IN-VITRO AND IN-VIVO GROWTH-INHIBITION OF CANCER-CELLS BY ADAMANTYLMALEIMIDE DERIVATIVES

We have previously found that adamantylmaleimide derivatives inhibited the growth of several cancer cell lines in vitro. In this study we ex amined the effect of adamantylmaleimide derivatives on the in vivo and in vitro growth of human gastric cancer cells. Experimental results s howed that N-1-adamantylmaleimide (AMI) and N-1-(3,5-dimethyladamantyl )maleimide (DMAMI) exert modest growth inhibitory activities in vitro against five different cancer cell lines. In contrast, N-1-(3,5-dimeth yladamantyl)maleamic acid (DMAMA), N-1-adamantylmaleamic acid (AMA) an d N-1-adamantylsuccinimide (ASI) were virtually inactive. These result s suggest that the double bond of N-substituted maleimide plays a prom inent role in their antitumor activities. Further analysis with flow c ytometry showed an accumulation of apoptotic SC-M1 cells after treatme nt with 3-10 mu M AMI or 5-20 mu M DMAMI for up to 72 h. DNA fragmenta tion by gel electrophoresis confirmed that AMI- and DMAMI- induced cyt otoxicity led to cell apoptosis;In addition, scanning electron microsc opy (SEM) showed that treating cells with AMI (greater than or equal t o 10 mu M) for 24 h significantly changed the morphology of SC-MI cell s, i.e. they had an irregular flat shape and the cell membrane was por ous. The AMI-induced morphological changes of the cell membrane may le ad to apoptosis of SC-Mi cells. AMI-induced growth inhibition was obse rved in vivo using SCID mice bearing SC-Mi tumors. The AMI-induced gro wth inhibition of SC-MI tumor was dose-dependent.