Regulation of Low Km (Ecto) 5’-Nucleotidase Gene Expression in Leukemic Cells

Spychała, Józef; Mitchell, Beverly S.

doi:10.1007/978-1-4615-2584-4_142

Cited by 8 publications

(2 citation statements)

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“…In contrast, several intracellular 5Ј-NU activities have been identified and cloned to date. [139][140][141] The 'low-Michaelis-Menten constant' (K m ) 5Ј-NU is specific for pyrimidine monophosphates at low micromolar K m values and is inhibited by ATP. The other, high K m 5Ј-NU is purine selective at high micromolar K m values, and it is activated by ATP.…”

Section: ј-Nucleotidasementioning

confidence: 99%

Nucleoside analogues: mechanisms of drug resistance and reversal strategies

2001

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Section: ј-Nucleotidasementioning

confidence: 99%

Nucleoside analogues: mechanisms of drug resistance and reversal strategies

2001

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“…Measurement of dCK and 5′‐NT enzymes in crude extract dCK activity was measured radiochemically using a method previously described by Spasokoukotskaja et al (1995) with [8– 3 H]‐CdA as a substrate. The activity of 5′‐NT was measured as previously described by Spychala and Mitchell (1994). The dCK activity was expressed as pmol of CdAMP/min/10 6 cells (pmol/min/10 6 ).…”

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confidence: 99%

Pharmacological basis for cladribine resistance in a human acute T lymphoblastic leukaemia cell line selected for resistance to etoposide

et al. 2001

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Summary. Cross-resistance between different classes of antineoplastic agents can jeopardize successful combination cancer chemotherapy. In this study, we observed an unexpected cross-resistance between the podophyllotoxine derivative etoposide (VP) and the nucleoside analogue cladribine (CdA) in CCRF-CEM cells developed for resistance to VP. The resistant cells also displayed 14-and twofold resistance to cytarabine (ara-C) and gemcitabine respectively. Closer analysis of these cells showed that they contained lower amounts of topoisomerase (topo) IIa (P , 0´001) and b protein (P , 0´026), formed substantially lower amounts of the topo II±DNA complex, and had a markedly decreased level of Fas (CD95/APO-1)-ligand mRNA expression. Interestingly, Fas expression in the resistant cells did not differ from that in the parental cell line. No differences were observed in the accumulation/ efflux of daunorubicin or in the gene expressions of Pglycoprotein, multidrug resistance-associated protein and the lung resistance-related protein. The activity of deoxycytidine kinase (dCK), responsible for activation of CdA and ara-C, was the same for resistant and wild-type cells. However, there was an increase in the activity of the cytosolic 5 0 -nucleotidases (5 0 -NT), responsible for deactivation of nucleotides, amounting to 206% (P , 0´001) for the high K m and 134% (P , 0´331) for the low K m 5 0 -NT in resistant cells. The high K m 5 0 -NT is probably responsible for the decreased amount of the active metabolite CdA 5 0 -triphosphate [40% decreased (P , 0´045)], as well as for other purine ribonucleosides and deoxyribonucleosides triphosphates in the resistant cells. In contrast, a significantly higher deoxycytidine triphosphate (dCTP) level (167%, P , 0´001) was observed in the resistant cells. Thus, this study suggests that the major cause of resistance to the nucleoside analogues CdA and ara-C in cells selected for resistance to VP is a result of metabolic alterations producing increased activity of 5 0 -NT and higher dCTP levels. Furthermore, these results indicate that there is a common factor in the regulation of nucleotide-degrading enzymes and DNA topoisomerases, which may be altered in cross-resistant cells.

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