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Phase I trial of the selective mitochondrial toxin MKT077 in chemo-resistant solid tumours
D J Propper1, J P Braybrooke, D J Taylor
1ICRF Medical Oncology Unit, Churchill Hospital, Headington, Oxford, UK.
Background:
MKT077 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, MKT077 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 MKT077 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 (> or = 1 microM).
Conclusions:
Because of the renal toxicity, and animal studies showing MKT077 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.
Insights
MKT077, a tumor-targeting drug, showed renal toxicity in a phase I trial. While it demonstrated mitochondrial targeting feasibility, further development requires agents with better safety profiles.
Area of Science:
- Oncology
- Pharmacology
- Mitochondrial Biology
Background:
- MKT077 is a rhodacyanine dye analogue that targets tumor cell mitochondria.
- It exhibits cytotoxicity against various cancer types.
Purpose of the Study:
- To evaluate the safety and tolerability of MKT077 in patients with advanced solid cancers.
- To assess the impact of MKT077 on skeletal muscle mitochondrial function using 31Phosphorus magnetic resonance spectroscopy (MRS).
Main Methods:
- Phase I clinical trial involving ten patients with advanced solid cancers.
- MKT077 administered via five-day infusion every three weeks at escalating doses (30, 40, 50 mg/m2/day).
- Skeletal muscle mitochondrial function assessed using 31Phosphorus MRS.
Main Results:
- Predominant toxicity was reversible renal impairment (grade 2 in two patients).
- One patient achieved stable disease; others had progressive disease.
- No significant MRS changes observed early in treatment, but one patient developed a mitochondrial myopathy after 11 cycles.
Conclusions:
- Renal toxicity and potential for irreversible damage in animal studies led to halting recruitment.
- The study confirms the feasibility of targeting mitochondria with rhodacyanine analogues.
- Further development necessitates rhodacyanine analogues with improved therapeutic indices.