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Contenuto archiviato il 2022-12-23

Molecular Targeting of Leukaemic Differentiation Therapy Using Acute Promyelocytic Leukaemia as Model

Obiettivo



Balanced dNTP pool sizes are prerequisites for controlled cell proliferation, any disturbance causes mutations and cell transformation. Mammalian cells have to adapt rapidly to their microenvironment, especially during cell differentiation. This might be the reason why the nucleoside salvage has a vital importance during lymphocyte differentiation. If cells cannot salvage purine nucleosides (ADA and PNP deficiencies) severe immunodeficiencis are developing (SCIOS), however their molecular mechanisms are still not clear (Van Learhoven 1983, Reichard 1989). Deoxycytidilate Deaminase is one of the most important enzyme inthe regulation of nucleotide pools, which is modulating not only the native nucleotide concentrations but also the concentrations of the active metabolites of anticancer and cell-differentiating drugs. The function of this well regulated enzyme is essential in the action of the anti-leucaemic drug 2-Cl-dADO, as well in development of new nucleoside analogues. Intracellular activation of CdA leads to formation of 2-Cl-dAMP and to 2-Cl-dATP. 2-Cl-dATP is known to inhibit ribonucleotide reductase. However, there are contradictions in the literature regarding the active intracellular intermedier and the target enzyme of this very important antileucaemic agent. Preliminary data, found in the laboratory of the proposer show that the active interme of CdA is rather 2-Cl-AMP than 2-Cl-ATP, so the proposer suggest a new target enzyme in the action of this drug: deoxycytidylat deaminase (dCMP-deaminase). dCMP-deaminase is a new target enzyme in anticancer and antiviral therapy, like in treatment of hepatitis with 2,3-dideoxycytidine, or in treatment with 2,2-difluorodeoxycytidine. In the proposal, the exact mode of CdA inhibition will be investigated in human lymphocytes including the investigation of several subpopulations at various level of differentiation, as well as in other lymphoma cell lines.

Invito a presentare proposte

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Meccanismo di finanziamento

CSC - Cost-sharing contracts

Coordinatore

ASSOCIATION CLAUDE BERNARD
Contributo UE
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Indirizzo
Rue Scipion, 13
75005 PARIS
Francia

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