Exatecan Mesylate

Exatecan mesylate (DX-8951f) is a synthetic derivative of camptothecin, a natural alkaloid extracted from the bark and leaves of the tree, Camptotheca acuminata. The activity of the drug is linked to its lactone form, which is in equilibrium with a carboxylate (open E ring) form. The equilibrium favors the carboxylate form at physiologic pH. The chemical structure of exatecan mesylate (DX-8951f) has been modified to render the molecule water soluble by adding a ring structure between rings A (in position 9) and B (in position 7), and a fluor in position 11. DX-8951f has shown both high in vitro potency against a series of 32 malignant cell lines and significant topoisomerase I inhibition. The antiproliferative activity of exatecan mesylate (DX-8951f) in this system was 28 times greater than that of topotecan, and the antiproliferative activity of DX-8951f was about seven times greater than that of SN-38 (an active metabolite of irinotecan). Because of the demonstration of greater activity of DX-8951f than other camptothecin derivatives at equimolar concentrations in these pre- clinical studies, this phase II study was initiated.

One of the recently introduced members of camptothecin analogs, exatecan mesylate (DX-8951f), is a synthetic water-soluble hexacyclic camptothecin analogue with broad anti-tumor activity. In pre-clinical studies, DX-8951 revealed highly potent inhibition of tumor cell growth in vitro and in vivo,evenin cells resistant to other members of the camptothecin family. In com- parison to other camptothecins, DX-8951 showed up to 20-fold higher topoisomerase-I inhibition and up to 30-fold more potent cell growth inhibition in vitro in various cancer cell lines.With its anti-tumor activity against irinotecan- and topotecan-resistant tumors, in phase II clinical DX-8951 demonstrated anti-tumor activity in several cancer types; phase III studies in pancreatic cancerare ongoing.

Exatecan mesylate (DX-8951f; Daiichi Pharmaceutical Co., Ltd., Japan) is a synthetic camptothecin analogue (Figure 1) that is amore potent inhibitor of topoisomerase I than camptothecin, topotecan, and the active metabolite of irinotecan, SN-38. In preclinical studies, DX-8951f demonstrated broad antitumor activity compared with available camptothecin analogues. Cyclical dosing at lower doses demonstrated higher antitumor activity compared to single dose administration. Furthermore, the antitumor activity documented in phase I trials made DX-8951f an attractive compound for clinical development. We have completed a phase II trial designed to evaluate the activity and toxicity of exatecan mesylate (DX-8951f) in patients with previously untreated gastric carcinoma given as a thirty minute infusion daily for 5 days every 3 weeks. This schedule was selected from six phase I regimens because of the level of antitumor activity observed and its favorable toxicity profile.