Combination antiangiogenesis therapy with marimastat, captopril and fragmin in patients with advanced cancer.
Jones PH., Christodoulos K., Dobbs N., Thavasu P., Balkwill F., Blann AD., Caine GJ., Kumar S., Kakkar AJ., Gompertz N., Talbot DC., Ganesan TS., Harris AL.
Marimastat, low molecular weight heparins and captopril have antiangiogenic activity in vitro and in animal models. We studied the safety and efficacy of the combination of these drugs in patients with advanced cancer. In all, 50 patients were enrolled. Captopril was given orally at a dose of 50 mg bd daily. Fragmin was administered as a daily subcutaneous injection of 200 units kg(-1) for the first 28 days and 5000 units thereafter. Marimastat was given at 10 mg bd orally. Serum, plasma and urinary angiogenic factors were measured at baseline and after 1 month of treatment. Inhibition of release of tumour necrosis factor alpha (TNF-alpha) from peripheral lymphocytes was used as a surrogate pharmacodynamic end point. There was one case of haemorrhagic stroke and one upper gastrointestinal haemorrhage. The commonest toxicity was myalgia. One of 10 patients with renal cancer had a partial response, and three patients had a prolonged period of stable disease. The treatment significantly inhibited phytohaemagglutinin (PHA)-stimulated TNF-alpha release from patient's lymphocytes. The combination of marimastat, fragmin and captopril is well tolerated and has in vivo activity. Inhibition of PHA-stimulated TNF-alpha release from lymphocytes is a surrogate pharmacodynamic marker of metalloprotease inhibition.