ASSOCIATION OF CYP3A4 GENOTYPE WITH TREATMENT-RELATED LEUKEMIA

Epipodophyllotoxins are associated with leukemias characterized by tra nslocations of the MLL gene at chromosome band 11q23 and other translo cations. Cytochrome P450 (CYP) 3A metabolizes epipodophyllotoxins and other chemotherapeutic agents. CYP3A metabolism generates epipodophyll otoxin catechol and quinone metabolites, which could damage DNA There is a polymorphism in the 5' promoter region of the CYP3A4 gene (CYP3A4 -V) that might alter the metabolism of anticancer drugs, We examined 9 9 de novo and 30 treatment-related leukemias with a conformation-sensi tive gel electrophoresis assay for the presence of the CYP3A4-V. In al l treatment-related cases, there was prior exposure to one or more ant icancer drugs metabolized by CYP3A, Nineteen of 99 de novo (19%) and 1 of 30 treatment-related (3%) leukemias carried the CYP3A4-V (P = 0.02 6; Fisher's Exact Test, FET), Nine of 42 de novo leukemias with MLL ge ne translocations (21%), and 0 of 22 treatment-related leukemias with MLL gene translocations carried the CYP3A4-V(P = 0.016, FET), This rel ationship remained significant when 19 treatment-related leukemias wit h MLL gene translocations that followed epipodophyllotoxin exposure we re compared with the same 42 de novo cases (P = 0.026, FET), These dat a suggest that individuals with CYP3A4-W genotype may be at increased risk for treatment-related leukemia and that epipodophyllotoxin metabo lism by CYP3A4 may contribute to the secondary cancer risk The CYP3A4- W genotype may increase production of potentially DNA-damaging reactiv e intermediates, The variant may decrease production of the epipodophy llotoxin catechol metabolite, which is the precursor of the potentiall y DNA-damaging quinone.