In vivo perturbation of human marrow cell cycle progression by ifosfamide
Rentschler, R.E.; Barlogie, B.; Johnston, D.A.; Bodey, G.P.
Cancer Research 38(8): 2209-2215
1978
ISSN/ISBN: 0008-5472 PMID: 667817 Document Number: 136544
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 1.0-1.8 g/m2. 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 G1/0 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 cloesly 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 G1/0 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.