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In Vivo Perturbation of Human Marrow Cell Cycle Progression by Ifosfamide¹

Departments of Developmental Therapeutics [R. E. R., B. B., G. P. B.] and Biomathematics [D. A. J.], The University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas 77030

The in vivo cytokinetic effects on bone marrow cells from 19 patients with leukemia and lymphoma were investigated 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 replacement. Ifosfamide induced a shift in DNA compartment distribution as determined by pulse cytophotometry, promoting a significant increase of the proportion of cells in (G₂ + M) phase and a decrement of the G_1/0 fraction. The mitotic index prior to and after ifosfamide administration seldom exceeded the corresponding (G₂ + M) compartment size, and the relative changes of DNA histogram-derived (G₂ + M) fractions and mitotic indices were consistent with a relative increase of cells in G₂ phase in 13 of 16 evaluable observations. Among the variables tested (ifosfamide dose, degree of marrow replacement by neoplastic cells, size of pretreatment S-phase compartment, percentage of myeloid and erythroid precursors), the percentage of nucleated red cells in the bone marrow prior to therapy was most closely related to the degree of ifosfamide-induced (G₂ + M) accumulation. This suggests that the kinetic changes primarily involve the erythroid precursor compartment. Absence of drug-induced anemia indicates a transient G₂ delay rather than an irreversible G₂ block preceding cell death and/or preferential kill of G_1/0 cells. In the subgroup of patients with more than 75% neoplastic cells in their bone marrow, S-phase increment was the predominant kinetic effect, which was not associated with clinical response.

¹ Supported in part by Grants CA-05831, CA-14528, and CA-11430 from the National Cancer Institute, NIH, Bethesda, Md. 20014.

Received 1/16/78. Accepted 4/24/78.