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 inhibitory effect of difluoromethylornithine (DFMO) synthesized by the authors on the activity of the ornithine decarboxylase (ODC) and proliferation of microbial and mammalian cells in vitro was studied. The in vivo growth of ascite plasmocytoma of solid melanoma B-16 cells in mice was also effectively inhibited by DFMO. But the antiproliferative activity of DFMO in solid tumours was substantially lower. Such a decrease in the antitumour activity may be associated with polyamines released from necrotic areas of solid tumours. As the tumour cells "catch" the vitally important metabolites, their effect inside solid tumours is turned against the tumour cells themselves. The second reason of the decrease in the DFMO activity is adsorption of polyamines on the erythrocyte surface.
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PMID:[Antiproliferative activity of difluoromethylornithine and the factors decreasing its effectiveness in malignant growth]. 308 32

Difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, and human leukocyte interferon (IFN-alpha) have synergistic anti-tumor activities in vivo in B 16 melanoma and in vitro against several human cancer cell lines. We have, therefore, carried out a phase I combination study with DFMO plus alpha interferon in the following manner: DFMO was maintained at a steady dose for the first four levels, 1.5 g/m2 every 6 hr. IFN-alpha was given in 100% increments ranging from 0.4 X 10(6)U/m2 to 3.2 X 10(6)U/m2 i.m. daily. At the fifth dose level both IFN-alpha and DFMO were raised by 100 and 50% respectively. From levels one through four the combination was well tolerated with no dose interruptions required because of G.I. toxicity or myelosuppression. However, at dose level 5, one-third of the patients required dose cessation and decrease due to nausea, vomiting and diarrhea. We conclude that for phase II studies the maximal tolerated dose is 3.2 million units of IFN-alpha/m2 and 1.5 g/m2 of DFMO every 6 hr. Of 12 patients with metastatic melanoma, 2 had partial remissions lasting 58+ and 36+ weeks. Two additional patients had minor responses lasting 29 and 32+ weeks. Minor responses were observed in a patient with colon carcinoma and a patient with renal carcinoma. The clinical activity of the combination is currently being pursued in a phase II study among patients with metastatic malignant melanoma.
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PMID:Difluoromethylornithine and leukocyte interferon: a phase I study in cancer patients. 309 71

The objective of the present investigation was to examine the effect of in vivo polyamine depletion by DL-alpha-difluoromethylornithine (DFMO), a specific irreversible inhibitor of ornithine decarboxylase, on cell-mediated tumoricidal activity in normal and tumor-bearing (B16 melanoma) mice. DFMO treatment in vivo for 6 days reduced splenic leukocyte polyamine levels and the induction of cytotoxic T-lymphocytes (greater than 50%) in both normal and tumor-bearing mice. However, substantially less inhibition was observed in the ability to generate cytotoxic T-lymphocytes following 18 days of DFMO treatment. In contrast, DFMO treatment for 6 or 18 days did not impair splenic natural cell-mediated cytotoxicity, assessed against natural killer sensitive YAC-1 target cells and natural cytotoxic sensitive WEHI-164 target cells, in normal or tumor-bearing mice. Natural cell-mediated cytotoxicity was not observed against fresh B16 melanoma cells. However, macrophage-mediated tumoricidal activity directed against B16 melanoma cells was augmented 79% following 6 but not 18 days of DFMO treatment. These results demonstrate that DFMO can exert very selective effects on functionally distinct populations of antitumor effector cells in vivo depending upon the schedule of DFMO administration.
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PMID:Effect of polyamine depletion in vivo by DL-alpha-difluoromethylornithine on functionally distinct populations of tumoricidal effector cells in normal and tumor-bearing mice. 309 66

