Synchronization effect of cis-dichlorodiammineplatinum on a human neuroblastoma in vitro and in nude mice

The effects of cis-dichlorodiammineplatinum (CDDP) on the cell kinetics of human neuroblastoma both in vitro and in vivo were analyzed by computer-aided flow cytometry. In the in vitro system, CDDP at the concentration of 1.0 microgram/ml of medium blocked early S phase and synchronized proliferating cells into the S phase within 24 hr. By 72 hr, cells in G2 + M phase reached the maximum level. CDDP at concentrations either lower or higher than 1.0 microgram/ml showed no synchronization effect. In the in vivo system, human neuroblastoma grown in nude mice had a larger proportion of cells in G0 + G1 phase than did in vitro cells of the same origin, explaining the refractory nature of the tumors to therapy. CDDP, when given as a single dose of 10 mg/kg of mouse weight showed a maximum synchronization of cells in the S phase by 48 hr, and caused an accumulation of cells in G2 + M phase by 72 hr. This accumulation of cells in G2 + M phase was thought to represent the overflow of cells from the S phase into G2 + M phase, resulting from the disappearance of the blocking effect of CDDP with time. Judging from these sequential changes in vivo, a second drug with specific cytocidal effect on S phase cells should work best 48 hr after the initial CDDP therapy, and drugs specific to G2 + M phase or radiotherapy should be added at 72 hr. Such preclinical experiments may be useful in the design of combination chemotherapy regimens against human neuroblastoma.