Wen-Chien Chou1, Chi V Dang. 1. Department of Laboratory Medicine and Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Abstract
PURPOSE OF REVIEW: While arsenic has long been known as a poison and environmental carcinogen, its dramatic effect in the treatment of acute promyelocytic leukemia (APL) has made its mechanism of action a topic of intense interest. This paper reviews recent findings that reveal why a traditional poison has become a magical potion for a major type of APL, which is characterized by a balanced chromosomal translocation t(15;17). RECENT FINDINGS: Daily IV infusion of arsenic trioxide (As2O3; ATO) for 30 to 40 days can lead to complete remission in about 85% of patients with newly diagnosed or relapsed APL. Oral preparations of ATO and tetra-arsenic tetra-sulfide (As4S4) seem to be as effective as parenteral ATO, with similar toxicity profiles. The combination of all-trans retinoic acid and ATO in patients with newly diagnosed APL has yielded more durable remission than monotherapy. The mechanism of arsenic cytotoxicity is thought to involve posttranslational modification followed by degradation of the PML-retinoic acid receptor-alpha (PML-RARalpha) fusion protein; targeting of PML to nuclear bodies with restoration of its physiologic functions; and production of reactive oxygen species (ROS) by NADPH oxidase in leukemic cells or collapse of the mitochondrial transmembrane potential. The understanding of arsenic cytotoxicity has stimulated modifications that promise to improve efficacy, such as interfering with ROS scavenging or boosting of ROS production to enhance the cytotoxicity, and adding cAMP or interferons to ATO regimens. SUMMARY: Recent advances in the clinical use of arsenic, the mechanism of arsenic-mediated cytotoxicity, and modulations of ATO to increase its efficacy and expand its clinical spectrum are reviewed.
PURPOSE OF REVIEW: While arsenic has long been known as a poison and environmental carcinogen, its dramatic effect in the treatment of acute promyelocytic leukemia (APL) has made its mechanism of action a topic of intense interest. This paper reviews recent findings that reveal why a traditional poison has become a magical potion for a major type of APL, which is characterized by a balanced chromosomal translocation t(15;17). RECENT FINDINGS: Daily IV infusion of arsenic trioxide (As2O3; ATO) for 30 to 40 days can lead to complete remission in about 85% of patients with newly diagnosed or relapsed APL. Oral preparations of ATO and tetra-arsenictetra-sulfide (As4S4) seem to be as effective as parenteral ATO, with similar toxicity profiles. The combination of all-transretinoic acid and ATO in patients with newly diagnosed APL has yielded more durable remission than monotherapy. The mechanism of arseniccytotoxicity is thought to involve posttranslational modification followed by degradation of the PML-retinoic acid receptor-alpha (PML-RARalpha) fusion protein; targeting of PML to nuclear bodies with restoration of its physiologic functions; and production of reactive oxygen species (ROS) by NADPH oxidase in leukemic cells or collapse of the mitochondrial transmembrane potential. The understanding of arseniccytotoxicity has stimulated modifications that promise to improve efficacy, such as interfering with ROS scavenging or boosting of ROS production to enhance the cytotoxicity, and adding cAMP or interferons to ATO regimens. SUMMARY: Recent advances in the clinical use of arsenic, the mechanism of arsenic-mediated cytotoxicity, and modulations of ATO to increase its efficacy and expand its clinical spectrum are reviewed.
Authors: Yun Ge; Idalia Montano; Gabriella Rustici; Wendy J Freebern; Cynthia M Haggerty; Wenwu Cui; Damaris Ponciano-Jackson; G V R Chandramouli; Erin R Gardner; William D Figg; Mones Abu-Asab; Maria Tsokos; Sharon H Jackson; Kevin Gardner Journal: Blood Date: 2006-08-29 Impact factor: 22.113
Authors: Ana María Salazar; Heather L Miller; Samuel C McNeely; Monserrat Sordo; Patricia Ostrosky-Wegman; J Christopher States Journal: Chem Res Toxicol Date: 2010-02-15 Impact factor: 3.739