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MKT-077, a Novel Rhodacyanine Dye in Clinical Trials, Exhibits Anticarcinoma Activity in Preclinical Studies Based on Selective Mitochondrial Accumulation

Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 [K. K., Y. L., H. W., L. B. C.], and Ashigara Research Laboratories, Fuji Photo Film Co., Ltd., Minamiashigara, Kanagawa, 250-01, Japan [T. U., N. T., M. K., T. S.]

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 CRL1420, 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.

¹ To whom requests for reprints should be addressed, at Dana-Farber Cancer Institute, M840, 44 Binney Street, Boston, MA 02115. Phone: (617) 632-3386; Fax: (617) 863-5917.

Received 6/ 7/95. Accepted 11/17/95.

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