In Vivo Perturbation of Human Marrow Cell Cycle Progression by Ifosfamide1

The in vivo cytokinetic effects on bone marrow cells from 19 patients with leukemia and lymphoma were inves tigated following a 5-day continuous i.v. infusion of ifosfamide (a congener of cyclophosphamide) at a daily dose of 1.0 to 1.8 g/sq m. There were 8 patients without bone marrow involvement by tumor cells at the time of study, and 11 patients had various degrees of neoplastic re placement. Ifosfamide induced a shift in DMA compart ment distribution as determined by pulse cytophotometry, promoting a significant increase of the proportion of cells in (G, + M) phase and a decrement of the G,.,, fraction. The mitotic index prior to and after ifosfamide administra tion seldom exceeded the corresponding (G2 + M) com partment size, and the relative changes of DMA histo gram-derived (G, + M) fractions and mitotic indices were consistent with a relative increase of cells in G. phase in 13 of 16 évaluableobservations. Among the variables tested (ifosfamide dose, degree of marrow replacement by neoplastic cells, size of pretreatment S-phase com partment, percentage of myeloid and erythroid precur sors), the percentage of nucleated red cells in the bone marrow prior to therapy was most closely related to the degree of ifosfamide-induced (G, + M) accumulation. This suggests that the kinetic changes primarily involve the erythroid precursor compartment. Absence of drug-in duced anemia indicates a transient G., delay rather than an irreversible G_,block preceding cell death and/or pref erential kill of G, „¿ cells. In the subgroup of patients with more than 75% neoplastic cells in their bone marrow, Sphase increment was the predominant kinetic effect, which was not associated with clinical response.