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Cyclophosphamide (CP) is a widely used antitumor prodrug that is effective against a broad spectrum of
human cancers including breast cancer and lymphomas. The toxicity profile is characterized by myelosuppression
and urotoxicity. This diagram shows the genes involved in the biotransformation of CP and its metabolites
and includes pathways of activation, deactivation and toxicity. Activation of CP to 4-hydroxycyclophosphamide
is catalyzed by the hepatic cytochrome P450 (CYP) isozymes CYP2B6, 2C9 and 3A4 (with 2A6, 2C8 and 2C19
making more minor contributions). Competing with C-4 hydroxylation of CP is a minor (~10%) oxidative
pathway that leads to N-dechloroethylation and the formation of the neurotoxic chloroacetaldehyde.
CYP3A4 is primarily responsible for this undesirable side-chain oxidation with a minor contribution
from CYP2B6. 4-Hydroxycyclophosphamide interconverts rapidly with its tautomer, aldophosphamide and
it is likely that both of these metabolites passively diffuse out of hepatic cells, circulate, and
then passively enter other cells. Aldophosphamide undergoes a spontaneous (non-enzymatic) elimination
reaction to yield phosphoramide mustard (PM) and acrolein (associated with bladder toxicity). PM, which
is generally believed to be the DNA crosslinking agent of clinical significance, is a circulating
metabolite with its anionic form not entering cells very easily. Thus, the intracellular generation
of PM from aldophosphamide is believed to be important to a therapeutic result. A major detoxification
route is the oxidation of aldophosphamide to the inactive carboxyphosphamide by ALDH1A1 and, to a much
lesser extent, by ALDH3A1 and ALDH5A1. Multiple CP metabolites can react with glutathione (GSH)
resulting in the formation of various conjugates at different sites along the pathway. Some of these
reactions with GSH may be reversible while others are irreversible; the latter are associated with
detoxification pathways. Several-fold differences in the extent of metabolite formation have been
observed among patients and these inter-individual differences may be due to polymorphisms in CYP
enzymes. There are reports of association between CYP3A4 and 3A5 genotypes and response or survival
in patients treated with CP. Many of the genetic variants that affect CP metabolism may still be
unknown and further evidence of these variants will be needed to better assess clinical outcomes.
It is noteworthy that CP is chiral at phosphorus and is administered as a racemate; however,
enantioselectivity in the metabolism of CP does not appear to result in clinical significance.
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| Sunita Shukla (PAAR), Susan M. Ludeman,
Jackie Ramirez (PAAR), Norman E. Sladek, David Flockhart (COBRA), Zeruesenay Desta (COBRA), Anne Nguyen (COBRA),
Sharon Marsh (CREATE), Caroline Thorn (PharmGKB), Howard McLeod (CREATE), Irving Wainer (NIH), M. Eileen Dolan (PAAR)
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| January 18, 2005 |
| August 1, 2007 |
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