Tas103

TAS-103 (21) is a synthetic indenoquinoline that intercalates into DNA with a moderate binding constant (2.2 x 10_6M_ 1).121 While TAS-103 was initially reported as a dual topo I/II inhibitor, later studies suggested that its cytotoxicity is due to topo IIa poisoning via blockage of DNA religation.122 TAS-103 induces cellular apoptosis123 by a pathway that involves interleukin-1 converting enzyme (ICE)-like proteases, and which is blocked by Bcl-2. It is a potent cytotoxin, with IC50 values in the low nM range and a broad spectrum of activity in human lung, colon, stomach, breast, and pancreatic tumor xenografts.124 It was not affected by the overexpression of P-gp or other transporters, or by mutations in the topo I enzyme.123 In a series of three cell lines made resistant to TAS-103 by chronic exposure to increasing concentrations of drug, topo II levels decreased by > 75%, with lower expression of both mRNA and protein than in the wild-type line.125 The drug is extensively metabolized in humans, primarily to glucuronides.126 A Phase I trial of a weekly x 3 protocol suggested a maximum tolerated dose of 130-160 mgm _2, with the immediate toxicity being neutropenia,127 but a prolonged QTc interval was seen in some patients, suggestive of cardiotoxicity. Probably because of this, no Phase II trials have been reported.

7.05.3.4 Etoposide and Analogs

The epipodophyllin etoposide (22) is a semisynthetic drug, prepared from the natural product podophyllotoxin, which is isolated from the plant Podophyllum peliatum.128 It is been widely used in cancer therapy, and has sparked intense research into other derivatives, of which teniposide (23) is also a well-established cancer drug,129 and other analogs continue to be developed.

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