Phase I trial of the selective mitochondrial toxin MKT 077 in chemo-resistant solid tumours
DJ Propper, JP Braybrooke, DJ Taylor, R Lodi… - Annals of oncology, 1999 - Elsevier
DJ Propper, JP Braybrooke, DJ Taylor, R Lodi, P Styles, JA Cramer, WCJ Collins, NC Levitt…
Annals of oncology, 1999•ElsevierBackground 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/m 2/day for a total of 18 cycles. 31 Phosphorus magnetic
resonance spectroscopy (MRS) was used to evaluate the effect of MKT 077 on skeletal …
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/m 2/day for a total of 18 cycles. 31 Phosphorus magnetic
resonance spectroscopy (MRS) was used to evaluate the effect of MKT 077 on skeletal …
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. 31Phosphorus 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.
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