (dexamethasone, hydrocortisone, and paramethasone acetate), tilorone, and protein kinase C inhibitors (1-[5-isoquinolinyl-sulfonyl]-2-methylpiperazine and staurosporine) significantly inhibited IL-1 beta-mediated A375.6 cytolysis. These compounds also interfered with tumor necrosis factor-mediated lysis of A375.6, suggesting common mechanisms of tumor cytotoxicity by these monokines. This model may be useful for delineating intracellular biochemical events integral to IL-1 action.
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PMID:Potent inhibition of interleukin 1 beta-mediated human melanoma (A375.6) lysis by corticosteroids, staurosporine, and tilorone. 262 25

Malignant transformation of melanocytes may be associated with changes in the expression of HLA antigens and melanoma-associated antigens (MAA). To determine whether these changes reflect the differential expression of HLA antigens and MAA by melanocytes at different stages of differentiation, we have studied the effect of the reversible induction of differentiation by fibroblast interferon (interferon beta) and/or 12-O-tetradecanoyl-phorbol 13-acetate (TPA) on the expression of HLA antigens and MAA by the melanoma cell lines DU-2, FO-1 and HO-1. The three melanoma cell lines differed in their sensitivity to the differentiating and antiproliferative activity of these two compounds and displayed an increased growth suppression and induction of differentiation, when incubated with the combination of TPA and interferon beta. Incubation of the three melanoma cell lines with interferon beta, TPA or their combination resulted in a differential modulation of the expression of membrane-bound high-molecular-mass melanoma-associated antigen, 115-kDa MAA, 100-kDa MAA, intercellular adhesion molecule 1, HLA class I antigens and gene products of the HLA-D region. Each melanoma cell line displayed a unique pattern of antigenic modulation when exposed to the two differentiating agents alone or in combination. No direct relationship was found between the effects of interferon beta and/or TPA on the growth and differentiation of the three melanoma cell lines and the expression of HLA antigens or the MAA evaluated in the present study. These findings argue against a direct role of any of the antigens tested in the reversible induction of human melanoma cell differentiation in the in vitro system.
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PMID:In vitro differentiation and antigenic changes in human melanoma cell lines. 262 19

In light of some evidence that hormonal factors may impact on malignant melanoma, we performed a randomized trial of megestrol acetate versus observation among 67 patients with high-risk resected stage I or stage II (nodal) malignant melanoma. Following stratification by relevant prognostic factors, we observed a statistical significance in survival advantage for megestrol acetate that approached 7.6 versus 2.6 years, median survival; two-sided log rank p = 0.06. Disease-free survival was also greater for patients who received this hormonal therapy (3.4 versus 1.1 years, median disease-free survival), but the difference was not statistically significant (two-sided log rank p = 0.20). The most noteworthy side effects were weight gain (median 6-month gain of 8.2 kg) and impotence. Fully recognizing the hazards of limited sample analyses and the need for confirmatory trials, our findings suggest a possible role for megestrol acetate as adjuvant therapy for selected patients with malignant melanoma.
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PMID:A prospective, randomized controlled trial of megestrol acetate among high-risk patients with resected malignant melanoma. 270 5

Interleukin 2 (IL-2) receptor expression was examined on recombinant IL-2 (rIL-2)-propagated tumor-infiltrating lymphocytes (TIL) from eight metastatic melanoma and three sarcoma samples. All 11 TIL expanded with similar growth rates. rIL-2 propagated TIL from five of eight metastatic melanoma specimens contained no Tac antigen-positive lymphocytes as determined by immunofluorescence and flow cytometry performed multiple times during the 4 to 8 week culture period. However, "Tac-negative" TIL did express the non-Tac IL-2-binding peptide, p70-75 as determined by [125I]IL-2 cross-linking and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. IL-2-binding assays revealed that these "Tac-negative" TIL expressed only an intermediate affinity IL-2 receptor. In contrast, TIL from the other three of eight melanoma and all three sarcoma contained one-third Tac-positive cells as assessed by flow cytometry analysis, and expressed surface non-Tac (p70-75) and Tac (p55) peptides by [125I]IL-2 cross-linking. These "Tac-positive" TIL displayed both the high and intermediate affinity IL-2 receptors. However, rIL-2-dependent growth of both "Tac-negative" and "Tac-positive" TIL was significantly inhibited by anti-Tac mAb, suggesting a transient Tac expression on the "Tac-negative" TIL. Additionally, due to the limits of our methodology, we cannot rule out the possibility of a constitutive expression of a low level of Tac, with an indicible expression of higher levels. Addition of culture supernatants from phytohemagglutinin- and phorbol myristate acetate-stimulated peripheral blood mononuclear cells to the "Tac-negative" TIL-induced detectable Tac expression within 48 h. These results indicate that both non-Tac and Tac IL-2 receptors play important roles during IL-2-dependent proliferation of TIL.
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PMID:Involvement of both Tac and non-Tac interleukin 2-binding peptides in the interleukin 2-dependent proliferation of human tumor-infiltrating lymphocytes. 278 85


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