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Volume 339:1341-1348 November 5, 1998 Number 19 Next

	Full Text PDF Editorial by Gallagher, R. E. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background Two reports from China have suggested that arsenic trioxide can induce complete remissions in patients with acute promyelocytic leukemia (APL). We evaluated this drug in patients with APL in an attempt to elucidate its mechanism of action.

Methods Twelve patients with APL who had relapsed after extensive prior therapy were treated with arsenic trioxide at doses ranging from 0.06 to 0.2 mg per kilogram of body weight per day until visible leukemic cells were eliminated from the bone marrow. Bone marrow mononuclear cells were serially monitored by flow cytometry for immunophenotype, fluorescence in situ hybridization, reverse-transcription–polymerase-chain-reaction (RT-PCR) assay for PML–RAR- fusion transcripts, and Western blot analysis for expression of the apoptosis-associated proteins caspases 1, 2, and 3.

Results Of the 12 patients studied, 11 had a complete remission after treatment that lasted from 12 to 39 days (range of cumulative doses, 160 to 515 mg). Adverse effects were relatively mild and included rash, lightheadedness, fatigue, and musculoskeletal pain. Cells that expressed both CD11b and CD33 (antigens characteristic of mature and immature cells, respectively), and which were found by fluorescence in situ hybridization to carry the t(15;17) translocation, increased progressively in number during treatment and persisted in the early phase of complete remission. Eight of 11 patients who initially tested positive for the PML–RAR- fusion transcript by the RT-PCR assay later tested negative; 3 other patients, who persistently tested positive, relapsed early. Arsenic trioxide induced the expression of the proenzymes of caspase 2 and caspase 3 and activation of both caspase 1 and caspase 3.

Conclusions Low doses of arsenic trioxide can induce complete remissions in patients with APL who have relapsed. The clinical response is associated with incomplete cytodifferentiation and the induction of apoptosis with caspase activation in leukemic cells.

Source Information

From the Developmental Chemotherapy Service (S.L.S., L.J.D., R.P.W.) and the Leukemia Service (P.M., A.D., J.G., D.A.S.), Department of Medicine; the Departments of Human Genetics (Z.-G.W., S.J., P.P.P.) and Pediatrics (E.C.); and the Division of Pharmacy (D.C.) — all at Memorial Sloan-Kettering Cancer Center and the Cornell University Medical College, New York.

Address reprint requests to Dr. Warrell at the Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021.

Full Text of this Article

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Treatment of Acute Promyelocytic Leukemia with Arsenic Trioxide
Tamm I., Paternostro G., Zapata J. M., Conrad M. E., Warrell R. P., Pandolfi P. P.
Extract | Full Text  
N Engl J Med 1999; 340:1043-1045, Apr 1, 1999. Correspondence

