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)

Antitumor effect of N-1554 (alpha-dihydrodecaprenyl phosphate containing eight trans internal isoprene residues) against B16-F10 melanoma in syngeneic C57BL/6 mice was examined. B16-F10 cells were inoculated into the footpad of mice and N-1554 was intraperitoneally administered after the inoculation. The drug significantly inhibited the tumor growth in the footpad and dramatically reduced the pulmonary metastasis from the tumor. The antitumor effect of N-1554 was almost abolished when the immunosuppressant carrageenan or anti-asialo GM1 antibody was administered to mice. In addition, pretreatment of host mice with N-1554 reduced the growth of subcutaneously inoculated B16-F10 melanoma. These results suggest that enhancement of host immune system may be involved in the antitumor effect of N-1554.
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PMID:Inhibition of growth and pulmonary metastasis of B16-F10 murine melanoma by N-1554, a polyprenyl phosphate. 202 88

Kinetic experiments are reported showing that mammalian tyrosinase from B16 mouse melanoma is significantly activated by catalytic amounts of ferrous ions. Monitoring of tyrosine oxidation by both dopachrome formation and oxygen consumption showed that ferrous ions at micromolar concentrations induce a marked enzymatic activity with 0.01 U/ml of highly purified tyrosinase, whereas no detectable reaction occurs in the absence of metal over a sufficiently prolonged period of time. The extent of the activating effect, which is specific for the reduced form of iron, is proportional to the concentration of the added metal with a typical saturation profile, no further effect being observed beyond a threshold value. Changing the buffer system from phosphate to hepes or tris results in a marked decrease of the Fe2(+)-induced activation. Scavengers of active oxygen species, such as superoxide dismutase, catalase, formate and mannitol have no detectable effect on the tyrosinase activity. These results are accounted for in terms of an activation mechanism involving reduction of the cupric ions at the active site of the resting enzyme.
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PMID:Activation of mammalian tyrosinase by ferrous ions. 210 73

2-Thiouracil (TU), an antithyroid drug, is receiving growing interest as a specific tumor marker for malignant melanoma, owing to its capability of being selectively accumulated into active melanin-producing tissues. However, up until now, the molecular mechanism of TU uptake by growing melanin has remained largely unknown. In an attempt to fill this gap, we have investigated the effect of TU on the tyrosinase catalyzed oxidation of tyrosine. At a concentration of 0.5 mM, TU was found to totally inhibit melanin formation by tyrosinase catalyzed oxidation of 0.25 mM tyrosine in phosphate buffer at pH 6.8. Polarographical monitoring of oxygen consumption under conditions of complete suppression of melanogenesis revealed a significant tyrosinase activity, with TU acting as a modest non-competitive inhibitor of the enzyme (Ki = 0.6 mM). HPLC and TLC analysis of the tyrosine-tyrosinase reaction in the presence of excess TU showed that the substrate is progressively consumed and a major hitherto unknown product (lambda max = 284 nm), positive to ninhydrin and ferric chloride, is concomitantly formed. This was isolated by repeated gel filtration chromatography of the reaction mixture on Sephadex G-10 and was formulated as the TU-dopa adduct 3,4-dihydroxy-6-(4'-hydroxypyrimidinyl-2'-thio)phenylalanine by spectral analysis. These results suggest that selective TU incorporation in pigmented melanomas and other melanin-producing systems is due to the covalent binding to dopaquinone, produced by tyrosinase catalyzed oxidation of tyrosine.
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PMID:Selective uptake of 2-thiouracil into melanin-producing systems depends on chemical binding to enzymically generated dopaquinone. 212 40

With dopa as substrat the enzyme were incubated 20 min in 0.1 M phosphate buffer, pH 6.8. After that the activity was detected at wavelengths of 313 and 492 nm using a layer thickness of 10 mm. Employing this conditions higher activities were estimated in the commercial preparates as indicated. The high sensitivity commends this standardized method to use in melanoma research.
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PMID:[Quantitative determination of phenoloxidase (EC 1.14.18.1). Spectrophotometry measurement of the activity of mushroom and potato tyrosinase]. 212 30

