Arsenic Trioxide



Arsenic Trioxide


Bruce A. Chabner



A remarkable addition to the treatment for acute promyelocytic leukemia (APL) emanated from investigators in Harbin, China, who reported that the majority of patients relapsing and/or refractory to standard ATRA/anthracycline regimens achieved complete response to a single agent arsenic trioxide (ATO).1 Arsenicals have been used in folk medicine for various conditions, including warts, syphilis, ulcers, and leukemia. Several forms of arsenic derivatives have been administered to patients, but white arsenic (arsenic trioxide), which forms arsenous acid (AS(OH)3) in aqueous solution, is easily formulated for intravenous administration and is well absorbed orally2 (see Fig. 23-1). Its key features are shown in Table 24-1.


Mechanism of Action

ATO enters cells via the AQP9 transporter,3 which is expressed at higher levels in APL and in the M2 AML subtype, as compared to other subtypes of AML. As a general property of arsenicals, ATO readily interacts with sulfhydryl and other reducing molecules.4 It inactivates the critical enzyme thioredoxin reductase, thereby disabling cellular defenses against reactive oxygen species (ROS).5 APL cells have a generous intracellular concentration of ROS, probably as the result of their intracellular NADPH oxidase activity,6 and are particularly susceptible to redox inactivation. Consistent with the free radical mechanism of toxicity is the observation that the antitumor effects of ATO are antagonized in cell culture by free radical scavengers, such as N-acetylcysteine.7








TABLE 24.1 Key features of ATO






























Features


ATO


Mechanism of action


Induces degradation of fusion protein Increases ROS damage


Metabolism


CYP-mediated methylation Inactivates ATO


Dosage and schedule


0.15 mg/kg/d for 28 d


Eliminations


“Rapid” disappearance from plasma


Toxicity


Lengthens QTc, torsade de pointes, leukemic cell maturation syndrome, hypertriglyceridemia, hepatic enzyme elevations


Drug interactions


Avoid drugs that prolong QTc (macrolide antibiotics, quinidine, methadone)


Precautions


Monitor and correct serum electrolytes



Monitor QTc on EKG during treatment


ATO has a number of additional biological effects that may contribute to its cytotoxicity. It activates the intrinsic apoptotic pathway that responds to ROS and down-regulates antiapoptotic proteins such as bcl-2 and dampens survival and angiogenic signals.8

Only gold members can continue reading. Log In or Register to continue

Stay updated, free articles. Join our Telegram channel

May 27, 2016 | Posted by in ONCOLOGY | Comments Off on Arsenic Trioxide

Full access? Get Clinical Tree

Get Clinical Tree app for offline access