The Real Mechanism of Action of Cyclophosphamide and Other Oxazaphosphorine Cytostatics

Abstract

Cyclophosphamide (CP), an alkylating cytostatic
that has been successfully applied in the clinic
for more than 50 years, is a prodrug that is
hydroxylated in the liver by P450 enzymes to
4-hydroxy-cyclophosphamide (OHCP). OHCP
forms an equilibrium mixture with its tautomeric
aldehyde aldophosphamide (ALDO). Like CP
itself, OHCP and ALDO are prodrugs for the
actual alkylating phosphoreamidemustard
(PAM), which stops cell proliferation by DNA
alkylation.
The therapeutic index, that is the ratio from
the amount of a drug that causes toxicity to the
amount that causes the therapeutic effect is a
measure of the therapeutic efficiency of a drug.
In this special case the ratio of the dose which
kills 50% of the rats (LD50) to the dose which
cures 50% of Yoshida ascites sarcoma-bearing
rats (CD50) was determined for CP, OHCP and
PAM. The therapeutic index (LD50/CD50) was
determined to be 120 for CP and OHCP but only
3.5 for PAM [1]. Why is the therapeutic efficiency
of the prodrugs CP and OHCP more than 30 times
greater than that of PAM which is the metabolite,
for the actually therapeutic alkylation reaction?