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 mechanism of action of NSC 368390 (DUP-785, 6-fluoro-2-(2'-fluoro-1, 1'-biphenyl-4-yl)-3-methyl-4-quinoline carboxylic acid sodium salt) was studied using three different approaches. First, we studied growth inhibition by DUP-785 in L1210 leukemia cells and M5 melanoma cells. The concentrations causing 50% growth inhibition after 48 hr of culture were 5.8 and 0.6 microM, respectively. DUP-785 had to be present continuously throughout culture. Growth inhibition by 25 microM DUP-785 could be prevented by addition of 1 mM uridine or orotic acid to cultures of these cell lines; in M5 cells cytidine was also able to prevent growth inhibition. Dihydro-orotic acid (DHO) and carbamyl-aspartate were not able to prevent growth inhibition by DUP-785. Second, we studied accumulation of orotic acid and of orotidine induced by incubation with 1 microM pyrazofurin, an inhibitor of the orotate phosphoribosyl-transferase-orotidine-monophosphate decarboxylase complex. Addition of DUP-785 to the culture medium prevented the orotic acid accumulation. Furthermore, DUP-785 prevented accumulation of H14CO3- into orotic acid of pyrazofurin-treated L1210 cells. Third, we measured the effect of DUP-785 on DHO-dehydrogenase (DHO-DH), since the results indicated that this enzyme was affected by DUP-785. DHO-DH was assayed in isolated rat liver mitochondria. The Km for L-DHO was about 12 microM. DUP-785 appeared to be a potent inhibitor of DHO-DH with an apparent Ki of about 0.1 microM and an apparent Ki' of about 0.8 microM. The mode of inhibition appeared to be linear mixed type. After exposure of L1210 cells to 25 microM DUP-785 for 2 hr DHO-DH was almost completely inhibited. After suspension in fresh medium without drug, DHO-DH activity was recovered to about 60% after 24 hr. In conclusion, DUP-785 is a potent inhibitor of pyrimidine de novo biosynthesis, by inhibition of the mitochondrial enzyme DHO-DH.
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PMID:Inhibition of pyrimidine de novo synthesis by DUP-785 (NSC 368390). 282 96

The role of antiplatelet drugs in relation to their potential antimetastatic activities has been reviewed and the effects of two pyrimido-pyrimidine derivatives (RX-RA69 and RX-RA85) with strong antiplatelet activities investigated in metastasizing tumour models. The routes of administration and drug dosages were always chosen in such a way that good antiplatelet activities were obtained. RX-RA69 (20 mg/kg/day) given in the drinking water had no effect on spontaneous metastasis of Lewis lung carcinoma. RX-RA85 (20 mg/kg/day) did not influence spontaneous metastasis of B16 melanoma. On the other hand, giving RX-RA85 (8 mg/kg) daily i.p. to Lewis lung carcinoma bearing mice significantly increased the number of lung metastases but had no significant effect on primary tumour implant growth. Pretreating mice orally with 20 mg/kg RX-RA85 1 h before i.v. injection of B16 melanoma cells had no significant effect on lung colony number or distribution of extrapulmonary tumours while injecting the same dosage of RX-RA85 i.v. 1-2 h before tumour-cell injection decreased lung colony formation, but increased extrapulmonary tumour burden. This investigation like many others does not support the importance of platelets in metastasis formation.
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PMID:Antiplatelet pyrimido-pyrimidines and metastasis. 300 13

The pyrimido-pyrimidine derivative RA233 was found to selectively kill cultured mouse B16 melanoma cells after prolonged hypoxia. At the optimum cytotoxic concentration (100 microM), RA233 reduced cell clonogenicity by about 80% when administered during long-term hypoxia of 4 days. Comparable cytotoxicity was also evident when RA233 was present only during re-oxygenation following 4 days of hypoxia. RA233 treatment during both hypoxia and re-oxygenation resulted in the greatest cytotoxicity, with only about 1% of cells surviving such treatment. By contrast, the hypoxic cell sensitizer misonidazole was cytotoxic only when administered during hypoxia. RA233 appears to be a unique hypoxic cell sensitizer that kills long-term hypoxic tumor cells principally during re-oxygenation.
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PMID:Cytotoxic effect of RA233 on hypoxic B16 melanoma cells in vitro. 318 30

