Hepatotoxicity From Arsenic Trioxide for Pediatric Acute Promyelocytic Leukemia

Abstract

The aim of this study was to investigate the hepatotoxicity induced by arsenic trioxide (As2O3) at a therapeutic dose for pediatric acute promyelocytic leukemia (APL). A total of APL patients received As2O3 treatment by IV drip. Hepatotoxicity was monitored based on the observations of the dynamic changes in liver function and treatment responses. The influencing factors of hepatotoxicity were further analyzed. Liver impairment occurred in 24.4% of the patients, most of which was mild and moderate in severity. Liver impairment was primarily manifested by increases in alanine aminotransferase, aspertate aminotransferase, and γ-glutamyl transferase, and these increases mostly occurred within 1 to 3 weeks and then returned to normal levels after 4 weeks. Patients' ages, sex, disease time, hepatomegaly and liver dysfunction, and disseminated intravascular coagulation did not show correlations with hepatotoxicity. Their hemogram and lactate dehydrogenase numerical values obtained from preliminary diagnosis did not show significant correlations with hepatotoxicity. Aggravated hepatotoxicity was not observed in patients receiving marcellomycin for the sake of complete remission. Changes in short-term cumulative dose of As2O3 did not exhibit a correlation with hepatotoxicity. However, patients suffering from differentiation syndrome were more likely at the risk of hepatotoxicity. Liver impairment improved after the suspension of As2O3 and liver protection treatment. No patient died of liver failure. Hepatotoxicity induced by As2O3 at a therapeutic dose for pediatric APL is mild and temporary. The first to the third week of the remission induction is the important period for monitoring. Great attention should be given to differentiation syndrome as it may worsen hepatotoxicity.

Rearing medium dictates variability across replicates in untreated and arsenic challenged zebrafish larvae

“…Moreover, these experiments demonstrate that iAs toxicity during chronic exposure is largely due to effects sustained during the latter part of the exposure. These data are consistent with findings in humans and other animal models showing that iAs is a hepatotoxicant [14,22,[34][35][36] and suggest that hepatic toxicity is responsible for lethality in this system, regardless if larvae are reared in egg water or embryo medium.…”

“…Strong data from epidemiological and animal studies have shown that exposure to high levels of arsenic are associated with diabetes, liver disease, cardiovascular disease, cancer, and premature death, and acute to high levels are lethal [11][12][13]. Hepatocytes are among the most severely affected cells, as the liver is the site where majority of iAs is metabolized [14][15][16][17][18][19][20][21][22][23]. Indeed, we found that one stress response pathway, the unfolded protein response (UPR), was activated after chronic (6-120 hpf) iAs exposure in the liver of zebrafish larvae [9].…”

Resveratrol protects against arsenic trioxide‐induced oxidative damage through maintenance of glutathione homeostasis and inhibition of apoptotic progression

“…As 2 O 3 is currently used as a first-line chemotherapeutic drug for APL because it can effectively induce apoptosis in leukemia cells [Zhang et al, 2001]. However, the clinical application of the agent is limited by its side effects that include hepatotoxicity [Hao et al, 2013], cardiotoxicity [Barbey et al, 2003], and nephrotoxicity [Vuky et al, 2002], as well as sudden death [Westervelt et al, 2001]. The adverse effects of As 2 O 3 are usually caused by its cytoand genotoxic effects that are mediated by oxidative stress in normal cells.…”

The role of NF-κB in PARP-inhibitor-mediated sensitization and detoxification of arsenic trioxide in hepatocellular carcinoma cells

“…However, in most phase II clinical trials, the curative benefit of ATO against solid tumors is much less effective than that against APL because its dosage required to exert anticancer effect is higher than those required in hematologic malignancies (Lin et al, 2007;Liu et al, 2013). High doses of ATO are prone to cause severe toxic effects, including hepatotoxicity, cardiotoxicity, nephrotoxicity, and even sudden death (Hao et al, 2013;Vineetha et al, 2014). Therefore, dose-dependent toxicity and drug resistance considerably restrict ATO application for treatment of solid tumors.…”

“…ious anti-cancer drugs (Curtin and Szabo, 2013;Hao et al, 2013). Apoptosis is a complex process mainly regulated by the Bcl-2 family of anti-and pro-apoptotic proteins, such as Bcl-2 and Bax, respectively.…”