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• Tallman, M. S., Nabhan, C., Feusner, J. H., Rowe, J. M. (2002). Acute promyelocytic leukemia: evolving therapeutic strategies. Blood 99: 759-767 [Abstract] [Full Text]  
• Dvorakova, K., Payne, C. M., Tome, M. E., Briehl, M. M., Vasquez, M. A., Waltmire, C. N., Coon, A., Dorr, R. T. (2002). Molecular and Cellular Characterization of Imexon-resistant RPMI8226/I Myeloma Cells. Molecular Cancer Therapeutics 1: 185-195 [Abstract] [Full Text]  
• Hong, S.-H., Yang, Z., Privalsky, M. L. (2001). Arsenic Trioxide Is a Potent Inhibitor of the Interaction of SMRT Corepressor with Its Transcription Factor Partners, Including the PML-Retinoic Acid Receptor {alpha} Oncoprotein Found in Human Acute Promyelocytic Leukemia. Mol. Cell. Biol. 21: 7172-7182 [Abstract] [Full Text]  
• Jurcic, J. G., Nimer, S. D., Scheinberg, D. A., DeBlasio, T., Warrell, R. P. Jr, Miller, W. H. Jr (2001). Prognostic significance of minimal residual disease detection and PML/RAR-alpha isoform type: long-term follow-up in acute promyelocytic leukemia. Blood 98: 2651-2656 [Abstract] [Full Text]  
• Soignet, S. L., Frankel, S. R., Douer, D., Tallman, M. S., Kantarjian, H., Calleja, E., Stone, R. M., Kalaycio, M., Scheinberg, D. A., Steinherz, P., Sievers, E. L., Coutre, S., Dahlberg, S., Ellison, R., Warrell, R. P. Jr (2001). United States Multicenter Study of Arsenic Trioxide in Relapsed Acute Promyelocytic Leukemia. JCO 19: 3852-3860 [Abstract] [Full Text]  
• Liu, J., Chen, H., Miller, D. S., Saavedra, J. E., Keefer, L. K., Johnson, D. R., Klaassen, C. D., Waalkes, M. P. (2001). Overexpression of Glutathione S-Transferase II and Multidrug Resistance Transport Proteins Is Associated with Acquired Tolerance to Inorganic Arsenic. Mol. Pharmacol. 60: 302-309 [Abstract] [Full Text]  
• Grad, J. M., Bahlis, N. J., Reis, I., Oshiro, M. M., Dalton, W. S., Boise, L. H. (2001). Ascorbic acid enhances arsenic trioxide-induced cytotoxicity in multiple myeloma cells. Blood 98: 805-813 [Abstract] [Full Text]  
• Westervelt, P., Brown, R. A., Adkins, D. R., Khoury, H., Curtin, P., Hurd, D., Luger, S. M., Ma, M. K., Ley, T. J., DiPersio, J. F. (2001). Sudden death among patients with acute promyelocytic leukemia treated with arsenic trioxide. Blood 98: 266-271 [Abstract] [Full Text]  
• Vernhet, L., Seite, M.-P., Allain, N., Guillouzo, A., Fardel, O. (2001). Arsenic Induces Expression of the Multidrug Resistance-Associated Protein 2 (MRP2) Gene in Primary Rat and Human Hepatocytes. J. Pharmacol. Exp. Ther. 298: 234-239 [Abstract] [Full Text]  
• Frumkin, H., Thun, M. J. (2001). Arsenic. CA Cancer J Clin 51: 254-262 [Full Text]  
• Sordet, O., Rebe, C., Leroy, I., Bruey, J.-M., Garrido, C., Miguet, C., Lizard, G., Plenchette, S., Corcos, L., Solary, E. (2001). Mitochondria-targeting drugs arsenic trioxide and lonidamine bypass the resistance of TPA-differentiated leukemic cells to apoptosis. Blood 97: 3931-3940 [Abstract] [Full Text]  
• Li, X.-K., Motwani, M., Tong, W., Bornmann, W., Schwartz, G. K. (2001). Huanglian, A Chinese Herbal Extract, Inhibits Cell Growth by Suppressing the Expression of Cyclin B1 and Inhibiting CDC2 Kinase Activity in Human Cancer Cells. Mol. Pharmacol. 58: 1287-1293 [Abstract] [Full Text]  
• Pandolfi, P. P. (2001). Oncogenes and tumor suppressors in the molecular pathogenesis of acute promyelocytic leukemia. Hum Mol Genet 10: 769-775 [Abstract] [Full Text]  
• Chim, C.S., Liang, R., Tam, C.Y.Y., Kwong, Y.L. (2001). Methylation of p15 and p16 Genes in Acute Promyelocytic Leukemia: Potential Diagnostic and Prognostic Significance. JCO 19: 2033-2040 [Abstract] [Full Text]  
• Antman, K. H. (2001). Introduction: The History of Arsenic Trioxide in Cancer Therapy. The Oncologist 6: 1-2 [Abstract] [Full Text]  
• Waxman, S., Anderson, K. C. (2001). History of the Development of Arsenic Derivatives in Cancer Therapy. The Oncologist 6: 3-10 [Abstract] [Full Text]  
• Soignet, S. L. (2001). Clinical Experience of Arsenic Trioxide in Relapsed Acute Promyelocytic Leukemia. The Oncologist 6: 11-16 [Abstract] [Full Text]