Certain lipophilic
cations have been reported to display anticarcinoma activities because of their selective uptake and retention by mitochondria of
cancer cells. Thus, these agents may comprise a unique class of agents directed against
carcinoma. After screening more than 1000 lipophilic
cations, we found that the monovalent lipophilic
cation, 2,6-bis(4-amino-phenyl)-4-[4-(dimethylamino)phenyl]
thiopyrylium chloride (AA1), displayed remarkable anticarcinoma activity both in vitro and in vivo. Unlike most other lipophilic
cations, AA1 is stable and displays minimal
light sensitivity. In vitro testing showed that AA1 was 10 times more toxic to the
carcinoma cell line CX-1 than to the normal epithelial cell line
CV-1. In vivo animal experiments showed that AA1 significantly prolonged the survival of mice implanted with
tumors. For C57BL x DBA/2 F1 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 was 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 exhibited little inhibition of electron transport in isolated rat liver mitochondria; however, it inhibited mitochondrial
ATPase with 50% inhibitory concentration of 6 microM. Compared with previously reported anticarcinoma lipophilic
cations such as
rhodamine 123 and
dequalinium chloride, AA1 appeared to display more effective in vivo anticarcinoma activity. Thus, AA1 could be considered for further clinical development as a candidate for anticarcinoma
chemotherapy.