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Blood, 1 September 2004, Vol. 104, No. 5, pp. 1450-1458. Prepublished online as a Blood First Edition Paper on May 18, 2004; DOI 10.1182/blood-2004-03-0868. This Article Full Text (PDF) All Versions of this Article: 2004-03-0868v1 104/5/1450    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Yuan, J. Articles by Richardson, D. R Search for Related Content PubMed PubMed Citation Articles by Yuan, J. Articles by Richardson, D. R Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 9, 2004 Accepted April 12, 2004 Novel Di-2-Pyridyl-Derived Iron Chelators with Marked and Selective Anti-Tumor Activity: In Vitro and In Vivo Assessment Jun Yuan, David B Lovejoy, and Des R Richardson* Children's Cancer Institute Australia, University of New South Wales, Sydney, NSW, Australia * Corresponding author; email: d.richardson{at}ccia.org.au. Aroylhydrazone and thiosemicarbazone iron (Fe) chelators possess potent anti-tumor activity (Lovejoy DB, Richardson DR Blood 2002;100:666-676). The current aim was to examine the anti-tumor effects and mechanisms of action of a novel series of Fe chelators, the di-2-pyridyl thiosemicarbazones. Of seven new chelators synthesized, four showed pronounced anti-proliferative effects. The most active chelator was Dp44mT, which had marked and selective anti-tumor activity eg., IC50 of 0.03 µM in neuroepithelioma cells compared to >25 µM in mortal fibroblasts. Indeed, this anti-proliferative activity was the greatest yet observed for an Fe chelator, having greater efficacy than the cytotoxic ligand, 311, and being comparable to the anti-tumor agent, doxorubicin. Strikingly, Dp44mT significantly (p < 0.01) decreased tumor weight in mice to 47% of the control after only 5 days, while there was no marked change in animal weight or hematological indices. TUNEL staining demonstrated apoptosis in tumors taken from mice treated with Dp44mT, and this chelator caused a marked increase of caspase-3 activity in M109 cells. Caspase activation was at least partially mediated by the release of mitochondrial holo-cytochrome c (h-cytc) after incubation with Dp44mT. In conclusion, Dp44mT is a novel highly effective anti-tumor agent in vitro and in vivo that induces apoptosis. 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Yuan, and D. R. Richardson Potent Antitumor Activity of Novel Iron Chelators Derived from Di-2-Pyridylketone Isonicotinoyl Hydrazone Involves Fenton-Derived Free Radical Generation Clin. Cancer Res., November 1, 2004; 10(21): 7365 - 7374. [Abstract] [Full Text] [PDF] N. T.V. Le and D. R. Richardson Iron chelators with high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation Blood, November 1, 2004; 104(9): 2967 - 2975. [Abstract] [Full Text] [PDF]

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