Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of the irreversible S-adenosyl-L-homocysteine hydrolase inhibitor, (Z)-5'-fluoro-4',5'-didehydro-5'-deoxyadenosine (MDL 28,842), on C-1300 murine neuroblastoma (MNB) cell proliferation in tissue culture and MNB tumor growth in vivo were investigated. MNB cells were incubated with MDL 28,842 at concentrations ranging from 8 x 10(-9) M to 1.6 x 10(-5) M for 3 days, and cell proliferation was determined by use of a CellTiter 96-well Proliferation Assay Kit. In tissue culture, MDL 28,842 inhibited MNB cell proliferation in a concentration-dependent manner, and the IC50 of MDL 28,842 against MNB in tissue culture was 1.8 x 10(-7) M. The response of in vivo tumor growth and host survival to MDL 28,842d was evaluated in a syngeneic mouse tumor model prepared by s.c. implantation of 1 x 10(6) MNB cells into A/J mice. Following palpation of a tumor mass, osmotic minipumps were implanted into each mouse. MDL 28,842 was infused at rates of 1.0 or 1.5 mg/kg/day over a 10-day period and 1.25 mg/kg/day over a 30-day period. The mean survival time of tumor-bearing mice significantly increased from 28.75 +/- 1.06 days (mean +/- 2 SEM) in the control group (diluent infusion) to 39.33 +/- 1.58 days, 44.11 +/- 1.74 days, and 41.0 +/- 1.30 days in the MDL 28,842-treated groups receiving 10-day infusions of 1.0 and 1.5 mg/kg/day or 30-day infusions of 1.25 mg/kg/day, respectively. No significant differences in survival rate were noted between groups receiving 10 vs 30 days of drug treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Suppression of C-1300 murine neuroblastoma cell proliferation in tissue culture and tumor growth in vivo by (Z)5'-fluoro-4',5'-didehydro-5'-deoxyadenosine (MDL 28,842), an irreversible inhibitor of S-adenosyl-L-homocysteine hydrolase. 805 4

Adaptive changes occurring in C1300 murine neuroblastoma cell lines developed for resistance to nucleoside analogue inhibitors of S-adenosyl-L-homocysteine hydrolase (AdoHcyase, EC 3.3.1.1) were investigated. Two drug-resistant cell lines, rMNB-MDL-7-2 and rMNB-Deaz-7-2, were established from wild-type C1300 neuroblastoma cells (wMNB) following incubation with the AdoHcyase inhibitors (Z)-4',5'-didehydro-5'-deoxy-5'-fluoroadenosine (MDL 28,842) and 3-deazaneplanocin A, respectively. The nucleoside analogue concentration required to inhibit cellular proliferation by 50% (IC50) was 3.2 x 10(2) to 4.3 x 10(3) fold higher in the resistant cells when compared with the wMNB cell line. The proliferation rates of the resistant cell lines under in vitro or in vivo conditions were significantly lower than the wMNB cell line. In contrast to wMNB, both resistant cell lines had slower doubling times in tissue culture (22% longer) and smaller tumor weights (55% smaller) 14 days after implantation in A/J mice. No significant differences in AdoHcyase activity were noted between the resistant and wild-type cell lines. The resistant cell lines had concentrations of S-adenosyl-L-methionine that were five times higher and methionine adenosyltransferase (MAT, EC 2.5.1.6) activities that were two to four times greater than the wMNB phenotype. These data indicate that neuroblastoma tumor cell resistance to AdoHcyase inhibitors is associated with an adaptive increase in MAT activity. This cellular response facilitates methylation by elevating intracellular concentrations of the methyl donor S-adenosyl-L-methionine, thereby sustaining tumor cell viability in the presence of MDL 28,842 and 3-deazaneplanocin A.
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PMID:Resistance to inhibitors of S-adenosyl-L-homocysteine hydrolase in C1300 murine neuroblastoma tumor cells is associated with increased methionine adenosyltransferase activity. 886 60

S-Adenosylmethionine (AdoMet) synthetase (EC 2.5.1.6), which catalyzes the synthesis of AdoMet from methionine and ATP, is the major methyl donor for transmethylation reactions and propylamino donor for the biosynthesis of polyamines in biological systems. We have reported previously that wild-type C-1300 murine neuroblastoma (wMNB) cells, made resistant to the nucleoside analogue (Z)-5'-fluoro-4',5'-didehydro-5'-deoxyadenosine (MDL 28,842), an irreversible inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase (EC 3.3.1.1), express increased AdoMet synthetase activity (M. R. Hamre et al., Oncol. Res., 7: 487-492, 1995). In the present study, immunoblot analyses of AdoMet Synthetase with isoform-specific (MATII) antibodies demonstrated an elevation in the AdoMet synthetase immunoprotein in nucleoside analogue-resistant MNB cells (rMNB-MDL) when compared to wild-type, nonresistant MNB cells. An increase of 2.1-fold was observed in the alpha2/alpha2' catalytic subunit, which differed significantly from the much smaller increment in the noncatalytic beta-subunit of AdoMet synthetase. Densitometric analyses revealed that an increased expression of AdoMet synthetase in rMNB-MDL cells was due to overexpression of the alpha2 (Mr 53,000; 2.6-fold) and alpha2' (Mr 51,000; 1.8-fold) subunits. AdoMet synthetase mRNA expression in rMNB-MDL cells was remarkably greater than wMNB cells, as determined by quantitative competitive reverse transcription-PCR (QC-PCR) analysis. DNA (cytosine) methyl transferase expression, measured by reverse transcription-PCR analysis, was also elevated significantly in rMNB-MDL cells. In contrast, Western blot analyses demonstrated down-regulation (1.6-fold) of AdoMet synthetase in doxorubicin-resistant human leukemia cells (HL-60-R) expressing multidrug resistance protein when compared with wild-type, nonresistant HL-60 cells. The resistance of rMNB-MDL cells to nucleoside analogue inhibitors of S-adenosylhomocysteine hydrolase correlates directly with overexpression of the alpha2/alpha2' subunits of AdoMet synthetase. Cellular adaptation allows sufficient AdoMet to be synthesized, so that viability of the MNB cells can be maintained even in the presence of high AdoHcy concentrations. This novel mechanism of drug resistance does not appear to require multidrug resistance protein (P-glycoprotein) overexpression.
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PMID:S-adenosylmethionine synthetase is overexpressed in murine neuroblastoma cells resistant to nucleoside analogue inhibitors of S-adenosylhomocysteine hydrolase: a novel mechanism of drug resistance. 1021 91

The pharmacological mechanism of the anti-cancer effect of cisplatin is well known to be DNA intercalation, but the direct or indirect effects of cisplatin on protein expression in cancer cells remain to be explained. In this study, we used a proteomic approach to clarify the early impact of cisplatin on protein expression. In a 2-dimensional gel electrophoresis proteomic experiment, the application of cisplatin for 24 h increased the expression of four proteins and decreased the levels of one protein in neuroblastoma IMR-32 cells. Levels of S-adenosyl-L-homocysteine hydrolase, a key enzyme in methylation metabolism, were increased the most. Therefore, we examined the methylation status of histone proteins. Histone H3K9 methylation was reduced by the application of cisplatin for 24 h. These results suggest that acute cisplatin treatment alters methylation status. Thus, these data can help clarify the unknown pharmacological mechanisms of cisplatin, including the anticancer effect, adverse effects and/or the mechanism of drug resistance.
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PMID:Acute application of cisplatin affects methylation status in neuroblastoma cells. 2142 31