MST-16, a derivative of bis(2,6-dioxopiperazine), is a newly developed
anticancer agent that is potentially effective in combination with
anthracyclines. It has a structural similarity to
ICRF-187. The effects of
MST-16 and its active form,
ICRF-154, on the cytotoxic activities of six
anthracyclines were investigated both in vitro and in vivo.
Adriamycin (ADM),
therarubicin (THP) and ME2303 (ME) showed synergistic cytotoxicity against colon 26 cells, when combined with
MST-16.
Epirubicin (EPI) and
menogaril (TUT-7) and
daunomycin (DM) all had a combination index of less than 1.0 only in the lower fraction affected range and, so there were probably no synergistic interactions between these drugs and
MST-16. In colon 26
tumor-bearing mice, a significant delay in
tumor growth was noted in the mice treated with ADM (7.5 mg/kg) and
MST-16 (750 mg/kg) compared with mice given either
drug alone. Similarly,
tumor growth in mice treated with THP (10 mg/kg) or ME (10 mg/kg) with
MST-16 (750 mg/kg) was significantly delayed. To elucidate the mechanism of synergy between these
anthracyclines and
MST-16, the concentration of
anthracyclines in the treated cells was measured by flow cytometry. No increased intracellular accumulation of ADM. THP or ME was evident even when combined with
MST-16. Cell cycle analysis revealed that
MST-16 enhanced the accumulation of cells in G2M induced by ADM, THP and ME 1.6, 1.4, and 1.5 times, respectively. We thus conclude that the administration of ADM, THP and ME combined with
MST-16 is synergistic and that the mechanism may not include an increase in the intracellular
drug uptake but rather an increase in G2M accumulation.