Anticancer agent - exatecan

The enzyme topoisomerase I triggers the process of DNA unravelling prior to transcription by relaxing the torsionally strained duplex molecule.

The enzyme bonds covalently to double stranded DNA, making a cleavable complex where the strand can break. This break is then resealed, and the enzyme dissociates itself from the complex. Inhibitors of the topoisomerase enzyme prevent the DNA resealing, which ultimately leads to cell death.

The first topoisomerase I inhibitor, camptothecin, was introduced in the 1960s, but it has poor cytotoxicity, and its safety profile is not good. Derivatives including irinotecan and topotecan have since been introduced, but the side-effects can be dose limiting. Variations in effects between patients can also be marked. Now a new derivative, exatecan, has been developed by Daiichi Pharmaceutical.¹ Unlike the earlier compounds, it is water soluble, and the variability in activity between patients is less pronounced, with low cross resistance.

A number of Phase II trials have been carried out. A total of 47 patients with advanced refractory ovarian cancer were given 0.3mg/m² a day for five days every three weeks, or 2.1mg/m² a week for three weeks every four weeks, as an intravenous infusion.² Of the 23 valuable patients, two had a partial response, five stable disease and in the remaining 16, the disease progressed. The 5-day regimen was considered preferable, and myelosuppression was the major side effect. Its efficacy and tolerability were investigated in 29 patients with advanced pancreatic cancer, using the 5-day regimen and a dose of 0.5mg/m² a day.³ Partial response was observed in 5% of the patients, minor response in 3% and stable disease in 39% of the patients.

Patients with hepatocellular and hepatobiliary cancer showed only limited response, but it could be of use in combination with other anticancer agents in these cancers.^4,5