Exatecan mesylate

Maintenance of DNA topology is critical for normal DNA replication, transcription and repair in eukaryotic cells. One family of enzymes, the topoisomerases, is essential for this process. Eukaryotic topoisomerase I can remove positive and negative DNA supercoils by introducing transient single-stranded DNA breaks. The natural alkaloid camptothecin, isolated from the Chinese tree Camptotheca acuminata, was the first selective topoisomerase I inhibitor shown to have cytotoxic activity in experimental models. However, in clinical trials, camptothecin had low therapeutic activity and was associated with severe and unpredictable toxicity. Derivatives of camptothecin were developed, including the water-soluble analogues irinotecan (CPT-11) and topotecan. Both of these drugs have shown antitumour activity in clinical trials, with irinotecan now being used in the treatment of colorectal cancer, whilst topotecan is effective in ovarian cancer. However, despite being widely used, irinotecan is associated with considerable haematological and gastrointestinal toxicity whilst the major side effect from topotecan is myelosuppression.

Exatecan mesylate [DX-8951f: (1S,9S)-1-amino-9-ethyl-5-fluoro-1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13Hbenzo (de)-pyrano(3’,4’: 6,7)-indolizino (1,2-b) quinoline-10,13-dione monomethane sulfonate (salt), dihydrate] (Daiichi Pharmaceutical Co., Ltd, Tokyo, Japan) is a water-soluble hexacyclic analogue of camptothecin that does not require enzymatic activation. In vitro, DX-8951f was shown to be a more potent topoisomerase I inhibitor than camptothecin, topotecan and 10-hydroxy-7-ethylcamptothecin (SN-38), the active metabolite of irinotecan, against various human cancer cell lines. The anhydrous free-base form of the drug is referred to as DX-8951. Similar to other camptothecin derivatives, the lactone form of DX-8951 is hydrolyzed into an open ring hydroxy-acid form. The two species coexist in solution according to a reversible pH-dependent equilibrium. DX-8951f was approximately 3 times more potent than SN-38, the active metabolite of CPT-11, 10 times more potent than topotecan, and 20 times more potent than camptothecin as an inhibitor of topoisomerase I activity in vitro, and 5 times more potent than SN-38 as an inhibitor of DNA synthesis. The inhibition of human topoisomerase I by the lactone form was about 300-fold more potent than that by the hydroxy-acid form.

In cell-based cytotoxicity assays, DX-8951f was 7-30 times more active than SN-38 or topotecan against a wide range of breast, lung, gastrointestinal, prostate, brain, and pediatric tumor cell lines. DX-8951f was also effective in inhibiting the growth of clonogenic cells from human head and neck, liver, non-small cell lung, breast, colon, and ovarian and prostate tumors in vitro. DX-8951f has shown activity in vivo against a wide range of human tumor xenografts in nude mice, including gastric, pancreatic, colon, breast, ovary, and lung tumors. In addition, DX-8951f exhibited potent antitumor activity in an intracranial xenograft of human RH 30 rhabdomyosarcoma, murine lung and liver metastasis models, and early and late disease models of human acute myelogenous leukemia. Several in vitro and in vivo experiments using human tumor cell lines and drug-resistant variants have demonstrated that DX8951f, unlike SN-38 or topotecan, is not affected by mechanisms of drug resistance based on the overexpression of P glycoprotein or the decrease in levels of topoisomerase I mRNA or protein. DX-8951f is not a substrate for the P glycoprotein multidrug carrier associated with the MDR phenotype, whereas topotecan and SN-38 are weak substrates. Studies in the in vivo homologous Meth A mouse fibrosarcoma model demonstrated that a cyclical dosing pattern gave superior antitumor activity, at lower doses of DX-8951f, than was seen with single dose administration.


Braybrooke, J. P., Boven, E., Bates, N. P., Ruijter, R., Dobbs, N., Cheverton, P. D., … & Talbot, D. C. (2003). Phase I and pharmacokinetic study of the topoisomerase I inhibitor, exatecan mesylate (DX-8951f), using a weekly 30-minute intravenous infusion, in patients with advanced solid malignancies. Annals of oncology, 14(6), 913-921.

Jager, R., Cheverton, P., Tamanoi, K., Coyle, J., Ducharme, M., Sakamoto, N., … & Suzuki, M. (2000). DX-8951f: Summary of Phase I Clinical Trials. Annals of the New York Academy of Sciences, 922(1), 260-273.

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