Cyclopentenylcytosine (CPE-C, 2), a pyrimidine analogue of the fermentation derived carbocyclic nucleoside neplanocin A, has been synthesized from the optically active cyclopentenylamine 3b by two synthetic routes. CPE-C demonstrates significant antitumor activity against both the sensitive and ara-C resistant lines of L1210 leukemia in vivo. Multiple long term survivors are produced in both tumor models. The compound also gives 100% growth inhibition of the solid human A549 lung and MX-1 mammary tumor xenografts grown in athymic mice. Good activity is also observed against a third human tumor xenograft model, metastatic LOX melanoma. CPE-C has significant activity against both DNA and RNA viruses in vitro. Potent activity is observed against HSV-1 (TK+ and TK-), HSV-2, vaccinia, cytomegalovirus, and varicella-zoster virus. Good activity is also found against a strain of influenza virus (Hong Kong flu), vesicular stomatitis virus, Japanese encephalitis virus, and Punta Toro virus.
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PMID:Cyclopentenylcytosine. A carbocyclic nucleoside with antitumor and antiviral properties. 341 97

Possible prophylactic antitumor and/or antimetastatic effects of long-term oral administration of a potent inhibitor of platelet aggregation, the pyrimido-pyrimidine derivative RA233, were assessed using four phenotypically distinct clones of the mouse B16 melanoma. The clones tested included: a poorly tumorigenic, very slowly growing and poorly metastatic population (G3.15); a moderately tumorigenic and slowly growing population that frequently metastasizes to the lungs (G3.5); a highly tumorigenic, moderately growing and highly metastatic population (G3.12); and a highly tumorigenic and rapidly growing population that is generally nonmetastatic but can be slightly metastatic when tumors are initiated by very small numbers of cells (G3.26). Addition of 0.5 mg/ml RA233 to the drinking water continuously from the time of subcutaneous injection of cultured tumor cells until death from tumor growth, which resulted in a daily uptake of 80-100 mg/kg of drug per mouse, failed to significantly influence the tumorigenicities, tumor growth rates, metastatic incidences, or metastatic burdens of any of these clones. RA233 at doses equivalent to those delivered daily to experimental animals strongly inhibited ADP-induced aggregation of homologous C57BL/6 mouse platelets and exhibited selective anti-proliferative effects on cultured cells. Although RA233 prolonged bleeding times, pharmacokinetic analysis indicated that clearance of RA233 from mice was so rapid that achievement of sustained circulating levels sufficient to influence tumor cells or platelet-tumor cell interactions by oral administration was unlikely.
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PMID:Failure of orally administered RA233 to influence B16 melanoma growth or metastasis. 359 74

31P nuclear magnetic resonance spectra of human melanoma (BRO) cells implanted in nude mice were obtained both in vitro and in vivo. The tumors were allowed to grow in the right axillary region of six adult Swiss nude mice to a transverse diameter of 1.5-2 cm, at which point the in vivo 31P nuclear magnetic resonance spectra were obtained. The animals were subsequently sacrificed and the tumor perchloric acid extract was studied in vitro. Relative peak areas are comparable in the two experiments with the exception of inorganic phosphate, which is more abundant in vivo than in vitro by a factor of 4. This difference may be attributed to a greater contribution of the necrotic portion of the tumor to the in vivo spectra. Resonance peaks in the spectrum of the extract were identified on the basis of their coincidence with standards added at pH 7 and 10. Non-energy phosphorylated metabolites present in the tumor at high levels include phosphoethanolamine, phosphocholine, glycerol phosphocholine, and uridine-5'-diphospho-N-acetyl glucosamine. Sugar phosphates and 2,3-diphosphoglycerate from blood made minor contributions to the spectrum. The tumor also contained substantial amounts of pyrimidine triphosphates accounting for 34% of the total nucleoside triphosphate pool.
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PMID:Characterization of the 31P nuclear magnetic resonance spectrum from human melanoma tumors implanted in nude mice. 362 Nov 91

Carbetimer, an intermediate molecular-weight-derivatized copolymer of maleic anhydride and ethylene, has been shown to possess significant antineoplastic activity in the stem cell assay. We have examined the antitumor activity of carbetimer in vivo and in vitro against HM5-Carb/S and M21, both primary human melanoma cell lines sensitive and resistant to carbetimer, respectively. The mechanism of action of carbetimer in HM5-Carb/S has been determined. Mice bearing palpable sensitive tumors were treated with 10% lethal doses of carbetimer (1500 mg/kg i.p.). The tumor nucleotide profile was determined 4 hours later. Uridine and cytidine nucleoside triphosphates were reduced by 36.6 and 58.2%, respectively. In a similar experiment using carbetimer-resistant tumor, there was no change in the tumor pool sizes of uridine and cytidine nucleoside triphosphate pools in carbetimer- or saline-treated animals. Following 24-h exposure of the cells to 1000 microM concentration of carbetimer, the carbetimer-sensitive cells were pulsed with [14C]uridine, cytidine, or thymidine for 30 min. Pyrimidine nucleotides, in particular triphosphates, were reduced significantly as compared to the saline-treated control. Similar treatment of carbetimer-resistant cells resulted in no change in the pool sizes of the nucleotides. [14C]Bicarbonate flux studies demonstrated that [14C]CO2 conversion into UMP and CMP was increased 200 and 140% of control in the carbetimer-sensitive cells treated with 1000 microM carbetimer; however, a similar treatment of the resistant cells showed no change in the pool sizes of the nucleotide. Examination of pyrimidine salvage enzymes demonstrated that, in the sensitive cells, carbetimer treatment reduced the specific activity of uridine, cytidine, and thymidine kinase by 46, 37, and 60%. In a similar study using resistant cells, the specific activities were reduced 7 and 0%, respectively. In the restitution studies coincubation of carbetimer-sensitive cells with carbetimer and uridine resulted in essentially the reversal of carbetimer cytotoxicity. Thus, carbetimer inhibits the growth of the sensitive cells by inhibiting the uptake and metabolism of performed nucleosides both in vivo and in vitro.
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PMID:Mechanism of action of a new antitumor agent, carbetimer. 375 94