Our earlier studies indicated a role for polyamines (namely, putrescine, spermidine, and spermine) not only in tumor growth but also in tumor metastases. We have observed that administration of alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, resulted in significant inhibition of visually detectable pulmonary metastases in mice implanted with Lewis lung carcinoma. The objective of the present study is to investigate the effect of DFMO on other spontaneous and experimental metastatic models and also to determine which step(s) in the tumor metastatic cascade is sensitive to DFMO. The results presented in this study with malignant mouse B16 amelanotic melanoma (B16a) showed a dose-dependent effect of DFMO on the inhibition of both tumor growth and grossly detectable pulmonary metastases. DFMO, when administered as 0.5, 1, and 2% solution in drinking water, resulted in 0, 24.5, and 60% inhibition of tumor growth, respectively, whereas at the same doses an inhibition of 55, 83, and 96% of visible metastases was observed. At treatment levels of 1 and 2% DFMO, 30 and 65% of the animals were free of metastases. DFMO, at 0.5%, did not show any effect on tumor growth, while a significant 55% inhibition of visible pulmonary metastasis was observed, suggesting a specific role for polyamines in tumor metastasis. DFMO treatment also resulted in a significant reduction of putrescine and spermidine levels with a slight increase in spermine concentration in the tumor tissue. DFMO administration did not inhibit the experimental metastases induced as a result of i.v. injection of B16 melanoma (line F10) tumor and Lewis lung carcinoma cells into the tail vein. These results provide preliminary evidence to indicate that tumor cell polyamine depletion by DFMO might affect the first step in the metastatic cascade, intravasation (i.e., prevent the invasion of metastatic tumor cells into lymphatics or blood vessels), although the effect of DFMO on other steps in the metastatic cascade cannot be ruled out.
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PMID:Antimetastatic activity of DL-alpha-difluoromethylornithine, an inhibitor of polyamine biosynthesis, in mice. 310 31

The effects of DL-alpha-difluoromethylornithine (DFMO), a specific irreversible inhibitor of ornithine decarboxylase, on the growth of experimental mouse B16-F10 melanoma cells were investigated. DFMO (3%) in drinking water was administered to B16-F10 melanoma-bearing mice. At 24 days, B16-F10 melanomas in DFMO-fed mice weighed 75% less than those in control mice (p less than 0.001). DFMO reduced putrescine and spermidine levels in B16-F10 melanoma by 98% and 84%, respectively, and prolonged the mean survival time from 25.9 +/- 1.2 to 35.7 +/- 2.2 days (p less than 0.001). The effects of DFMO on experimental metastasis were also investigated. DFMO treatment resulted in a significant decrease in pulmonary metastasis induced by i.v. injection of B16-F10 melanoma cells.
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PMID:Effects of DL-alpha-difluoromethylornithine on the growth and metastasis of B16 melanoma in vivo. 310 Apr 60

Difluoromethylornithine (DFMO) is an irreversible enzyme-activated inhibitor of ornithine decarboxylase, a key enzyme in polyamine synthesis. We have screened for potential anti-cancer activity of DFMO using a clonogenic assay, which suggested that melanoma might have sensitivity to this agent. Accordingly, we have performed a phase II trial of DFMO (2 g/m2 po q 8 h) in 24 patients, 21 of whom were evaluable for response. One patient achieved a complete response of a large subcutaneous mass for 11 months. Although stabilization is frequently difficult to measure, seven patients appeared to stabilize previously active disease, with a median duration of response of eight weeks. Toxicity was significant and DFMO was discontinued in five patients due to side effects - hearing loss alone in four and hearing loss associated with thrombocytopenia in the fifth patient. Hearing changes occurred in ten patients. Other side effects were mild. These data indicate that DFMO as a single agent may be an effective therapy for melanoma. A phase II trial of DFMO in previously untreated patients using a different schedule to decrease hearing loss is warranted. Additionally, several in vitro and animal models suggest that DFMO plus interferon are synergistic, and this combination might be used for a clinical trial as well.
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PMID:A phase II study of alpha-difluoromethylornithine (DFMO) for the treatment of metastatic melanoma. 310 97

The anti-metastatic effect of two chemotherapeutic agents was analyzed in a murine melanoma model. Difluoromethylornithine (DFMO), a specific irreversible inhibitor of ornithine decarboxylase, was administered as a 2% aqueous solution in the drinking water. A second drug, dacarbazine (DTIC) was administered intravenously in single bolus injections. Each drug produced significant anti-metastatic effects that were manifested by a reduction in the number of pulmonary metastases and in the prolongation of host survival times. Maximal chemotherapy was achieved when both drugs were combined. The specificity, low toxicity, ease of administration, infrequent side effects, and therapeutic effectiveness of DFMO make it an attractive candidate for clinical use in human subjects being treated for uveal melanoma. The effectiveness of DTIC against blood-borne melanoma cells suggests that this drug may prove useful as a prophylactic adjunct in patients undergoing enucleation of a melanoma-containing eye.
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PMID:Suicide enzyme inhibition as a chemotherapeutic strategy for controlling metastases derived from intraocular melanomas. 311 18

