Effect of procarbazine and cyclophosphamide on chromosome breakage in Fanconi anemia cells: relevance to bone marrow transplantation

Fanconi anemia (FA) patients develop stem cell defect-based pancytopenia for which bone marrow transplantation offers the potential for correction. Recently, it has become apparent that the outcome of marrow transplantation in FA patients is poor because of the hypersensitivity of these patients to the pretransplantation conditioning regimen which includes immunosuppression with high doses of the difunctional alkylating agent cyclophosphamide. In an effort to devise a less toxic immunosuppressive regimen, we compared the clastogenic effect of cyclophosphamide with that of procarbazine in cells from FA patients and normal controls. Activation of the drugs was achieved by two alternative methods, either by injection into rats (the in vivo activation method) or by incubation with a rat-liver microsome system (the in vitro activation method). Increased sister chromatid exchange following treatment of cells with cyclophosphamide or procarbazine was used as an indicator for the presence of activated drug metabolites in the system. Although FA cells were hypersensitive to the clastogenic effect of cyclophosphamide, they were not more sensitive than normal cell to procarbazine-induced chromosome breakage. Procarbazine may thus be a safer drug than cyclophosphamide for conditioning FA patients for bone marrow transplantation.