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)

Methylglyoxal bis(guanylhydrazone) (MGBG) has been studied clinically as an antitumor and antileukemic agent and is recognized as a potent but nonspecific inhibitor of the key polyamine biosynthetic enzyme, S-adenosylmethionine decarboxylase (SAMDC). A series of four SAMDC inhibitors with structural features similar to MGBG have been found to have improved potency and specificity toward the target enzyme, SAMDC. Relative to MGBG, the new derivatives were much more effective in inhibiting partially purified preparations of SAMDC (50% inhibitory concentration, 10 to 100 nM), much less effective at inhibiting diamine oxidase, and inactive toward ornithine decarboxylase. The inhibitors varied relative to MGBG in their ability to compete with spermidine for uptake, with two being similar and two being less effective. Against L1210 leukemic cells and T24 bladder carcinoma cells, the compounds were slightly less effective than MGBG at inhibiting cell growth, with 50% inhibitory concentration values of 1 to 10 microM as compared with 0.5 and 1.1 microM, respectively, for MGBG. Under 50% growth-inhibitory conditions, the inhibitors decreased SAMDC activity, increased ornithine decarboxylase activity and putrescine pools, and markedly depleted spermidine and spermine pools of L1210 cells. At the same time, mitochondrial integrity as assessed by whole-cell pyruvate oxidation and mitochondrial DNA content was not affected as it was with MGBG. At doses less than one tenth that of the maximally tolerated dose, all of the new inhibitors strongly suppressed the growth of B16 melanoma in vivo with minimal weight loss or toxicity. At doses less than one sixth the maximally tolerated dose, they effectively inhibited the growth of T24 human bladder carcinoma xenografts. In these same systems, MGBG showed only marginal antitumor activity. These studies identify two potent and efficacious inhibitors of SAMDC as potential antitumor agents and reaffirm the importance of SAMDC as a target in anticancer drug discovery.
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PMID:New S-adenosylmethionine decarboxylase inhibitors with potent antitumor activity. 151 37

alpha-Difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, inhibited B16 melanoma-induced angiogenesis in chick embryo chorioallantoic membrane and subsequently the growth of the tumor on the chorioallantoic membrane. These inhibitions were reversed by exogenous putrescine and spermidine. DFMO also inhibited rapid neovascularization in yolk sac membrane of 4-day-old chick embryos and the inhibition was reversed by exogenous putrescine and spermidine. DFMO strongly inhibited DNA synthesis and proliferation of bovine pulmonary artery endothelial (BPAE) cells in culture and decreased their ornithine decarboxylase activity and intracellular polyamine concentrations. Addition of putrescine to the culture medium of DFMO-treated BPAE cells restored their intracellular putrescine and spermidine concentrations and their DNA synthesis and proliferation. Addition of spermidine to cultures of DFMO-treated BPAE cells restored their intracellular spermidine concentration and their DNA synthesis and proliferation. DFMO inhibited the proliferation of B16 melanoma cells in culture but the inhibitory effect was much less than that on BPAE cells. When one-half the monolayer of confluent cultures of BPAE cells had been peeled off, addition of DFMO to the cultures inhibited the proliferation and extension of the BPAE cells into the vacant area but had no effect on stationary cells in the remaining half of the monolayer, suggesting that it inhibited induction of proliferation of endothelial cells. These findings suggest that the antitumor activity of DFMO against solid tumors is probably due more to its inhibition of tumor-induced angiogenesis by inhibition of proliferation of endothelial cells induced by polyamine depletion than to a direct effect on tumor cell proliferation.
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PMID:Tumor angiogenesis and polyamines: alpha-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase, inhibits B16 melanoma-induced angiogenesis in ovo and the proliferation of vascular endothelial cells in vitro. 169 80

