Study of the selective cytotoxic properties of cationic, lipophilic mitochondrial-specific compounds in gynecologic malignancies.
Cationic lipophilic compounds have a unique cytotoxic mechanism of action which is dependent on mitochondrial-specific localization of these fluorescent dyes. We have demonstrated in vitro that carcinoma cells, which have a higher negative mitochondrial membrane potential than normal cells, have an increased accumulation and retention of two of these compounds. The compounds tested were rhodamine 123 and dequalinium (DECA). After the development of a reproducible murine intraperitoneal (ip) human ovarian cancer model, which maintained the biologic characteristics of the parent cell line, we undertook in vivo evaluation of DECA. Mice with intraperitoneal tumor inoculations were treated with cisplatin, and/or DECA. When compared to cisplatin, a chemotherapeutic agent known to be effective in the treatment of clinical ovarian cancer, DECA was significantly more efficacious and seemed less toxic in the murine model. Cisplatin and DECA used together were possibly synergistic. Cationic lipophilic compounds may prove to be an exciting new class of antineoplastic agents which exploit intracellular, mitochondrial differences between normal cells and cancer cells.
Christman
J E
JE
Department of Obstetrics and Gynecology, David Grant USAF Medical Center, Travis Air Force Base, California 94535.
Miller
D S
DS
Coward
P
P
Smith
L H
LH
Teng
N N
NN
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003868:Dequalinium / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects*; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000401:mortality; D020112:Rhodamine 123; D012235:Rhodamines / Q000494:pharmacology* / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D014410:Tumor Stem Cell Assay
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D012235:Rhodamines; D020112:Rhodamine 123; D003868:Dequalinium