A pilot study of the safety and effects of the matrix metalloproteinase inhibitor marimastat in gastric cancer.

The aim of this study was to evaluate the safety and tolerability of 4 weeks administration of marimastat, and to seek evidence of biological activity as observed by changes in the endoscopic appearance of the gastric tumours. 35 patients with advanced, inoperable gastric or gastro-oesophageal tumours were recruited. The dose of marimastat was reduced from the starting dose of 50 mg twice daily (6 patients) to 25 mg once daily (29 patients). 31 completed the 28 day study period. Marimastat was generally well tolerated, with the principal treatment-related toxicity being pain and stiffness of the musculoskeletal system. These symptoms occurred more frequently at the higher-dose, and increased to involve a total of 13 patients (37%) with longer-term treatment. The events were usually rapidly reversible on drug discontinuation. 3 patients receiving prolonged treatment experienced more severe symptoms, with the development of skin thickening and contractures in the hands. At endoscopy, 10 patients showed an increased fibrotic cover of the tumour, 8 had decreased haemorrhagic appearance, and in at least 2 cases where comparative tumour histology was assessable, there was evidence of increased stromal fibrotic tissue.

Marimastat in recurrent colorectal cancer: exploratory evaluation of biological activity by measurement of carcinoembryonic antigen.

Marimastat is a specific inhibitor of matrix metalloproteinases that has been shown to be effective in cancer models. A pilot, escalating-dose study of oral marimastat was performed in patients with recurrent colorectal cancer, in whom evaluation of serological response was made by measurement of carcinoembryonic antigen (CEA) levels. The study assessed the safety and tolerability of 4 weeks administration of marimastat, and determined a dose range producing detectable serological effects. Patients were recruited with a serum CEA level greater than 5 ng ml(-1), and rising by more than 25% over a 4-week screening period. Patients were treated for 28 days and entered into a continuation protocol if a serological response or clinical benefit was observed. Pharmacokinetic and safety data determined that groups of patients were recruited sequentially at 25 mg and 50 mg twice daily, and, thereafter, 10 mg twice daily, 10 mg once daily, 5 mg once daily and 20 mg once daily. A biological effect (BE) was defined as a CEA value on day 28 no greater than on day 0; a partial biological effect (PBE) was defined as a rise in CEA over the 28-day treatment period of less than 25%. Of 70 patients recruited, 63 completed the 28-day treatment period, and 55 were eligible for cancer antigen analysis. Examination of the dose-effect relationships provides evidence for a causal relationship between marimastat and biological effects: the proportion of patients with BE or PBE was higher with twice daily dosing (16 out of 25, 64%) than with once daily dosing (11 out of 30, 37%) (P = 0.043, chi2 test). Furthermore, the median rates of rise of CEA fell markedly during treatment compared with the screening period for patients receiving twice daily marimastat (P<0.0001), but not for patients receiving marimastat once daily (P = 0.25). Musculoskeletal adverse events emerged as the principal drug-related toxicity of marimastat, occurring in a dose- and time-dependent fashion. It was concluded that marimastat was associated with dose-dependent biological effects in cancer patients. The occurrence of musculoskeletal side-effects define 25 mg twice daily as the upper limit of the dose range for continuous use in further studies. Therefore, a dose range of 20 mg once daily to 25 mg twice daily seems appropriate for further studies, which should aim to demonstrate the efficacy of the drug in terms of conventional clinical end points and describe the long-term tolerability of this novel agent.

Results of single and repeat dose studies of the oral matrix metalloproteinase inhibitor marimastat in healthy male volunteers.

AIMS: To assess the tolerability and pharmacokinetic profile of single and repeat doses of the oral matrix metalloproteinase inhibitor marimastat in healthy male volunteers. METHODS: A total of 31 subjects participated in two placebo-controlled, rising-dose studies. The first study assessed the pharmacokinetics and tolerability of single doses of marimastat of 25, 50, 100, 200, 400 and 800 mg. In the second study, continuous dosing over 6.5 days with three incremental dose levels of 50, 100 and 200 mg twice daily was assessed. Full pharmacokinetic profiles were obtained on days 0 and 6, and trough concentrations were measured on all days. For each pharmacokinetic profile in the studies, summary measures including Cmax, tmax, elimination half-life and AUC were calculated. Urinary drug weights were also measured. All adverse events were documented, and haematological and biochemical variables, vital signs and ECGs were monitored throughout the study. RESULTS: Peak plasma concentrations were observed at 1.5-3 h for all subjects at all doses. Peak levels were approximately proportional to dose, as was drug exposure as calculated by AUC. Data from both studies indicate that the terminal elimination half-life is of the order of 8-10 h, and that there is no unexpected drug accumulation. Marimastat was well-tolerated, with adverse effects being mild and occurring with similar frequency to placebo. Small but reversible elevations in liver transaminases were noted with repeat dosing of marimastat, the most significant of these occurring at a dose of 200 mg twice daily. CONCLUSION: Single and repeat oral doses of marimastat in healthy male subjects appear to be well-tolerated. The drug is rapidly absorbed with high peak levels achieved. It has a terminal elimination half-life of 8-10 h which would support twice daily dosing in further clinical trials.

Nucleotide sequence of the 3'-terminal region of Helenium virus S RNA.

The sequence of 1390 nucleotides of the 3'-terminal region of Helenium virus S RNA was determined from cloned cDNA. This portion of the viral RNA contains two major open reading frames (ORFs) encoding proteins of Mr 32.9K and 12.6K. The 32.9K protein, which is similar in size to the capsid protein of the virus, shares marked homology with the coat proteins of potexviruses and two other carlaviruses. The ORF, corresponding to Mr 12.6K, nearest to the 3'-terminal poly(A) tail shows extensive similarity with the corresponding proteins of potato virus S and potato virus M. We propose that this protein may be involved in nucleic acid binding within infected cells.