Previous studies have shown that melanoma is very sensitive to inhibitors of polyamine biosynthesis. In this work, we have studied changes in polyamine concentrations and the activities of two key enzymes of their biosynthetic pathway at different stages of growth of Harding-Passey melanoma transplanted to mice. We found that the peak activity of ornithine decarboxylase and S-adenosylmethionine decarboxylase corresponded with maximal rate of tumour growth, but showed no clear correlation with polyamine content of the tumour. The ratio of spermidine to spermine was extremely low, decreasing from 0.80 to 0.46 through the different stages of growth. The half-lives of ornithine decarboxylase and S-adenosylmethionine decarboxylase were 15 and 30 min, respectively. The half-life of melanomal S-adenosylmethionine decarboxylase increased to 110 min in difluoromethylornithine-treated animals. The activities of both decarboxylases were markedly decreased by administration of exogenous polyamines, ornithine decarboxylase being more sensitive than S-adenosylmethionine decarboxylase. Spermidine and spermine were more effective than putrescine or diaminopropane. The results indicate that the melanoma ornithine and S-adenosylmethionine decarboxylases behave in the same way as the enzymes from non-neoplastic tissues.
Melanoma Res
PMID:Polyamine metabolism in Harding-Passey murine melanoma. 184 14

The oral administration of alpha-difluoromethylornithine (DFMO), an enzyme-activated inhibitor of ornithine decarboxylase (ODC), produced a marked decrease in the rate of growth of amelanotic Harding-Passey melanoma transplanted in mice. The half-life of this compound in Harding-Pasey melanoma was 30 min. A combined treatment of DFMO and hyperthermia did not show any synergistic effect on the inhibition of tumor growth, and no differences in the levels of tumor ODC, S-Adenosylmethionine decarboxylase (SAMDC) and polyamines were observed between single and combination treatments. DFMO-treatment alone produced a decrease of about 80% in spermidine concentration in melanoma, while in other tissues such as kidney, the diminution of spermidine was only moderate. ODC activity was reduced greatly in the kidney and moderately in melanoma. However, the activity of SAMDC increased up to 30-fold in DFMO-treated melanoma, while only a moderate increase was observed in the renal enzyme. Melanoma tyrosinase activity did not increase with the treatment with DFMO. These results indicate that the inhibition of amelanotic Harding-Passey melanoma growth by DFMO is not caused by the stimulation of cell differentiation, and that in this system polyamine depletion caused by this drug does not produce an enhancement in the heat-induced cytotoxicity.
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PMID:Effects of treatments with alpha-difluoromethylornithine and hyperthermia on the growth and polyamine metabolism of Harding-Passey murine melanoma. 190 4

Type I interferon and difluoromethylornithine have been shown to exert an antiproliferative effect, both alone and in combination, in several tumor cell lines. Using B16 melanoma cells, we have shown that these two drugs inhibit growth over 72 hr in vitro. The estimated ED50 values for difluoromethylornithine and type I interferon were 31.1 +/- 1.1 microM and 22.3 +/- 2.7 IU/ml, respectively. When used in combination, a marked synergism was observed, as detected by isobologram analysis. Type I interferon, at concentrations that exhibited synergistic activity with difluoromethylornithine, did not affect ornithine decarboxylase activity or intracellular polyamine concentrations. These data suggest that the synergistic antiproliferative effect of murine type I interferon in combination with difluoromethylornithine is not mediated via polyamine depletion. When we examined the type I interferon receptor numbers on the B16 cells exposed to 5 IU/ml murine type I interferon for 72 hr, a 40% decrease was observed, compared with that seen in control cells. Difluoromethylornithine, at 10 microM, did not affect type I interferon receptor numbers. However, when added to the cells in the presence of murine type I interferon, difluoromethylornithine completely inhibited down-regulation, suggesting that down-regulation of the type I interferon receptor is a polyamine-dependent process. These observations may provide a basis for enhancing the therapeutic efficacy of interferon treatment through control of interferon receptor down-regulation.
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PMID:Difluoromethylornithine prevents the down-regulation of type I interferon receptors: a possible mechanism for a synergistic antiproliferative effect. 214 87

