Nucleoside salvage and resistance to antimetabolite anticancer agents

Fox, Margaret; Boyle, John M; Kinsella, Anne R.

doi:10.1038/bjc.1991.327

Cited by 35 publications

(14 citation statements)

References 85 publications

(58 reference statements)

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“…The most credible explanation is the dependency of hematopoietic cells on salvage synthesis of nucleosides [1] and their expression of several membrane transporters that take up nucleoside analogues [2]. Their structural similarity to physiological nucleosides allows these analogues to be taken up by cells, metabolized, and incorporated into DNA or RNA.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of anti-cancer action and pharmacology of clofarabine

Zhenchuk

Lotfi

Juliusson

et al. 2009

Biochemical Pharmacology

106

114

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Section: Introductionmentioning

confidence: 99%

Mechanisms of anti-cancer action and pharmacology of clofarabine

Zhenchuk

Lotfi

Juliusson

et al. 2009

Biochemical Pharmacology

106

114

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“…Clinically, this may be exacerbated by two factors. First, malignant cells frequently have higher salvage activity than normal cells (Fox et al, 1991;Kinsella and Harran, 1991). Second, release of nucleic acids from dead cells and their breakdown can result in locally high concentrations of salvageable nucleosides and bases in tumours.…”

mentioning

confidence: 99%

Selective potentiation of lometrexol growth inhibition by dipyridamole through cell-specific inhibition of hypoxanthine salvage

Turner

Aherne²,

Curtin³

1997

Br J Cancer

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Summary The novel antifolate lometrexol (5,10-dideazatetrahydrofolate) inhibits de novo purine biosynthesis, and co-incubation with hypoxanthine abolishes its cytotoxicity. The prevention of hypoxanthine rescue from an antipurine antifolate by the nucleoside transport inhibitor dipyridamole was investigated for the first time in nine human and rodent cell lines from seven different tissues of origin. In A549, HeLa and CHO cells, dipyridamole prevented hypoxanthine rescue and so growth was inhibited by the combination of lometrexol, dipyridamole and hypoxanthine, but in HT29, HCT116, KK47, MDA231, CCRF CEM and L1210 cells dipyridamole had no effect and the combination did not inhibit growth. Dipyridamole inhibited hypoxanthine uptake in A549 but not in CCRF CEM cells. Dipyridamole prevented the hypoxanthine-induced repletion of dGTP pools, depleted by lometrexol, in A549 but not in CCRF CEM cells. Thus, the selective growthinhibitory effect of the combination of lometrexol, dipyridamole and hypoxanthine is apparently due to the dipyridamole sensitivity (ds) or insensitivity (di) of hypoxanthine transport. Both the human and murine leukaemic cells are of the di phenotype. If this reflects the transport phenotype of normal bone marrow it would suggest that the combination of lometrexol, dipyridamole and hypoxanthine might be selectively toxic to certain tumour types and have reduced toxicity to the bone marrow.

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“…Electroporation was chosen to transiently transfect and downregulate dCK in the human T-cell acute lymphoblastic leukemia CEM cell line. This cell line was chosen because it, like other hematopoietic cells, expresses high levels of dCK, and since nucleoside analogs primarily are used to treat different types of leukemias (Fox et al 1991). There were limited data available on transient siRNA transfection in CEM cells using electroporation, and therefore attempts were carried out to optimize a protocol addressing this.…”

Section: Introductionmentioning

confidence: 99%

Optimization and evaluation of electroporation delivery of siRNA in the human leukemic CEM cell line

Fyrberg

Lotfi

2010

Cytotechnology

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In order to study nucleoside analog activation in the CEM cell line, a transfection protocol had to be optimized in order to silence an enzyme involved in nucleoside analog activation. Hematopoetic cell lines can be difficult to transfect with traditional lipid-based transfection, so the electroporation technique was used. Field strength, pulse length, temperature, electroporation media, siRNA concentration, among other conditions were tested in order to obtain approximately 70-80% mRNA and enzyme activity downregulation of the cytosolic enzyme deoxycytidine kinase (dCK), necessary for nucleoside analog activation. Downregulation was assessed at mRNA and enzyme activity levels. After optimizing the protocol, a microarray analysis was performed in order to investigate whether the downregulation was specific. Additionally two genes were differentially expressed besides the downregulation of dCK. These were however of unknown function. The leakage of intracellular nucleotides was also addressed in the electroporated cells since it can affect the DNA repair mechansism and the efficiency of nucleoside analogs. Three of these pools were increased compared to untreated, unelectroporated cells. The siRNA transfected cells with reduced dCK expression and activity showed reduced sensitivity to several nucleoside analogs as expected. The multidrug resistance to other drugs, as seen in nucleoside analog-induced resistant cells, was not seen with this model.

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Nucleoside salvage and resistance to antimetabolite anticancer agents

Cited by 35 publications

References 85 publications

Mechanisms of anti-cancer action and pharmacology of clofarabine

Mechanisms of anti-cancer action and pharmacology of clofarabine

Selective potentiation of lometrexol growth inhibition by dipyridamole through cell-specific inhibition of hypoxanthine salvage

Optimization and evaluation of electroporation delivery of siRNA in the human leukemic CEM cell line

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