Arsenic Trioxide for Non Acute Promyelocytic Leukemia Hematological Malignancies: A New Frontier

References

J Blood Disord. 2014;1(4): 1018.

Arsenic Trioxide for Non Acute Promyelocytic Leukemia Hematological Malignancies: A New Frontier

LiLi Zhou1, JianHou1, Godfrey Chi-Fung Chan2 and Daniel Man-Yuen Sze3*

1Department of Hematology, Shanghai Changzheng Hospital, Affiliated Hospital to the Second Military Medical University, China

2Department of Pediatrics & Adolescent Medicine, Queen Mary Hospital, The University of Hong Kong, HKSAR, China

3School of Medical Sciences and Health Innovations Research Institute (HiRi), RMIT University, Australia

*Corresponding author: Daniel Man-Yuen Sze, School of Medical Sciences, RMIT University, PO Box 71, Bundoora, Vic 3083 Australia.

Received: November 14, 2014; Accepted: December 25, 2014; Published: December 31, 2014

Abstract

Arsenic trioxide (As2O3) has been confirmed to be effective in the treatment of Acute Promyelocytic Leukemia (APL). Also, encouraging results have been reported in preclinical studies and pilot clinical trials of As2O3 in other hematological malignancies such as Multiple Myeloma (MM), Myeloplastic syndromes (MDS), T-cell leukemia-lymphoma and Chronic Myelogenous Leukemia (CML). However, conflicting findings have been reported in non-APL Acute Myeloid Leukemia (AML). The mechanisms of As2O3 activity are complex, with multiple modifications of cell growth and apoptosis control regulations of pro-survival and cell defense molecules, cell cycle arrest, glutathione redox system, p53-dependent apoptotic signals; telomerase activity and caspase pathway. It is now known that other mechanisms are also involved including the immunomodulatory and angiogenesis regulation. Recently there is a trend of investigating whether tetra-arsenic tetra-sulphide will be a better alternative for the arsenic trioxide. In summary this review describes emerging information that provides new insights for As2O3 as a broad spectrum chemotherapeutic agent in the treatment of hematological malignancies beyond APL.

Keywords: Arsenic trioxide; Leukemia; Mechanisms; Treatment

Introduction

Arsenic trioxide (As2O3) is a traditional folk medicine that has been used for over two thousand years in China [1]. During the 1970s, researchers working in China proposed As2O3 as part of the treatment for acute promyelocytic leukemia (APL) [2,3]. It has since been demonstrated that As2O3 can achieve complete remission rates that range from 70% to 90% in both newly diagnosed and relapsed APL patients [3-5]. Hence in the last decade, As2O3 has been widely accepted as an effective agent in both newly diagnosed and relapsed patients with cytogenetically confirmed APL. This effectiveness has been confirmed with a high Complete Remission rate (CR) and a low adverse effect rate with minimal myelosuppression [5].

The remarkable success of As2O3 in APL provides an impetus for the exploration of a possible role of As2O3 as an anti-cancer agent in other hematological cancers. Clinical studies of As2O3, singularly or in combination with other anti-tumor agents, revealed the potential wide applicability of this agent in patients with hematological malignancies beyond APL. These studies are supported by preclinical laboratory investigations indicating that As2O3 exhibits anti-tumor effects against cell lines derived from Multiple Myeloma (MM), Myelodysplastic Syndrome (MDS), non-APL Acute Myeloid Leukemia (AML), and lymphoma.

The first section of this review will discuss the various As2O3 anticancer mechanisms which are in common for many hematological malignancies. This will be followed by the second section of the tabulation of related clinical trials.

Mechanisms of action

The array of mechanisms that As2O3 achieves anti-cancer actions comprises induction of apoptosis; anti-proliferation; anti-angiogenic activity and immunomodulation as highlighted in Figure 1. The understanding of these As2O3 - related mechanisms is developed through many preclinical studies that provide valuable insights on the molecular and genetic processes involved in these pathways.