Anticancer agent - AG014699
One of the main ways in which tumours develop resistance to anticancer agents that damage DNA is by repairing the DNA. There are several pathways by which this occurs, and the drug AG014699 inhibits the enzyme PARP, or poly(ADP-ribose) polymerase, which promotes base excision repair.1
One of the main ways in which tumours develop resistance to anticancer agents that damage DNA is by repairing the DNA. There are several pathways by which this occurs, and the drug AG014699 inhibits the enzyme PARP, or poly(ADP-ribose) polymerase, which promotes base excision repair.1
This enzyme binds to DNA breaks and is activated by them, causing it to recruit other repair factors. PARP inhibitors appear to work synergistically with DNA damaging cytotoxic agents. Several have already been developed, and the new, more potent, drug is being developed by Cancer Research UK and Pfizer.
It is being investigated in clinical trials in combination with the cytotoxic agent temozolomide. In a Phase I trial, 32 male and female patients with advanced solid tumours were first administered a single dose of the new drug to give pharmacokinetic and pharmacodynamic data, and then given escalating doses of 4, 8, 12 and 18mg/m2 per day to identify the best dose for inhibiting PARP.2 This was found to be 12mg/m2, and they then received this plus the licensed dose of temozolomide, 200mg/m2, or the maximum tolerated dose. No dose limiting toxicities were seen at any stage. The enzyme recovered to about half its activity in peripheral blood lymphocytes after 72 hours.
Analysis of the lymphocytes showed that all subjects had DNA damage, and this was dependent on the dose of the new drug: 12mg/m2 caused significantly more damage than the lower doses. One complete response and one partial response were achieved in patients with metastatic melanoma, one further patient with a desmoid tumour achieved a partial response, and prolonged disease stabilisation occurred in a further seven patients with various tumour types.
A Phase II trial has also been carried out in 40 patients with metastatic melanoma. They were given 12mg/m2 of the new drug in combination with 200mg/m2 temozolomide for five days every 28 day cycle.3 Preliminary results showed that it enhanced temozolomide's immunosuppressive effects. One death, attributed to febrile neutropoenia, occurred during the first cycle, and three further patients were hospitalised because of myelosuppression. Twelve of the subjects had to have their temozolomide dose reduced. At this point in the study, four patients had achieved a partial response, and a further four prolonged stable disease. Those given the combination treatment had a better response rate than those given only temozolomide. Trials continue.