Poly(ADP-ribose)polymerase, or PARP, is an enzyme involved in the recognition of damage to DNA
Another important anticancer target, poly(ADP-ribose)polymerase, or PARP, is an enzyme involved in the recognition of damage to DNA, and its activation of PARP-1 and PARP-2 is an important stage in repairing single strand DNA breaks. Therefore, if its activity is inhibited, then cytotoxic agents that work by damaging DNA ought to be potentiated.
Anticancer agent veliparib
One such drug, veliparib, is being developed by Abbott.1 Its potential is being investigated in combination with a number of cytotoxic agents, with several successful Phase I trials having been carried out in patients with refractory solid tumours and lymphomas. These include in combination with cyclophosphamide,2 and topotecan.3 In all of these studies, the drug increased the DNA damage caused by the cytotoxic agent.
In a Phase II trial in patients with metastatic breast cancer, the drug was administered in combination with temozolomide, a drug that normally has little activity in breast cancer, which the clinicians postulated was probably a result of DNA repair taking place.4 A total of 41 patients were given 40mg oral doses of veliparib twice a day for seven days, plus 150mg/m2 of temozolomide orally four times a day on days 15 in a 28-day cycle. Veliparib doses were reduced to 30mg twice a day because of a higher than expected incidence of grade 4 thrombo-cytopoenia.
Initial results after about six months indicated that of 24 evaluable patients, there had been one complete response, two partial responses and seven instances of stable disease. Numerous further clinical trials are under way.
1. T.D. Penning et al. J. Med. Chem. 2009, 52, 514
2. J. Kummar et al. J. Clin. Oncol. 28 (15, suppl.), Abst. 2605; A.R. Tan et al. ibid. Abst. 3000
3. J.J. Ji et al. J. Clin. Oncol. 28 (15, suppl.), Abst. 2514
4. S.J. Isakoff et al. J. Clin. Oncol. 28 (15, suppl.),