Scleral surface coils were used to obtain in vivo magnetic resonance spectra (MRS) of Greene melanoma implanted in the rabbit uvea. Well-localized tumor spectra (4.7 Tesla) with good signal-to-noise ratios (S/N) were obtained from the tumor with a "single-pulse" sequence in less than 1 hour. Tumor localization was confirmed with one-dimensional spectroscopic imaging studies. Serial 31P spectra were obtained during tumor growth and after both optimal and suboptimal hyperthermia. Early 31P MRS change is correlated with tumor treatment response and preceded histologic evidence of cell destruction. Twenty-four to 48 hours after successful treatment, the inorganic phosphate/nucleoside triphosphate (NTP), and phosphomonoester/NTP ratios were significantly increased from 1.2 +/- 0.1 to 1.7 +/- 0.1 and 1.3 +/- 0.1 to 1.8 +/- 0.2, respectively. In contrast, untreated or ineffectively treated tumors showed little change. Interpretation of 31P MRS data in this animal uveal melanoma model after the first week was complicated by decreased S/N, increased contamination from contiguous tissues, ingrowth of fibroblasts, macrophages, and intratumor hemorrhage.
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PMID:31P magnetic resonance spectroscopy of animal uveal melanoma. 221 Oct 22

Nude mice bearing subcutaneous human colon cancer xenografts (LS174T) were treated with 120 microCi of yttrium 90-labeled anti-carcinoembryonic antigen monoclonal antibodies (specific therapy), 120 microCi of 90Y-labeled anti-melanoma monoclonal antibodies (nonspecific therapy), or phosphate-buffered saline solution (no treatment control). Mean (+/- SD) tumor growth rates (percent increase per day) over the first 30 days of the study were as follows: 0.6% +/- 0.2% per day (specific therapy); 17.7% +/- 5.7% per day (nonspecific therapy); and 30.5% +/- 4.2% per day (control). In all three groups, tumors over 1 g had similar doubling times (5.74 +/- 0.71 d). Specific therapy caused a lag in tumor growth corresponding to a 3-logarithm cell kill. Estimated tumor dose of radiation obtained by tissue analysis was 34 and 14 Gy for specific and nonspecific therapy, respectively. In conclusion, 120 microCi of 90Y-labeled anti-carcinoembryonic antigen monoclonal antibodies was effective in suppressing growth of human colon cancer xenografts. Clinical studies with this preparation are recommended.
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PMID:Radioimmunotherapy of human colon cancer in nude mice. 233 Dec 26

BMY-40481-30 is a new, water-soluble derivative and probable prodrug of etoposide characterized by the presence of a phosphate group in position 4' of the E ring of the etoposide molecule. The compound was only weakly cytotoxic in vitro and, consequently, an investigation of its antitumor activity was conducted in several murine and human tumor (xenograft) models. Etoposide was administered ip or po whereas BMY-40481-30 was given ip, po or iv. The potency of the derivative, when administered parenterally, as defined on the basis of maximum tolerated dose (MTD), was less than the parent compound on a weight (mg/kg) basis in some experiments but comparable to etoposide in other instances. Comparison at the MTD of the two compounds showed that BMY-40481-30 administered ip was as active as etoposide against ip P388 leukemia. BMY-40481-30 given iv was more active than etoposide given ip in two of five experiments versus iv P388 leukemia, but the two compounds were comparably active in the other three studies. Of particular interest was the finding that the derivative was more active than the parent compound at many of the comparable (on a mg/kg basis) dose levels of both evaluated po versus iv P388 leukemia; MTD levels were not achieved, and hence not compared, for either compound using the po route of administration. Both etoposide and BMY-40481-30 yielded comparable maximum effects against ic P388 leukemia, ic L1210 leukemia, and sc B16 melanoma, but etoposide was more efficacious versus sc M5076 sarcoma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Preclinical antitumor activity of a soluble etoposide analog, BMY-40481-30. 238 14

