Mutations in adenosine deaminase-like (ADAL) protein confer resistance to the antiproliferative agents N6-cyclopropyl-PMEDAP and GS-9219.

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.

• Authors: Christian R Frey, Graciela Andrei, Ivan Votruba, Carina Cannizzaro, Bin Han, Wanchi Fung, Magdeleine Hung, Xiaohong Liu, Romas Geleziunas, Pierre Fiten, Ghislain Opdenakker, Robert Snoeck, Tomas Cihlar
• Journal: Anticancer research (Anticancer Res) Vol. 33 Issue 5 Pg. 1899-912 (May 2013) ISSN: 1791-7530 [Electronic] Greece
• PMID: 23645737 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Prodrugs
• Purines
• rabacfosadine
• 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine
• ADAL protein, human
• Nucleoside Deaminases
• Adenine
• Alanine

Topics

• Adenine (analogs & derivatives, pharmacology)
• Alanine (analogs & derivatives, pharmacology)
• Amino Acid Sequence
• Antineoplastic Agents (pharmacology)
• Blotting, Western
• Drug Resistance, Neoplasm (genetics)
• Female
• Humans
• Molecular Sequence Data
• Mutation (genetics)
• Nucleoside Deaminases (chemistry, genetics, metabolism)
• Prodrugs (pharmacology)
• Protein Conformation
• Purines (pharmacology)
• Sequence Homology, Amino Acid
• Tumor Cells, Cultured
• Uterine Cervical Neoplasms (drug therapy, genetics)