Anticancer agent - 2-methoxyestradiol
Apoptosis, or programmed cell death, is an essential part of the normal life cycle. Normal cells will die after a certain number of divisions, which ensures that older cells die before their DNA can be damaged, the likelihood of which increases with the number of replications.
Apoptosis, or programmed cell death, is an essential part of the normal life cycle. Normal cells will die after a certain number of divisions, which ensures that older cells die before their DNA can be damaged, the likelihood of which increases with the number of replications.
In tumours, however, apoptosis all too often fails to occur, allowing the malignant cells to grow unchecked and invade the body. Apoptosis is mediated by the caspase proteins, and it appears that this dysregulation in tumour cells results from interference with the activity of caspase.
2-Methoxyestradiol has been found to induce apoptosis in tumour cells, and hence has promise as an anticancer agent. In addition, it inhibits cellular proliferation, and also decreases the rate of angiogenesis - blood vessel formation - around the tumour, both of which are important anticancer targets. It is a naturally occurring metabolite of oestrogen, and was originally thought to be an inactive end product of the oestrogen metabolism process, but now US company EntreMed has discovered its anticancer potential, and is developing the molecule in conjunction with Aventis Pharma.
Several clinical trials have now been carried out. A Phase I efficacy study took place in 31 patients suffering from advanced refractory breast cancer who had previously been treated for the disease.1 They were given doses of 200-1000mg/day for 28 days and, after a 14 day observation period, those whose disease had responded or stabilised continued with the drug until a 50% reduction in tumour size was seen. It was well tolerated, and 17 patients reported stable disease.
The drug has also been shown to have synergistic effects with docetaxel.2 A total of 15 patients with metastatic breast cancer were given 200-1000mg/day alongside 35 mg/m2 i.v. docetaxel once a week for four of six weeks. The overall response rate was 20%, and 47% of the patients maintained stable disease through the study.
A Phase II trial has also been carried out in 33 men with refractory prostate cancer.3 They were given 200 or 1200mg/day in a randomised double blind trial, and some response was seen, but bioavailability problems limited the concentration of the active in the body. A new formulation to increase bioavailability is now being developed, and trials continue.