PALA is thought to inhibit an early step in de novo pyrimidine synthesis, causing depletion of intracellular pyrimidine nucleotides. Dipyridamole, a nucleoside transport inhibitor which can block restoration of nucleotide levels via the salvage pathway, was tested for its ability to augment the cytotoxicity of PALA against normal and malignant human cells in vitro. At the clinically relevant concentration of 1 microM, dipyridamole increased the cytotoxicity of PALA against a melanoma, a colon carcinoma, a promyelocytic leukemia (HL-60), and normal marrow (CFU-GM) in clonogenic assays. Dipyridamole produced 50% inhibition of uridine uptake in these cells at concentrations of less than 0.1 microM and reduced the LD50 of PALA by approximately 50% in mice. These results indicate that dipyridamole can markedly potentiate the activity of PALA in vitro and in vivo.
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PMID:Modulation of the activity of PALA by dipyridamole. 385 69

It was suggested that the antitumor effect of the interferons is based in part on their ability to stimulate increased cAMP production. We have explored the interaction of human fibroblastic beta interferon (HFIF) with a cAMP decomposition inhibitory pyrimido-pyrimidine derivative, Mopidamole (RA-233) in cultures of neoplastic and normal cell lines. Mopidamole potentiated the growth inhibitory effect of HFIF in cultures of ES-1 malignant melanoma cells, LNCaP prostatic carcinoma cells, RT-4 transitional carcinoma cells, HT-29 colon adenocarcinoma cells and in diploid fibroblast cells.
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PMID:Potentiation of the cell growth inhibitory effect of beta interferon by mopidamole. 609 78

The pharmacological effects and metabolism of tiazofurin have been compared in the six transplantable tumors comprising the NCI rodent tumor panel, viz. the P388 leukemia (S); the L1210 leukemia (S); the Lewis lung carcinoma (S); the B16 melanoma (R); the colon 38 carcinoma (R); and the M5076 sarcoma (R), where (S) denotes sensitivity and (R) resistance to tiazofurin. In addition, a variant of the P388 leukemia rendered resistant to the drug in vitro, and maintaining stable resistance in vivo, P388/TR, was also studied. Intraperitoneal administration of tiazofurin (100 mg/kg) resulted in a 3- to 30-fold greater accumulation of thiazole-4-carboxamide adenine dinucleotide (TAD), the proposed active metabolite of the drug in S versus R lines. In general, levels of TAD, percent inhibition of IMP dehydrogenase (mean 40% in S versus 10% in R), depression in the concentration of guanosine nucleotides, (50% in S versus 20% in R) and percent elevation of levels of IMP (500% in S versus 60% in R) correlated well with sensitivity or resistance. However, the B16 melanoma, although resistant to tiazofurin treatment, showed certain biochemical features characteristic of an S line. The sensitive and resistant tumors displayed comparable abilities to phosphorylate tiazofurin, but there was significant depression only in the R lines of the pyrophosphorylase which converts tiazofurin-5'-monophosphate to TAD (mean 78 nmoles/mg protein/hr in S versus 22 nmoles/mg protein/hr in R). The naturally resistant tumors were also found to exhibit a greater ability to degrade synthetic TAD than the sensitive lines (mean 102 nmoles/mg protein/hr in R versus 29 nmoles/mg protein/hr in S lines). The state of sensitivity or resistance could not be attributed to the basal levels of IMP dehydrogenase, to the specific activities of the enzymes of purine salvage, or to the basal concentration of purine and pyrimidine nucleotides. Moreover, treatment with tiazofurin did not influence the enzymes of TAD synthesis or of purine salvage.
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PMID:Studies on the mechanism of action of 2-beta-D-ribofuranosylthiazole-4-carboxamide--V. Factors governing the response of murine tumors to tiazofurin. 614 62


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