Ornithine decarboxylase (ODC) is present in all nucleated cells and is the rate-limiting enzyme for synthesis of polyamines. In turn, the polyamines are required for DNA synthesis and cell growth. In Reuber H35 hepatoma cells, we show that ODC activity is increased by about 50% during exposure to a 1-h "athermal" (less than 0.1 degree C temperature rise) (450 MHz, 1.0 mW/cm2 peak-envelope-power) microwave field sinusoidally amplitude-modulated at 16 Hz. The increased activity of ODC persisted for several hours following the 1-h exposure to the field. A similar field amplitude-modulated at 60 and 100 Hz did not alter the hepatoma cell ODC activity. The stimulated ODC activity in the cultured cells that followed treatment with a phorbol ester tumor promoter (12-O-tetradecanoylphorbol-13-acetate) was further potentiated by prior exposure to the same low energy electromagnetic field. This field did not alter either basal or 12-O-tetradecanoylphorbol-13-acetate-stimulated DNA synthesis. We observed a similar increase in the basal ODC activity of cultures of two additional cell lines (Chinese hamster ovary; and 294T melanoma) exposed for 1 h to the amplitude-modulated field. Chinese hamster ovary cells exposed to the radio frequency field for 1 h also responded to subsequent treatment with 12-O-tetradecanoylphorbol-13-acetate by exhibiting a further increase in ODC activity. We have observed previously that the activity of this enzyme is increased in cultured cells following a transient exposure to a 60-Hz electric field. Altered ODC activity may serve as a sensitive and specific molecular marker of the transductive coupling of weak pericellular electromagnetic fields to biological systems.
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PMID:Increased ornithine decarboxylase activity in cultured cells exposed to low energy modulated microwave fields and phorbol ester tumor promoters. 339 Aug 16

In vitro studies suggest that purified IL 1 beta derived from normal human peripheral blood monocytes and human myelomonocytic cell line THP-1 cell supernatants was capable of modest augmentation of NK activity of purified LGL and of promoting monocyte cytotoxicity for the human melanoma A375 target cells. In addition, purified IL 1 beta also has direct cytostatic and cytocidal effects for A375 cells. A375 melanoma cells were cloned to obtain a homogeneous population of IL 1 receptor-bearing target cells. Recombinant human IL 1 alpha inhibited the proliferation of these cells within 48-72 h in a dose-dependent manner. Similar doses of recombinant IL 1 alpha exhibited inhibitory effects on the ornithine decarboxylase (ODC) activity of A375 cells by 6-24 h. Putrescine, a nontoxic product of the ODC pathway, could prevent the cytostatic effect of recombinant IL 1 alpha on these tumor target cells. This observation indicates that inhibition of the ODC pathway is causally related to the antiproliferative effect of IL 1 on these tumor cells.
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PMID:Mechanism of in vitro antitumor effects of interleukin 1 (IL 1). 349 32

Both 2-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (EC 4.1.1.17), and methylglyoxal bis(guanylhydrazone) (MGBG), a competitive inhibitor of S-adenosylmethionine decarboxylase (EC 4.1.1.50), strikingly stimulated melanotic expression of murine Cloudman S91 melanoma cells. The stimulation of tyrosinase (EC 1.10.3.1) activity and melanin formation by DFMO was closely associated with intracellular depletion of putrescine and spermidine developed in response to the drug. However, little or no evidence was obtained indicating that enhanced melanogenesis in response to MGBG was mediated through an inhibition of polyamine biosynthesis. Indirect inhibitors of ornithine decarboxylase, such as 1,3-diaminopropane and 1,3-diaminopropan-2-ol, but not putrescine, likewise inhibited the growth of the melanoma cells and stimulated their melanin production. The stimulation of melanogenesis by polyamine antimetabolites was not mediated by cyclic adenosine 3':5'-monophosphate, in contrast to the effect elicited by alpha-melanotropin. It is also unlikely that MGBG or the diamines acted as lysosomotropic agents capable of stimulating tyrosinase activity in situ, since the enzyme activity was stimulated by the drugs irrespective of whether assayed in cultured cells or using cell-free homogenates. None of the agents stimulated tyrosinase activity in vitro. The effect of DFMO and MGBG on melanoma cell proliferation was reversible, but the restoration of normal growth and melanin formation, especially in cells exposed to DFMO, was remarkably slow. The present results represent a further experimental model, in which the inhibition of polyamine accumulation is accompanied by signs of terminal differentiation.
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PMID:Effects of inhibitors of polyamine biosynthesis on the growth and melanogenesis of murine melanoma cells. 391 40


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