MKT-077, a novel rhodacyanine dye in clinical trials, exhibits anticarcinoma activity in preclinical studies based on selective mitochondrial accumulation.
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.
Koya
K
K
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Li
Y
Y
Wang
H
H
Ukai
T
T
Tatsuta
N
N
Kawakami
M
M
Shishido
Chen
L B
LB
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002522:Chlorocebus aethiops; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D000431:Ethanol / Q000737:chemistry; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D018715:Microscopy, Video; D008928:Mitochondria / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology* / Q000633:toxicity; D012995:Solubility; D013844:Thiazoles / Q000494:pharmacology* / Q000633:toxicity; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D011725:Pyridines; D013844:Thiazoles; D000431:Ethanol; D004317:Doxorubicin; C097880:MKT 077; D002945:Cisplatin