A phase I and pharmacokinetic study of the mitochondrial-specific rhodacyanine dye analog MKT 077.

This Phase I study was performed to evaluate the tolerability and pharmacokinetic behavior of MKT-077, a water soluble rhodacyanine dye analogue, which partitions into tumor cell mitochondria where it is thought to act as a metabolic poison, leading to G1 arrest and apoptosis. Thirteen patients with advanced solid malignancies were treated with MKT-077 administered as a 30-min i.v. infusion weekly for 4 weeks every 6 weeks at doses ranging from 42 to 126 mg/m2/week. The principal toxicity was renal magnesium wasting, which was dose-limiting (grade 3) in one patient at each of the 84- and 126-mg/m2 dose levels. The other three patients at the 126-mg/m2 dose level developed grade 2 hypomagnesemia, which was cumulative in nature, improved with i.v. magnesium supplementation, and was controlled in two patients by the administration of prophylactic magnesium before and after treatment with MKT-077. Given the requirement for extensive monitoring of serum magnesium levels, dose escalation >126 mg/m2 was not considered feasible. Thus, the recommended dose for disease-oriented studies with this schedule of MKT-077 is 126 mg/m2/week. Pharmacokinetic studies revealed a prolonged terminal half-life (37 +/- 17 h) and a large volume of distribution (685 +/- 430 liters/m2). Clearance averaged 39 +/- 13 liters/h/m2. Peak MKT-077 plasma concentrations (1.2 +/-0.31 to 6.3 +/- 5.3 microg/ml) exceeded the IC50 concentrations required for human CX-1 colon, MCF-breast, CRL-1420 pancreas, EJ bladder, and LOX melanoma tumor cell lines in vitro (0.15-0.5 microg/ml). These results indicate that at the recommended dose level of 126 mg/m2/week of MKT-077, the toxicity profile was consistent with the preferential accumulation of the agent within tumor cell mitochondria, and biologically relevant plasma concentrations were achieved.

[1]  Y Li,et al.  [Mitochondria and apoptosis]. , 2000, Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine].

[2]  D. V. Von Hoff,et al.  Activity of MKT 077, a rhodacyanine dye, against human tumor colony-forming units. , 1999, Anti-cancer drugs.

[3]  T. Kubota,et al.  Selective antitumor activity of MKT‐077, a delocalized lipophilic cation, on normal cells and cancer cells in vitro , 1998, Journal of surgical oncology.

[4]  J C Reed,et al.  Mitochondria and apoptosis. , 1998, Science.

[5]  T. Kubota,et al.  MKT-077, localized lipophilic cation: antitumor activity against human tumor xenografts serially transplanted into nude mice. , 1998, Anticancer research.

[6]  Shishido,et al.  MKT-077, a novel rhodacyanine dye in clinical trials, exhibits anticarcinoma activity in preclinical studies based on selective mitochondrial accumulation. , 1996, Cancer research.

[7]  J. Modica-Napolitano,et al.  Selective damage to carcinoma mitochondria by the rhodacyanine MKT-077. , 1996, Cancer research.

[8]  J. Modica-Napolitano,et al.  In vivo administration of MKT-077 causes partial yet reversible impairment of mitochondrial function. , 1996, Cancer research.

[9]  J. Modica-Napolitano,et al.  Basis for the selective cytotoxicity of rhodamine 123. , 1987, Cancer research.

[10]  J. Lemasters,et al.  Rhodamine 123 as a probe of transmembrane potential in isolated rat-liver mitochondria: spectral and metabolic properties. , 1986, Biochimica et biophysica acta.

[11]  J. J. Nadakavukaren,et al.  Increased rhodamine 123 uptake by carcinoma cells. , 1985, Cancer research.

[12]  T. Lampidis,et al.  Mitochondrial and plasma membrane potentials cause unusual accumulation and retention of rhodamine 123 by human breast adenocarcinoma-derived MCF-7 cells. , 1985, The Journal of biological chemistry.

[13]  J. Modica-Napolitano,et al.  Rhodamine 123 inhibits bioenergetic function in isolated rat liver mitochondria. , 1984, Biochemical and biophysical research communications.

[14]  W. Allison,et al.  Inhibition of an oligomycin-sensitive ATPase by cationic dyes, some of which are atypical uncouplers of intact mitochondria. , 1983, Archives of biochemistry and biophysics.

[15]  I. Summerhayes,et al.  Unusual retention of rhodamine 123 by mitochondria in muscle and carcinoma cells. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[16]  M L Walsh,et al.  Monitoring of relative mitochondrial membrane potential in living cells by fluorescence microscopy , 1981, The Journal of cell biology.

[17]  M L Walsh,et al.  Localization of mitochondria in living cells with rhodamine 123. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[18]  L. Sadoff.  Nephrotoxicity of streptozotocin (NSC-85998). , 1970, Cancer chemotherapy reports.

[19]  M. Kawakami,et al.  Pharmacokinetic analysis and antitumor efficacy of MKT-077, a novel antitumor agent , 1999, Cancer Chemotherapy and Pharmacology.

[20]  M. Kawakami,et al.  Structure-activity of novel rhodacyanine dyes as antitumor agents. , 1998, Journal of medicinal chemistry.

[21]  J. Modica-Napolitano,et al.  Photoactivation enhances the mitochondrial toxicity of the cationic rhodacyanine MKT-077. , 1998, Cancer research.

[22]  G. Kroemer,et al.  The mitochondrial death/life regulator in apoptosis and necrosis. , 1998, Annual review of physiology.

[23]  E. Kelepouris,et al.  Hypomagnesemia: renal magnesium handling. , 1998, Seminars in nephrology.

[24]  C. de Rouffignac.  Renal magnesium handling. , 1997, Advances in nephrology from the Necker Hospital.

[25]  C. deRouffignac.  Renal magnesium handling. , 1997 .