Combination therapy in childhood leukaemia: <i>in vitro</i>                studies of thiopurines and inhibitors of purine metabolism on                apoptosis

Abreu, Ronney A. De; Trueworthy, Robert C.; Kuilenburg, André B. P.; Vogels-Mentink, Trude M.; Lambooy, Lambert H.J.; Gennip, Albert H.

doi:10.1258/000456303321016196

Cited by 10 publications

(7 citation statements)

References 10 publications

(11 reference statements)

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“…Because 6-TG is a purine antimetabolite, with activity against lymphoproliferative diseases [ 27 , 28 ], we investigated its effect on cell survival in CLGL-90. Both 6-TG and Zeb have a dose-dependent and cumulative effect on cell viability.…”

Section: Discussionmentioning

confidence: 99%

6-Thioguanine and zebularine down-regulate DNMT1 and globally demethylate canine malignant lymphoid cells

2014

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BackgroundThe antimetabolite 6-thioguanine (6-TG) has been used to treat both human and canine lymphoid malignancies. 6-TG has been shown to be epigenetically active as a demethylating agent in a human lymphoma cell line, causing downregulation of DNA methyltransferase 1 (DNMT1) through ubiquitin-targeted degradation. Zebularine (Zeb), a similar cytidine analog, also has demethylating activity as well as oral bioavailability. The hypothesis of the present study was that 6-TG and Zeb would cause downregulation of DNMT1 and globally demethylate the genomic DNA of canine lymphoma cells. The secondary hypothesis was that these agents would cause a dose-dependent decrease in cell proliferation in canine lymphoma cells. Canine CLGL-90 malignant T cells and CLL 17–7 cells were incubated in modified RPMI media. They were treated with 6-TG, Zeb, or control media at biologically relevant concentrations.ResultsFollowing treatment with each agent, DNMT1 protein and global DNA methylation were significantly decreased. A dose-dependent decrease in cell survival was also observed, with apoptosis being the primary mode of cell death in the CLGL-90 cell line.ConclusionsThese results confirm the demethylating action of 6-TG and Zeb in canine cells which is similar to that shown in human cell lines. Confirmation of this mechanism supports the clinical application of these compounds as demethylating drugs in veterinary patients.

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Section: Discussionmentioning

confidence: 99%

6-Thioguanine and zebularine down-regulate DNMT1 and globally demethylate canine malignant lymphoid cells

2014

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“…We have examined the induction of cell death by combinations of 6-MP and MTX in MOLT-F4 cells [55]. We observed that MTX and 6-MP induced apoptosis and that sequential exposure to MTX for 24 h followed by 4 h exposure of 6-MP showed a synergistic induction of apoptosis compared with single drug exposure.…”

Section: In Vitro Studies Of Inhibitors Of Thiopurines/purine Metabolmentioning

confidence: 98%

Polyamines and DNA methylation in childhood leukaemia

Schipper

Heuvel

Verhofstad

et al. 2007

Biochemical Society Transactions

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Both polyamine metabolism and DNA methylation play an important role in normal and malignant growth. Specific enzyme inhibitors or drugs that interfere with these metabolic pathways have proven to be potential anticancer agents. Since DNA methylation and polyamine metabolism depend on a common substrate, i.e. S-adenosylmethionine, interaction between both pathways can be expected. Little is known about the relationship between these pathways but studies are available indicating that polyamines and DNA methylation are directly or indirectly interconnected, metabolically as well as physiologically with respect to the regulation of cell growth, differentiation and cancer development. These considerations give rise to the possibility that, by targeting both pathways, a more profound and effective inhibitory effect on the growth of malignant cells can be achieved. In previous studies we showed that 6-MP (6-mercaptopurine) as well as MTX (methotrexate), well-known drugs in the treatment of acute lymphoblastic leukaemia, inhibit DNA methylation and induce apoptosis in malignant blood cells. Our recent results show that combined treatment with 6-MP, MTX and drugs interfering with polyamine metabolism has additive/synergistic effects on the growth, cell viability and/or apoptotic death of leukaemic cells. Such a combination therapy could have great clinical value for patients in which therapy using inhibitors of thiopurines/purine metabolism has failed.

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“…56,57) In addition, 6-thioguanine, another metabolite, is frequently used in the treatment of leukemia. 58,59) Chlordiazepoxide Chlordiazepoxide was thê rst benzodiazepine derivative made available for clinical use. The drug is biotransformed to pharmacologically active products such as desmethylchlordiazepoxide, demoxepam, desmethyldiazepam, and oxazepam.…”

Section: O-dealkylationmentioning

confidence: 99%

Pharmacologically Active Metabolites of Currently Marketed Drugs: Potential Resources for New Drug Discovery and Development

et al. 2010

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Biotransformation is the major clearance mechanism of therapeutic agents from the body. Biotransformation is known not only to facilitate the elimination of drugs by changing the molecular structure to more hydrophilic, but also lead to pharmacological inactivation of therapeutic compounds. However, in some cases, the biotransformation of drugs can lead to the generation of pharmacologically active metabolites, responsible for the pharmacological actions. This review provides an update of the kinds of pharmacologically active metabolites and some of their individual pharmacological and pharmacokinetic aspects, and describes their importance as resources for drug discovery and development.

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Combination therapy in childhood leukaemia: in vitro studies of thiopurines and inhibitors of purine metabolism on apoptosis

Abstract: The results of this study indicate that sequential administration of MTX before 6MP and of TF before TG may be essential for therapeutic success in the treatment of leukaemia.

Cited by 10 publications

References 10 publications

6-Thioguanine and zebularine down-regulate DNMT1 and globally demethylate canine malignant lymphoid cells

6-Thioguanine and zebularine down-regulate DNMT1 and globally demethylate canine malignant lymphoid cells

Polyamines and DNA methylation in childhood leukaemia

Pharmacologically Active Metabolites of Currently Marketed Drugs: Potential Resources for New Drug Discovery and Development

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