(1)      ABSTRACT of article in The New England Journal of Medicine -- November 5, 1998 -- Vol. 339, No. 19

Complete Remission after Treatment of Acute Promyelocytic Leukemia
with Arsenic Trioxide

Steven L. Soignet, Peter Maslak, Zhu-Gang Wang, Suresh Jhanwar, Elizabeth Calleja, Laura J. Dardashti, Diane Corso,  Anthony DeBlasio, Janice Gabrilove, David A. Scheinberg, Pier Paolo Pandolfi, Raymond P. Warrell, Jr.

          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-(alpha) 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-(alpha) 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. (N Engl J Med 1998;339:1341-8.)

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.

For full article click on "Complete Remission After treatment of Acute Promyelocytic Leukemia with Arsenic Trioxide' published in the New England Journal of Medicine.

(2)    Article on the same topic as  the above NEJM article translated from the French.

Arsenic and retinoic acid: towards anti leukemia treatments targeted on the oncogene ?

    Arsenic, well known as a poison, can specifically target the product of a genetic lesion behind a specific type of leukemia... This is the paradoxical result that has just been reached by co-operation between a Chinese team from the Shanghai Institute of Hematology, and a French team from the "Cellular pathology: molecular and viral aspects" laboratory of the CNRS, led by Professor Hugues de Thé. Acute promyelocytic leukemia (a rare type of blood cancer) is specifically associated with a chromosome translocation which creates an oncogenic abnormal protein, PML/RARa, resulting from fusion between two genes: PML and RARa. This leukemia is currently well treated by retinoic acid (a hormone which binds RARa) in combination with chemotherapy, providing the first example of oncogene-targeted therapy. Recently, Chinese teams have shown that arsenic has a therapeutic effect on patients suffering from this type of leukemia. Unlike retinoic acid, which triggers cell differentiation, arsenic induces programmed death, or apoptosis. This Franco-Chinese co-operation examined the mode of action of arsenic and showed that, like retinoic acid, arsenic causes the oncogene PML/RARa to be degraded, highlighting a surprising similitude between the effects of the two agents. While retinoic acid acts on the RAR portion of the fusion, arsenic acts on its PML portion. This data can be used to propose a physio-pathological model of this disease in which RAR would control differentiation while PML would control apoptosis. Arsenic even acts in patients showing clinical resistance to retinoids, suggesting that combined treatments could be envisaged.

Researcher Contact:
Hugues de THÉ,
« Pathologie cellulaire : aspects moléculaires et viraux »
CNRS, Hôpital Saint-Louis, Paris
tél. : 01 53 72 40 80
télécopie : 01 53 72 40 90
courrier électronique :
dethe@chu-stlouis.fr

Department Contact:
Thierry PILORGE,
Communication Sciences de la vie,
tél. : 01 44 96 40 26

The above is an English translation of the abstract of the article which was originally in French and can be viewed by clicking here.

(3)    Abstract of article in Proc. Natl. Acad. Sci. USA   Vol. 94, pp. 3978-3983, April 1997  Medical Sciences

Arsenic-induced PML targeting onto nuclear bodies: Implications for the treatment of acute promyelocytic leukemia

Jun Zhu*,, Marcel H. M. Koken, Frédérique Quignon, Mounira K. Chelbi-Alix, Laurent Degos, Zhen Yi Wang*,Zhu Chen*, and Hugues de Thé,

* Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University, 197, Rui-Jin Road II, Shanghai 200025, China; and  Centre National de la Recherche Scientifique Unité Propre de Recherche 9051,Laboratoire Associé au Comite de Paris de la Ligue contre le Cancer,  Service Clinique des Maladies du Sang, and § Service de Biochimie B, Hôpital St. Louis, 1 Avenue Vellefaux, 75475 Paris Cedex 10, France

Communicated by Jean Dausset, Centre d'Étude du Polymorphisme Humain, Paris, France, January 8, 1997 (received for review October 29, 1996)
 

Acute promyelocytic leukemia (APL) is associated with the t(15;17) translocation, which generates a PML/RAR fusion proteinbetween PML, a growth suppressor localized on nuclear matrix-associatedbodies, and RAR, a nuclear receptor for retinoic acid (RA). PML/RARwas proposed to block myeloid differentiation through inhibitionof nuclear receptor response, as does a dominant negative RARmutant. In addition, in APL cells, PML/RAR displaces PML and other nuclear body (NB) antigens onto nuclear microspeckles, likely resulting in the loss of PML and/or NB functions. RA leads to clinical remissions through induction of terminal differentiation, for which the respective contributions of RAR (or PML/RAR) activation,PML/RAR degradation, and restoration of NB antigens localizationare poorly determined. Arsenic trioxide also leads to remissionsin APL patients, presumably through induction of apoptosis. Wedemonstrate that in non-APL cells, arsenic recruits the nucleoplasmicform of several NB antigens onto NB, but induces the degradationof PML only, identifying a powerful tool to approach NB function.In APL cells, arsenic targets PML and PML/RAR onto NB and inducestheir degradation. Thus, RA and arsenic target RAR and PML, respectively,but both induce the degradation of the PML/RAR fusion protein,which should contribute to their therapeutic effects. The differencein the cellular events triggered by these two agents likely stemsfrom RA-induced transcriptional activation and arsenic effectson NB proteins.
 

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