MKT-077, a novel rhodacyanine dye in clinical trials, exhibits anticarcinoma activity in preclinical studies based on selective mitochondrial accumulation

• Published in: Cancer research (Chicago, Ill.) Ill.), 1996-02, Vol.56 (3), p.538-543
• Main Authors: KOYA, K, YANG LI, HONG WANG, UKAI, T, TATSUTA, N, KAWAKAMI, M, SHISHIDO, T, LAN BO CHEN
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Biological and medical sciences; Cell Division - drug effects; Cell Line; Cercopithecus aethiops; Cisplatin - pharmacokinetics; Cisplatin - pharmacology; Doxorubicin - pharmacokinetics; Doxorubicin - pharmacology; Drug Screening Assays, Antitumor; Ethanol - chemistry; Female; Flow Cytometry; General aspects; Humans; Kidney - drug effects; Male; Medical sciences; Mice; Mice, Nude; Microscopy, Confocal; Microscopy, Video; Mitochondria - metabolism; Neoplasm Transplantation; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Pharmacology. Drug treatments; Pyridines - pharmacology; Pyridines - toxicity; Solubility; Thiazoles - pharmacology; Thiazoles - toxicity; Tumor Cells, Cultured - drug effects
• ISSN: 0008-5472; 1538-7445

MKT-077 (formerly known as FJ-776) is a newly synthesized, highly water-soluble ( > 200 mg/ml) rhodacyanine dye that exhibits significant antitumor activity in a variety of model systems. In culture, MKT-077 inhibits the growth of five human cancer cell lines (colon carcinoma CX-1, breast carcinoma MCF-7, pancreatic carcinoma (CRL 1420, bladder transitional cell carcinoma EJ, and melanoma LOX) but not monkey kidney CV-1, an indicator cell line for normal epithelial cells. In nude mice, MKT-077 inhibits the growth of s.c. implanted human renal carcinoma A498 and human prostate carcinoma DU145 and prolongs the survival of mice bearing i.p. implanted human melanoma LOX (tumor:control = 344%). Subcellular localization indicates that MKT-077 is taken up and retained by mitochondria, and flow cytometric analysis suggests that CX-1 cells take up MKT-077 to a much greater extent than CV-1 cells. Quantitation of MKT-077 uptake by ethanol extraction shows that CX-1 cells accumulate 65-fold more MKT-077 than do CV-1 cells. MKT-077 is the first delocalized lipophilic cation with a favorable pharmacological and toxicological profile in preclinical studies. MKT-077 is now being investigated in Phase I clinical trials.