The nature of in vivo cell-killing of deoxyspergualin, and its implication in combination with other antitumor agents.

The mode of in vivo cell-killing by 15-deoxyspergualin (NKT-01) was assessed by measuring change of whole body radioactivity of mice inoculated with 125I-iododeoxyuridine-labeled P388 leukemia cells. Although NKT-01 showed strong life prolonging effect on P388 leukemia-bearing mice, significant excretion of 125I was not observed within 4 days after the start of treatment with NKT-01. Thereafter, the remaining 125I was reduced gradually and reached about half of control level on day 7. Colony forming ability in soft agar media of peritoneal tumor cells taken after completion of 5-day treatment with NKT-01 was markedly reduced to less than 3%. These results suggested that life prolongation of NKT-01 was produced both by a cytostatic effect, which lasts for an extraordinarily long period, and by a subsequent cytotoxic effect. Cell cycle distribution analysis using flow cytometry showed the cytostatic action of NKT-01 caused G0/G1 arrest of the tumor cells. Therefore, the drug-sensitive cycling population of the tumor cells was reduced, and combination with other antitumor agents was antagonistic, if they were administered simultaneously or consecutively with NKT-01. In contrast, if the other drugs such as cyclophosphamide, cisplatin and cytosine arabinoside, were administered prior to NKT-01, a synergistic combination effect was obtained. This synergism might be due to prolongation of the period of cell cycle perturbation caused by other drugs (such as G2 arrest by cisplatin) by the cytostatic effect of NKT-01. Although the precise mechanisms of the cytostatic action of NKT-01 remain unclear, it might play an important role in the combination with other antitumor drugs.