Six cell lines differing in histological origin were studied regarding the growth inhibitory effect of fluoropyrimidines in relation to their metabolism. The human colon carcinoma cell line WiDr was most sensitive to 5-fluorouracil (FUra) (50% growth inhibitory concentration, 0.7 microM) and to its analogue 5'deoxy-5-fluorouridine (5'dFUR) (50% growth inhibitory concentration, 18 microM). The murine B16 melanoma cell line was moderately sensitive to FUra but least sensitive to 5'dFUR. The 50% growth inhibitory concentration values in the human melanoma cell lines IGR3 and M5, the transformed human intestine cell line intestine 407 and the rat hepatoma cell line H35 varied for FUra between 1.7 and 5.0 microM, and for 5'dFUR between 54 and 160 microM. Several enzymes from pyrimidine metabolism responsible for FUra metabolism were measured with FUra as a substrate. The activity of uridine phosphorylase, which catalyzes the conversion of 5'dFUR to FUra, was lowest in B16 cells correlating with the low sensitivity to 5'dFUR. When adenosine 5'-triphosphate was included in the reaction mixture for uridine phosphorylase, FUra was rapidly channeled into FUra nucleotides via its nucleoside. The rate of channeling appeared to correlate with the nucleoside phosphorylase activity in the various cell lines. In several cell lines activities of nucleotide-degrading enzymes were rather high and interfered with the measurement of orotate phosphoribosyl transferase (OPRT) with FUra as substrate. Addition of the phosphatase inhibitor glycerol-2-phosphate partly prevented breakdown of the newly formed 5-fluorouridine 5'-monophosphate and enabled measurement of OPRT. The WiDr cell line had a relatively high OPRT activity which could explain its sensitivity to FUra. The activity of thymidylate synthase was measured at a suboptimal concentration of 1 microM and at the optimal concentration of 10 microM deoxyuridine 5'-phosphate. With all cell lines the ratio between the activities at 10 and 1 microM was between 2.3 and 3.6. The activity of thymidylate synthase was lowest in WiDr and IGR3 cells and 3-4 times higher in M5 and Intestine 407 cells. The inhibition of 0.01 microM 5-fluorodeoxyuridine 5'-monophosphate was 80-90% at 1 microM deoxyuridine 5'-phosphate and 50-70% at 10 microM deoxyuridine 5'-phosphate with all cell lines. At 0.1 microM 5-fluorodeoxyuridine 5'-monophosphate enzyme activity was inhibited by 95-100%. The incorporation of FUra into RNA was relatively low in IGR3 cells and 3-5 times higher in all other cell lines.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Sensitivity of human, murine, and rat cells to 5-fluorouracil and 5'-deoxy-5-fluorouridine in relation to drug-metabolizing enzymes. 241 45

The in vitro toxicities of 19 analogues of deoxyadenosine were tested using a panel of human melanoma cell lines including two lines sensitive to deoxyadenosine and deoxyinosine. The 2-fluoro-, 2-chloro-, 2-bromo- and 2-amino-8-aza derivatives were the most toxic and showed selectivity against deoxyadenosine-sensitive cells. 2-Bromodeoxyadenosine (BrdAdo) and its 5'-phosphate were less potent than the chloro compound but showed the greatest selectivity. In further studies of BrdAdo a third sensitive melanoma line was identified of the eight tested. A treatment time of 24 hr or more was required to develop toxicity to BrAdo; this could be prevented by deoxycytidine or cytidine added to the medium but not by other nucleosides. Flow cytometry showed that BrdAdo blocked cells in the G1 and S phases of the cell cycle. DNA synthesis as judged by thymidine incorporation was rapidly inhibited by BrdAdo to an extent which reflected the sensitivity of the particular cell line; RNA synthesis was less affected. Exposure to BrdAdo for 48 hr induced breaks in the preformed DNA of sensitive but not resistant cells. The results suggest that the toxicity of BrdAdo is associated with prolonged inhibition of DNA synthesis and subsequent DNA fragmentation.
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PMID:Selective toxicity of deoxyadenosine analogues in human melanoma cell lines. 243 May 74

5-Iodo-2-thiouracil (ITU) is of interest due to its ability to bind specifically to the pigment melanin during melanogenesis and is of potential value in the diagnosis and treatment of malignant melanoma. Radioiodinated ITU was prepared directly from 2-thiouracil in a two-phase reaction using Iodo-Gen in 0.05 M phosphate buffer pH 7.0. The identity radiochemical purity and stability of the product were checked by reversed-phase high pressure liquid chromatography (HPLC). ITU labeled with 123I, 125I or 131I has been produced in millicurie amounts and isolated on a semi-preparative reversed-phase HPLC column. Production time was 2-3 h, overall radiochemical yields averaged 80%; the radiochemical purity was greater than 98%. Specific activities on the order of 20 Ci/mmol have been obtained.
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PMID:Direct electrophilic iodination of 2-thiouracil using Iodo-Gen. 255 65


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