Sodium phenylacetate enhances the inhibitory effect of dextran derivative on breast cancer cell growth in vitro and in nude mice

Sodium phenylacetate (NaPa) and carboxymethyl benzylamide dextran derivativ e (CMDBLS4) are able to inhibit growth of breast tumour cells. In this stud y, we explored whether the combination of NaPa and CMDBLS4 may enhance thei r respective inhibitory effects on the MCF-7ras cell growth in vitro and in vivo. NaPa inhibited MCF-7ras cell proliferation by reducing the DNA repli cation concomitantly with a recruitment of cells in G0/G1 phase and by indu cing apoptosis in a dose- and time-dependent manner. The addition of CMDBLS 4 potentiated the NaPa anti proliferative effect in the manner dependent on the ratio of CMDBLS4 and NaPa concentrations. In nude mice, CMDBLS4 (1150 mg kg(-1)) or NaPa (40 mg kg(-1)) administrated twice a week, for 7 weeks i nhibited MCF-7ras xenograft growth by 40% and 60%, respectively. The treatm ent by both, CMDBLS4 and NaPa, decreased tumour growth by 83% without any t oxicity. To better understand the mechanism of NaPa and CMDBLS4 action we a ssessed their effect on mitogenic activity of MCF-7ras conditioned medium ( CM) on BALBC/3T3 fibroblasts. CMDBLS4 added to the CM, inhibited its mitoge nic activity whereas NaPa had an anti-mitogenic effect when CM was prepared from MCF-7ras cells pretreated with NaPa. Thus, the antiproliferative effe cts of NaPa and CMDBLS4 involve 2 different mechanisms explaining, at least in part, the possible synergism between them. Overall, this study points t o the potential use of a combination of dextran derivatives with NaPa to in hibit the breast tumour growth. (C) 2001 Cancer Research Campaign.