UV radiation plays an important role in the induction of cutaneous malignancy, including basal cell and squamous cell carcinomas and malignant melanoma. In addition to its effects on DNA damage and repair mechanisms, UV radiation has been shown to modulate the expression of specific genes, altering the levels of their mRNAs and the synthesis of their corresponding proteins. In order to gain further information about the molecular effects of UV radiation, we have studied the regulation of ornithine decarboxylase (ODC) gene expression in response to UVB radiation. ODC is the rate-limiting enzyme in polyamine biosynthesis, is involved in growth and differentiation, and has been implicated in carcinogenesis. Keratinocytes grown in culture were either sham-irradiated or exposed to increasing doses of UVB (1-5 mJ/cm2). Northern blot analysis of keratinocyte RNA under basal conditions demonstrated the presence of two ODC mRNA transcripts. Increasing exposure to UVB resulted in a dose-dependent increase in the levels of both ODC mRNA transcripts. The induction of ODC gene expression following UVB was noted 2 h after UVB exposure, and ODC mRNA levels continued to increase up to 24 h after UVB exposure. The UVB-induced increase in ODC gene expression was not serum dependent, despite the ability of serum alone to induce ODC gene expression. The mRNA transcripts for actin and hexosaminidase A were not induced after UVB exposure. These studies show that the UVB-induced increase in ODC activity is due, at least in part, to an increase in ODC gene expression and they provide a useful model for the analysis of the molecular effects of UVB radiation.
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PMID:Ultraviolet radiation induction of ornithine decarboxylase in rat keratinocytes. 232 89

In this paper the biological activity of several newly synthesized benzoic acid derivatives of the Am- and Ch- series, which are structurally different from retinoic acid and arotinoids, was examined. These compounds inhibit squamous cell differentiation of rabbit tracheal epithelial cells in vitro as indicated by the inhibition of transglutaminase Type I and cholesterol 3-sulfate levels. In contrast to the inhibition of differentiation in rabbit tracheal cells, these compounds induce differentiation of mouse embryonal carcinoma F9 and human promyelocytic leukemia HL60 cells. The Am- and Ch- series of compounds also affect several parameters of cell proliferation. These agents are very potent inhibitors of growth of melanoma S91 cells and inhibit the induction of ornithine decarboxylase activity by phorbol 12-myristate 13-acetate in 3T6 fibroblasts. These results show that the Am- and Ch- derivatives elicit in several cell systems the same cellular responses as retinoic acid. We propose, therefore, that they exhibit mechanism(s) of action similar to those of retinoids. Comparison of the biological response with the binding capacity to the cellular retinoic acid-binding protein shows a lack of a direct correlation.
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PMID:New benzoic acid derivatives with retinoid activity: lack of direct correlation between biological activity and binding to cellular retinoic acid binding protein. 288 32

Ornithine decarboxylase (ODC) is a rate-limiting enzyme in polyamine synthesis, and polyamines are required for cell growth. As an approach to clarifying the mechanism of action IL-1, the effects of IL-1 on ODC activity were examined in various cell lines whose proliferation was either suppressed or enhanced by IL-1. The proliferation of all cell types used in these experiments was markedly suppressed by a specific ODC inhibitor, alpha-difluoromethyl ornithine (DFMO), substantiating the crucial role of ODC activity for cell proliferation. ODC activity also was considerably suppressed by IL-1 in those cells on which IL-1 exerts an antiproliferative effect, such as a human melanoma cell line (A375) and malignant human mammary cell lines (MCF-7 and T-47D). On the other hand, ODC activity was stimulated in cells that are stimulated to proliferate in response to IL-1, such as a mouse helper T cell line (D10.G4.1), a NK cell-like cell line (YT), and a human glioblastoma cell line (U373 MG). The effect of IL-1 on ODC activity preceded and directly correlated in a dose-dependent manner with its effect on DNA synthesis. Furthermore, putrescine, a product of the ODC reaction and a precursor of polyamines, was able to overcome most, but not all, the antiproliferative action of IL-1 in A375 melanoma cells, which were the most sensitive to suppression by IL-1. However, putrescine did not reverse the cytostatic effect of IL-1 on MCF-7 and T-47D cell lines. In contrast, putrescine, like IL-1, exhibited some co-mitogenic activity on D10.G4.1 cells. Because the biological activities of TNF and IL-1 show considerable overlap, the effect of TNF on ODC activity also was examined. TNF had an antiproliferative effect on A375 cells and stimulated the proliferation of U373 MG cells. The ODC activity in A375 cells was suppressed by TNF, and the ODC activity in U373 MG cells was stimulated by TNF. Putrescine also partially overcame the inhibitory effect of TNF. These results suggest that the regulation of ODC activity may be a key component in the antiproliferative and proliferative action of IL-1 and TNF in some tumor cell types.
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PMID:Role of ornithine decarboxylase in the regulation of cell growth by IL-1 and tumor necrosis factor. 297 24

