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R = CH3 Etoposide R = 2-Thienyl Teniposide

Etoposide and teniposide activity is cell cycle dependent and phase specific, with maximum effect on the S and G2 phases of cell division. They cause DNA damage through inhibition of topoisomerase II, and their mechanism of action has been studied specially for the case of etoposide. DNA religation inhibition by this compound seems to be due to inhibition of the release of ADP from the hydrolysis of ATP69 and to its activation through oxidation-reduction reactions to produce derivatives that bind directly to DNA. It has been shown that the O-demethylated metabolite of etoposide 7.10 has the same potency as the parent drug. This etoposide catechol is subsequently oxidized to an ortho-quinone metabolite 7.12 which is also a potent inhibitor of the topoisomerase II-DNA cleavable complex.70 It has been proposed that the presence of free radical intermediates such as semi-quinone 7.11 contribute to DNA strand breakage, which seems to be supported by the fact that the 4'-OH group of etoposide is essential for its activity as shown by the inactivity of its 4'-OMe derivative. On the other hand, etoposide is a substrate of myeloperoxidase, an enzyme with tyrosinase activity that catalyses a one-electron oxidation to form the phenoxyl radical 7.13 (Fig. 7.13). However, the formation of radicals 7.11 and 7.13 has been proposed to be related to the increased risk of secondary myeloid acute leukaemia induced by long-term etoposide treatment.71,72

Other interesting epipodophyllotoxins under clinical assay are TOP-53 and tafluposide. TOP-53,73 which bears a basic aminoalkyl side chain that improves its solubility while allowing its association with phosphatidylserine resulting in selective accumulation in lung and is in Phase I trials. The phosphate pro-drug tafluposide74 is a lipophilic perfluorinated epipodophyllotoxin that has a dual topoisomerase I and II inhibitory activity, has shown high in vivo activity and has entered Phase I clinical trials for solid tumours.

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