ISSN:
1569-8041
Keywords:
mitochondrial toxin
;
MKT 077
;
phase I trial
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract Background: MKT 077 is a rhodacyanine dye analogue which preferentially accumulates in tumour cell mitochondria. It is cytotoxic to a range of tumours. In this phase I study, MKT 077 was administered as a five-day infusion once every three weeks. Patients and methods: Ten patients, median age 59 (38–70) years, with advanced solid cancers were treated at three dose levels: 30, 40 and 50 mg/m2/day for a total of 18 cycles.31 Phosphorus magnetic resonance spectroscopy (MRS) was used to evaluate the effect of MKT 077 on skeletal muscle mitochondrial function. Results: The predominant toxicity was recurrent reversible functional renal impairment (grade 2, two patients). One patient with renal cancer attained stable disease and the remainder progressive disease. There were no MRS changes in the first or second treatment cycles but one patient received 11 treatment cycles and developed changes consistent with a mitochondrial myopathy. Mean values for all pharmacokinetic parameters were at sub micromolar levels and did not exceed IC50 values (≥1 µM). Conclusions: Because of the renal toxicity, and animal studies showing MKT 077 causes eventual irreversible renal toxicity, further recruitment was halted. The study shows, however, that it is feasible to target mitochondria with rhodacyanine analogues, if drugs with higher therapeutic indices could be developed.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1008336904585
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