title: Mutations in adenosine deaminase-like (ADAL) protein confer resistance to the antiproliferative agents N6-cyclopropyl-PMEDAP and GS-9219.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: Biology Department, Gilead Sciences, Inc., 362 Lakeside Dr., Foster City, CA 94404, USA. christian.frey@gilead.com
authors: Christian R
authors: CR
authors: Frey
authors: Graciela
authors: G
authors: Andrei
authors: Ivan
authors: I
authors: Votruba
authors: Carina
authors: C
authors: Cannizzaro
authors: Bin
authors: B
authors: Han
authors: Wanchi
authors: W
authors: Fung
authors: Magdeleine
authors: M
authors: Hung
authors: Xiaohong
authors: X
authors: Liu
authors: Romas
authors: R
authors: Geleziunas
authors: Pierre
authors: P
authors: Fiten
authors: Ghislain
authors: G
authors: Opdenakker
authors: Robert
authors: R
authors: Snoeck
authors: Tomas
authors: T
authors: Cihlar
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009700:Nucleoside Deaminases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011355:Prodrugs / Q000494:pharmacology; D011487:Protein Conformation; D011687:Purines / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics*
chemical_list: D000225:Adenine; D000409:Alanine; D000970:Antineoplastic Agents; D009700:Nucleoside Deaminases; D011355:Prodrugs; D011687:Purines; C531423:rabacfosadine; C059499:9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine; C568464:MAPDA protein, human
keywords: ADAL; GS-9219; PMEG; deamination