Relationship of drug metabolizing enzyme genotype to plasma levels as well as myelotoxicity of cyclophosphamide in breast cancer patients

Abstract

The myelotoxicity in patients receiving FAC is related to the activity of the phase-II enzyme GSTA1 but is independent of the formation of 4-OH-CP.

Cytochrome P450 2J2, a new key enzyme in cyclophosphamide bioactivation and a potential biomarker for hematological malignancies

“…[20][21][22] Phosphoramide alkylates the guanine base of DNA at the N7 position of the imidazole ring and hence triggers apoptosis due to the formation of guanine-adenine intrastrand cross-links. 23 Cy is converted to 4-OH-Cy in the liver, predominantly by CYP2B6 (Ekhart et al, 24 Raccor et al 25 and Cho et al 26 ) and to a lesser extent by CYP3A4, CYP3A5, CYP2C9 and CYP2C19 (Afsar et al 27 and Fernandes et al 28 ). High inter-and intra-individual variability in Cy kinetics has been reported, which affects treatment efficacy and toxicity.…”

“…32 However, recent studies have concluded that CYPs polymorphisms does not have a significant role in the response variation to Cy. 25,27,28 In the present study, we investigated the expression of CYP2J2 as well as several other CYPs in 20 patients undergoing stem cell transplantation and treated with Cy compared with 12 healthy volunteers. We also investigated the role of CYP2J2 in Cy bioactivation in vitro using leukemic cell lines as well as complementary DNA-expressed CYP2J2 microsomes.…”

Which CYP2B6 Variants Have Functional Consequences for Cyclophosphamide Bioactivation?: TABLE 1

“…There is evidence that both CYP2B6 and CYP2C19 are important in the biotransformation and activation of this prodrug in vitro (Chang et al, 1993(Chang et al, , 1997Huang et al, 2000;Griskevicius et al, 2003;Xie et al, 2003;Chen et al, 2004) and in vivo (Timm et al, 2005;Xie et al, 2006;Nakajima et al, 2007;Helsby et al, 2010;Afsar et al, 2011). However, whereas there is some evidence to support altered therapeutic response and/or toxicity in patients who have single nucleotide polymorphisms (SNP) variants of either of these P450 enzymes (Takada et al, 2004;Elmaagacli et al, 2007;Singh et al, 2007;Tran et al, 2008;Bray et al, 2010;Melanson et al, 2010;Afsar et al, 2011;Black et al, 2012), not all studies confirm this effect (Petros et al, 2005;Ekhart et al, 2008;Low et al, 2009;Yao et al, 2010;Winoto et al, 2011). This lack of consistency in the published literature may in part relate to invalid assumptions regarding the functional changes associated with each CYP2B6 genotype and hence misclassification of metabolizer categories.…”

“…More recently, these same CYP2B6 genotypes were grouped together as "variant," irrespective of whether individual genotypes led to increased or decreased function (Gor et al, 2010;Afsar et al, 2011). Such errors can lead to invalid analysis of the data, which emphasizes the importance of the correct assignment of CYP2B6 genetic variants with respect to cyclophosphamide metabolizer status (Helsby and Tingle, 2011).…”

“…However, it is also important to note that both CYP2B6 and CYP2C19 have roles in cyclophosphamide bioactivation. Roles for either variant CYP2B6 (Chang et al, 1993;Huang et al, 2000;Xie et al, 2003Xie et al, , 2006Chen et al, 2004;Nakajima et al, 2007), variant CYP2C19 (Chang et al, 1997;Griskevicius et al, 2003;Timm et al, 2005;Afsar et al, 2011), or a combination of both CYP2C19 and CYP2B6 loss-of-function variants (Helsby et al, 2010) have been reported. Hence, in addition to clarifying the functional variants of CYP2B6, analysis of the haplotype with respect to both these genes should be considered.…”