Arsenic trioxide, a therapeutic agent for APL.
Acute promyelocytic leukemia (APL) is an interesting model in cancer research, because it can respond to the differentiation/apoptosis induction therapy using all-trans retinoic acid (ATRA) and arsenic trioxide (As(2)O(3)). Over the past 5 years, it has been well demonstrated that As(2)O(3) induces a high complete remission (CR) rate in both primary and relapsed APL patients (around 85 to 90%). The side effects are mild to moderate in relapsed patients, while severe hepatic lesions have been found in some primary cases. After CR obtained in relapsed patients, chemotherapy in combination with As(2)O(3) as post-remission therapy has given better survival than those treated with As(2)O(3) alone. The effect of As(2)O(3) has been shown to be related to the expression of APL-specific PML-RARalpha oncoprotein, and there is a synergistic effect between As(2)O(3) and ATRA in an APL mouse model. Cell biology studies have revealed that As(2)O(3) exerts dose-dependent dual effects on APL cells. Apoptosis is evident when cells are treated with 0.5 approximately 2.0 microM of As(2)O(3) while partial differentiation is observed using low concentrations (0.1 approximately 0.5 microM) of the drug. The apoptosis-inducing effect is associated with the collapse of mitochondrial transmembrane potentials in a thiol-dependent manner, whereas the mechanisms underlying APL cell differentiation induced by low dose arsenic remain to be explored. Interestingly, As(2)O(3) over a wide range of concentration (0.1 approximately 2.0 microM) induces degradation of a key leukemogenic protein, PML-RARalpha, as well as the wild-type PML, thus setting up a good example of targeting therapy for human cancers.
Zhang
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The First Hospital affiliated to Harbin Medical University, 23 You Zheng Road, Nangang District, Harbin, 150001, PR China.
Chen
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Wang
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Wang
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Chen
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Chen
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D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000187:drug effects; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000187:drug effects; D010087:Oxides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000071156:Promyelocytic Leukemia Protein; D012074:Remission Induction; D015996:Survival Rate; D014157:Transcription Factors / Q000096:biosynthesis / Q000187:drug effects; D014212:Tretinoin / Q000008:administration & dosage; D025521:Tumor Suppressor Proteins
D000970:Antineoplastic Agents; D001152:Arsenicals; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D010087:Oxides; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C070576:PML protein, human; D014212:Tretinoin; D000077237:Arsenic Trioxide