Anticancer agent - voreloxin
The enzyme topoisomerase II is involved in cell replication activities, as it induces transient breaks in double stranded DNA, allowing it to uncoil, before rejoining the DNA. Inhibiting it damages the DNA, and apoptosis results.
The enzyme topoisomerase II is involved in cell replication activities, as it induces transient breaks in double stranded DNA, allowing it to uncoil, before rejoining the DNA. Inhibiting it damages the DNA, and apoptosis results.
Several drugs acting as direct inhibitors of the enzyme are available, including doxorubicin, but an alternative mechanism is DNA intercalation. One such drug is voreloxin, first discovered by Sainippon Sumitomo Pharma and being developed under licence by Sunesis Pharmaceuticals.1 It appears to have other anticancer effects, too, as it still has activity against cancer cells when the topoisomerase II enzyme has been knocked down.
It is being investigated in several types of cancer. For example, a Phase II trial has been carried out in 137 women with platinum-resistant ovarian epithelial cancer who had been given between one and four previous treatments, including some who had failed pegylated liposomal doxorubicin.2 Subjects were given 48mg/m2 every three weeks, 60mg/m2 every four weeks or 75mg/m2 every four weeks. Nearly half - 46% - of subjects achieved a complete or partial response or stable disease. The incidence of febrile neutropenia was low.
Two further trials are looking at its potential in acute myeloid leukaemia. A Phase Ib/II study looked at its effectiveness in combination with cytarabine in 57 patients with relapsed or refractory AML.3 The drug was given in doses escalating on days 1 and 5 with cytarabine as a continuous infusion of 400mg/m2 daily or a two-hour IV bolus of 1g/m2 daily for five days. The Phase I dose escalation part established the voreloxin doses at 80 and 90mg/m2 respectively.
Nine of the 39 patients in the infusion schedule and four of 18 in the bolus group experienced a complete or partial response, and when the data were reported, six of the infusion group had had a remission of at least eight months. In the Phase II part of the study, 16 AML patients in their first relapse were enrolled in the infusion schedule. There were six complete responses and one partial response.
A separate Phase II study looked at the drug as a single agent in elderly patients newly diagnosed with AML.4 In the dose regimen optimisation study, 29 patients were given 72mg/m2 weekly for three weeks, a further 35 the same dose for two weeks, and 28 the same doses on days 1 and 4. Of the first group, 12 achieved complete or partial remission, and 10 in the second group, which was better tolerated. Early indications from the third group are that it is also better tolerated, and at the time of reporting six of 19 evaluable patients achieved a response.