AA1, A NEWLY SYNTHESIZED MONOVALENT LIPOPHILIC CATION, EXPRESSES POTENT IN-VIVO ANTITUMOR-ACTIVITY

Certain lipophilic cations have been reported to display anticarcinoma activities because of their selective uptake and retention by mitocho ndria of cancer tells. Thus, these agents may comprise a unique class of agents directed against carcinoma. After screening more than 1000 l ipophilic cations, we found that the monovalent lipophilic cation, is( 4-aminophenyl)-4-[4-(dimethylamino)phenyl]thiop chloride (AA1), displa yed remarkable anticarcinoma activity both in vitro and in vivo. Unlik e most other lipophilic cations, AA1 is stable and displays minimal li ght sensitivity. In vitro testing showed that AA1 was 10 times more to xic to the carcinoma cell line CX-1 than to the normal epithelial cell line CV-1. In vivo animal experiments showed that AA1 significantly p rolonged the survival of mice implanted with tumors. For C57BL x DBA/2 F-1 mice implanted with the mouse bladder carcinoma cell line, MB49, the treated:control ratio was 344%. For Swiss nu/nu mice implanted i.p . with the human melanoma cell line, LOX, the treated:control ratio wa s 341%. The most significant observation was obtained with Swiss nu/nu mice that were implanted i.p. with the human ovarian cell line, OVCAR -III. The treated:control ratio in this situation was greater than 450 %. In all these tumor models, AA1 produced minimal toxicities. AA1 exh ibited little inhibition of electron transport in isolated rat liver m itochondria; however, it inhibited mitochondrial ATPase with 50% inhib itory concentration of 6 mu M. Compared with previously reported antic arcinoma lipophilic cations such as rhodamine 123 and dequalinium chlo ride, AA1 appeared to display more effective in vivo anticarcinoma act ivity. Thus, AA1 could be considered for further clinical development as a candidate for anticarcinoma chemotherapy.