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Dartmouth researchers find that arsenic triggers unique mechanism in rare leukemia

(10.01.2007)


Their study is published in the Jan. 3 issue of the Journal of the National Cancer Institute.



"We knew that arsenite was particularly effective against this cancer, and we wanted to figure out why," says Sutisak Kitareewan, an author on this paper and an instructor of pharmacology and toxicology at DMS. "Now we know that arsenite destabilizes lysosomes, a part of a cell that contains certain enzymes, which, when released, often kill APL cells."

APL is caused by the swapping of chromosomes 15 and 17, which forms a fusion protein. This fusion protein prevents certain blood cells from maturing and leads to an accumulation of immature leukemia cells. Researchers found that arsenite causes rapid destabilization of the lysosome in cells, and that breaks the lysosome apart, releasing enzymes that destroy these particular kinds of leukemia cells.

"We hope this finding will be used to inform further research into treating APL," says co-author Ethan Dmitrovsky, professor of medicine and of pharmacology and toxicology, who is also affiliated with the Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center. "We also hope that further studies examine if this same mode of action is the basis for arsenic toxicity."

In addition to Kitareewan and Dmitrovsky, the other authors on the paper include B.D. Roebuck, professor of pharmacology and toxicology; Eugene Demidenko, research professor of community and family medicine in the area of biostatistics; and Roger Sloboda, the Ira Allen Eastman Professor of Biological Sciences. Dmitrovsky also holds the Andrew G. Wallace Professorship at Dartmouth.

This research was supported by funds from the National Institutes of Health and the National Science Foundation.

Source: Dartmouth College Office of Public Affairs • Press Release


The cited study:

 Sutisak Kitareewan, B. D. Roebuck, Eugene Demidenko, Roger D. Sloboda,
Ethan Dmitrovsky, Lysosomes and Trivalent Arsenic Treatment in Acute Promyelocytic Leukemia, J. Natl. Cancer Inst., 99/1 (2007) 41-52. DOI: 10.1093/jnci/djk004



Related studies:

Yasuomi Fukai, Miyuki Hirata, Mayumi Ueno, Naoaki Ichikama, Hikaru  Kobayashi, Hiroshi Saitoh, T. Sakurai, K. Kinoshita, T. Kaise, S. Ohta, Clinical Pharmacokinetic Study of Arsenic Trioxide in an Acute Promyeloctic Leukemia (APL) Patient: Speciation of Arsenic Metabolites in Serum and Urine, Biol. Pharm. Bull., 29/5 (2006) 1022-1027. DOI: 10.1248/bpb.29.1022

A. Bonati, V. Rizzoli, P. Lunghi, Arsenic trioxide in hematological malignancies: the new discovery of an ancient drug,  Curr. Pharm. Biotechnol., 7/6 (2006) 397-405. DOI: 10.2174/138920106779116829

Z. Wang, J. Zhou, X. Lu, Z. Gong, X.C. Le, Arsenic speciation in urine from acute promyelocytic leukemia patients undergoing arsenic trioxide treatment, Chem. Res. Toxicol., 17 (2004) 95-103. DOI: 10.1021/tx0341714

G.-Q. Chen, L. Zhou, M. Styblo, F. Walton, R. Jing, R. Weinberg, Z. Chen, S. Waxman, Methylated metabolites of arsenic trioxide are more potent than arsenic oxide as apoptotic but not differentiation inducers in leukemia and lymphoma cells, Cancer Res., 63 (2003) 1853-1859.

Z. Chen, G.-Q. Chen, Z.X. Shen, S.J. Chen, Z.Y. Wang, Treatment of acute promyelocytic leukemia with arsenic compounds: in vitro and in vivo studies, Semin. Hematol., 38/1 (2001) 26-36. DOI: 10.1053/shem.2001.20863

 T.D. Zhang, G.Q. Chen, Z.G. Wang, Z.Y. Wang, S.J. Chen, Z. Chen, Arsenic trioxide, a therapeutic agent for APL, Oncogene, 20/49 (2001) 7146-7153. DOI: 10.1038/sj.onc.1204762





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