Phase I trial of the selective mitochondrial toxin MKT 077 in chemo-resistant solid tumours

Background: MKT 077 is a rhodacyanine dye analogue which preferentially acc umulates 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 on ce every three weeks. Patients and methods: Ten patients, median age 59 (38-70) years, with advan ced solid cancers were treated at three dose levels: 30, 40 and 50 mg/m(2)/ day for a total of 18 cycles. (3)1Phosphorus magnetic resonance spectroscop y (MRS) was used to evaluate the effect of MKT 077 on skeletal muscle mitoc hondrial 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 ch anges in the first or second treatment cycles but one patient received 11 t reatment cycles and developed changes consistent with a mitochondrial myopa thy. Mean values for all pharmacokinetic parameters were at sub micromolar levels and did not exceed IC50 values (greater than or equal to 1 mu M). Conclusions: Because of the renal toxicity, and animal studies showing MKT 077 causes eventual irreversible renal toxicity, further recruitment was ha lted. The study shows, however, that it is feasible to target mitochondria with rhodacyanine analogues, if drugs with higher therapeutic indices could be developed.