Anticancer agent - MGCD-0103
The enzyme histone deacetylase (HDAC) is an important part of the gene regulation process. Histone deacetylation is often seen in cancers, and the result is gene silencing. Inhibiting this enzyme can increase the expression of some genes that are active in the cell cycle, and HDAC inhibitors can induce cell cycle arrest and apoptosis. As a result, numerous drugs are in development that act via this mechanism.
The enzyme histone deacetylase (HDAC) is an important part of the gene regulation process. Histone deacetylation is often seen in cancers, and the result is gene silencing. Inhibiting this enzyme can increase the expression of some genes that are active in the cell cycle, and HDAC inhibitors can induce cell cycle arrest and apoptosis. As a result, numerous drugs are in development that act via this mechanism.
One of these, MGCD-0103,1 is being developed by MethylGene, in collaboration with Pharmion Corp, and several clinical trials have been carried out in various types of cancer. In one Phase I trial, 29 patients with leukaemia or myelodysplastic syndrome, three-quarters of whom had acute myelogenous leukaemia, were given the drug orally three times a week at dose levels of 20, 40 or 80mg/m2.2 The maximum tolerated dose was found to be 60mg/m2, and the dose limiting toxicities were fatigue, nausea, vomiting and diarrhoea. Three of the patients achieved a complete bone marrow response, and analysis of peripheral white cells showed a dose dependent inhibition of HDAC enzyme activity.
In another Phase I trial, it was given to 38 patients with a variety of solid tumours.3 It was given orally three times a week for two of every three weeks, in doses from 12.5 to 56mg/m2. Adverse events included fatigue, nausea, vomiting, anorexia and dehydration. Five of the 32 patients who were assessable for efficacy achieved stable disease for four or more cycles. The recommended dose for Phase II trials was set at 45mg/m2 a day.
Phase II trials are in progress. Interim results from one of these trials, in patients with relapsed or refractory Hodgkin's lymphoma, appear promising. Subjects were given the drug three times a week every four weeks, with a starting dose of 110mg. The dose was reduced in case of toxicity. In the 20 patients who were evaluable, two achieved a complete response and six a partial response, with adverse events including nausea, vomiting, fatigue, diarrhoea, anorexia and abdominal pain.4