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  • Title: Mutations in adenosine deaminase-like (ADAL) protein confer resistance to the antiproliferative agents N6-cyclopropyl-PMEDAP and GS-9219.
    Author: Frey CR, Andrei G, Votruba I, Cannizzaro C, Han B, Fung W, Hung M, Liu X, Geleziunas R, Fiten P, Opdenakker G, Snoeck R, Cihlar T.
    Journal: Anticancer Res; 2013 May; 33(5):1899-912. PubMed ID: 23645737.
    Abstract:
    BACKGROUND/AIM: GS 9219 is a double prodrug of antiproliferative nucleotide analog 9-(2-Phosphonylmethoxyethyl)guanine (PMEG), with potent in vivo efficacy against various hematological malignancies. This study investigates the role of adenosine deaminase-like (ADAL) protein in the intracellular activation of GS-9219. MATERIALS AND METHODS: A cell line resistant to 9-(2-Phosphonylmethoxyethyl)-N(6)-cyclopropyl-2,6-diaminopurine (cPrPMEDAP), an intermediate metabolite of GS-9219, was generated and characterized. RESULTS: The resistant cell line was cross-resistant to cPrPMEDAP and GS-9219, due to a defect in the deamination of cPrPMEDAP to PMEG. Mutations in the ADAL gene (H286R and S180N) were identified in the resistant cells that adversely-affected its enzymatic activity. Introduction of the wild-type ADAL gene re-sensitized resistant cells to both cPrPMEDAP and GS-9219. CONCLUSION: The ADAL protein plays an essential role in the intracellular activation of GS-9219 by catalyzing the deamination of cPrPMEDAP metabolite to PMEG. Mutations affecting the activity of ADAL confer resistance to both GS-9219 and its metabolite cPrPMEDAP.
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