Pharmacogenetics of oxazaphosphorines and its clinical implications

Zhou S.-F., Chowbay B. and Xue C.C. (2007) Pharmacogenetics of oxazaphosphorines and its clinical implications. Current Pharmacogenomics, 5 2: 143-156. doi:10.2174/157016007780831754


Author Zhou S.-F.
Chowbay B.
Xue C.C.
Title Pharmacogenetics of oxazaphosphorines and its clinical implications
Journal name Current Pharmacogenomics   Check publisher's open access policy
ISSN 1570-1603
Publication date 2007-01-01
Sub-type Critical review of research, literature review, critical commentary
DOI 10.2174/157016007780831754
Volume 5
Issue 2
Start page 143
End page 156
Total pages 14
Subject 3004 Pharmacology
1311 Genetics
Abstract The oxazaphosphorines including cyclophosphamide and ifosfamide represent an important group of drugs because of their wide use as antitumor and immuno-modulating agents. This review highlights the effects of polymorphisms of genes involved in the action, distribution, metabolism, and transport of oxazaphosphorines on their pharmacokinetic variability and therapeutic outcomes. Emerging data indicate that polymorphisms of genes encoding cytochrome P450 (CYP) enzymes (CYP3A4, CYP2B6, and CYP2C9), aldehyde dehydrogenases (ALDH1A1, ALDH3A1), glutathione S-transferases (GSTT1, GSTM1, GSTP1), multidrug resistance-associated proteins (ABCC1 and ABCC2), and methylgua-nine-DNA methyltransferase (MGMT) play an important role in the wide interindividual pharmacokinetic variability and altered clinical outcome of oxazaphosphorine chemotherapy. For example, CYP2B6*5 (C1459T giving rise to an Arg487Cys substitution) and CYP2C19*2 (C430T) are associated with altered response, toxicity, and survival in patients with proliferative lupus nephritis when treated with pulse cyclophosphamide regimens. In paediatric patients with corticosteroid-sensitive nephrotic syndrome, treatment with cyclophosphamide in patients with a GSTM1 null polymorphism gave a significantly higher rate of sustained remission than in patients with the heterozygous or homozygous GSTM1 wildtype. Preliminary preclinical and clinical studies indicate that a number of genetic polimorphisms can affect the disposition and action of oxazaphosphorines, causing large interpatient variability in their pharmacokineties, response rate and toxicity. A full identification of the role of these genetic polymorphisms would allow the identification of useful and novel strategies to overcome the resistance and toxicity of oxazaphosphorines and to design optimal therapeutic regimens.
Keyword Cyclophosphamide
Ifosfamide
Oxazaphosphorine
Pharmacodynamics
Pharmacogenetics
Pharmacokinetics
Resistance
Toxicity
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collection: Scopus Import
 
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Created: Wed, 27 Nov 2013, 05:06:41 EST by System User