Difluoromethylornithine (DFMO), a specific, irreversible, enzyme-activated inhibitor of ornithine decarboxylase activity, the first and rate-limiting step in polyamine biosynthesis, has been shown to inhibit neoplastic cell proliferation in culture. In most cases, such inhibition is not accompanied by cell loss, with the exception of multiple cell lines of human small cell lung carcinoma (SCC), a human leukemia cell line (HL-60), and possibly the B16 melanoma cell line. The first two cell types grow as anchorage-independent suspension cultures, the HL-60 as single cells and the SCC as multicellular spheroid aggregates. Moreover, in the spectrum of human lung carcinoma cells in culture, the SCC cells respond in a cytotoxic manner to DFMO, whereas the non-small cell lung carcinoma (non-SCC) cells, which are anchorage dependent, show only growth inhibition, without actual cell loss. In the present study, we have investigated relationships between anchorage-dependent and -independent growth patterns of cells in culture and their response to DFMO treatment. Two non-SCC lung cancer cell lines, which normally grow as anchorage-dependent monolayers, show growth inhibition but no cell loss with the addition of DFMO. When these anchorage-dependent cells were forced to grow as multicellular aggregates, by coating the culture flask with Teflon, the cells developed an increased sensitivity to DFMO. They showed not only inhibition of cell proliferation but also cell death. Two SCC cell lines, which normally grow as anchorage-independent spheroids, developed adherence to the culture dishes coated with fibronectin. These cells, which show a cytotoxic response to DFMO during normal anchorage-independent growth, developed a decreased sensitivity to DFMO, showing only cell growth inhibition, but no cell death when treated during anchorage-dependent growth. Our data thus suggest that the state of anchorage dependence of lung cancer cells in culture is a critical factor in determining their response to polyamine depletion during treatment with DFMO.
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PMID:Anchorage dependency effects on difluoromethylornithine cytotoxicity in human lung carcinoma cells. 300 7

Vitamin A is essential for normal cellular growth and differentiation. A vast amount of laboratory data have clearly demonstrated the potent antiproliferative and differentiation-inducing effects of vitamin A and the synthetic analogues (retinoids). Recent in-vitro work has led to the exciting proposal that protein kinase-C may be centrally involved in many of retinoids' anticancer actions including the effects on ornithine decarboxylase induction, intracellular polyamine levels, and epidermal growth factor receptor number. Several intervention trials have clearly indicated that natural vitamin A at clinically tolerable doses has only limited activity against human neoplastic processes. Therefore, clinical work has focused on the synthetic derivatives with higher therapeutic indexes. In human cancer prevention, retinoids have been most effective for skin diseases, including actinic keratosis, keratoacanthoma, epidermodysplasia verruciformis, dysplastic nevus syndrome, and basal cell carcinoma. Several noncutaneous premaligancies, however, are currently receiving more attention in retinoid trials. Definite retinoid activity has been documented in oral leukoplakia, laryngeal papillomatosis, superficial bladder carcinoma, cervical dysplasia, bronchial metaplasia, and preleukemia. Significant therapeutic advances are also occurring with this class of drugs in some drug-resistant malignancies and several others that have become refractory, including advanced basal cell cancer, mycosis fungoides, melanoma, acute promyelocytic leukemia, and squamous cell carcinoma of the skin and of the head and neck. This report comprehensively presents the clinical data using retinoids as anticancer agents in human premalignant disorders and outlines the ongoing and planned studies with retinoids in combination and adjuvant therapy.
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PMID:Vitamin A derivatives in the prevention and treatment of human cancer. 306 55


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