33 Tafluposide

34 Elsamitrucin Chartreusin Analogues Elsamitrucin

Elsamitrucin (elsamicin A) (34) is an antitumor antibiotic isolated from Actinomycete strain J-1907-21. It is related to chartreusin and to the topo II inhibitor XL-119 (see Section, but has a water-solubilizing amino sugar as part of the disaccharide side chain. Elsamitrucin generates single strand breaks at 5'-GG sites by hydroxyl radical-induced oxidative cleavage.182 It is a potent inhibitor of topo II (IC50 0.4 mM),183 and while it does not inhibit topo I by trapping of covalent DNA-enzyme cleavage complexes, it may do so simply by its tight binding to DNA. It also binds tightly to the P1 and P2 promoter regions of the c-myc oncogene and inhibits the binding of the Sp1 transcription factor.165 As a cytotoxin it is 10-15 times more potent than chartreusin,185 and has in vivo antitumor activity in a wide range of in vivo models, both murine and human.186 In early Phase I trials the major toxicity of elsamitrucin was established as reversible disruption of liver enzyme function, rather than the more usual myelosuppression. In Phase II

trials employing a dose of 25mgm _ 2 weekly, in patients with advanced solid tumors187 and with nonsmall cell lung

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