Impairment of heart rate variability control during arsenic trioxide treatment for acute promyelocytic leukemia

Dynamic regulation and involvement of the heat shock transcriptional response in arsenic carcinogenesis

“…For example, low concentrations of arsenite may specifically target signaling molecule(s) of the heat shock transcriptional response, and as the concentration of arsenite increases a progressively greater number of cellular proteins as well as nonprotein thiols are targeted, including eIF2a kinase which phosphorylates eIF2a resulting in inhibition of protein synthesis and the eventual cell death (Zhan et al, 2002). We further suggest this concentrationdependent differential targeting of protein and non-protein thiols may also underscore the many and diverse biological effects of arsenite-from carcinogenesis at a low-level chronic arsenic exposure to the use of arsenicals as chemotherapeutic agents in the treatment of acute promyelocytic leukemia (APL; Miller et al, 2002;Au et al, 2003;Takeshita et al, 2004;Sanz et al, 2005;Soignet et al, 2005), and as a first line drug for treatment of late stage HAT. We note that while the concentration of arsenic that poses a threat as an environmental carcinogen is measured in micrograms per liter (ppb; e.g., 10 mg/L ¼ 10 ppb ¼ 0.13 mM) concentration range, the in vivo therapeutic doses of arsenic trioxide (As 2 O 3 ; FW ¼ 198) for the treatment of APL is generally 0.15 mg/kg/day intravenously for 50 days.…”

“…The use of melarsoprol (Arsobal, an organic arsenical; C 12 H 15 AsN 6 OS 2 , FW ¼ 398) for the treatment of late stage HAT consists of 2-4 series of 3-4 daily injections of 3.6 mg/kg each with intervening rest periods of 7-10 days (Schmid et al, 2004; http:// www.sti.ch/scih/africa2.htm); this translates to 14.8 mM/ day for 4 Â 4 days for a maximum cumulative dose of 3,456 mg (or 236.8 mM). The clinical use of arsenicals is associated with many and significant side effects, including death (Takeshita et al, 2004).…”

“…This translates to $1.26 mM/day (60 kg body weight; 36 L total body water) or the equivalence in elemental arsenic of 2.5 mM/day of sodium arsenite (NaAsO 2 ; FW ¼ 130). The cumulative dose of arsenic trioxide of this treatment regiment is $400-500 mg, or approximately the equivalence of 125 mM of sodium arsenite (Au et al, 2003;Takeshita et al, 2004;Sanz et al, 2005;Soignet et al, 2005). The use of melarsoprol (Arsobal, an organic arsenical; C 12 H 15 AsN 6 OS 2 , FW ¼ 398) for the treatment of late stage HAT consists of 2-4 series of 3-4 daily injections of 3.6 mg/kg each with intervening rest periods of 7-10 days (Schmid et al, 2004; http:// www.sti.ch/scih/africa2.htm); this translates to 14.8 mM/ day for 4 Â 4 days for a maximum cumulative dose of 3,456 mg (or 236.8 mM).…”

“…On the one hand, epidemiological studies worldwide demonstrated a clear association of exposure to arsenic and the development of cancer, and the International Agency for Research on Cancer (IARC, 1980(IARC, , 1987 as well as the US Environmental Protection Agency (EPA, CASRN 7440-3802) have classified arsenic as a human carcinogen (for reviews, see Hughes, 2002;Miller et al, 2002;Rossman, 2003). On the other hand, arsenic has been used as a medicinal agent for more than 2000 years and contemporary studies show that arsenic is an effective therapeutic agent for the treatment of acute promyelocytic leukemia (APL) that is resistant to alltrans-retinoic acid (Miller et al, 2002;Au et al, 2003;Takeshita et al, 2004;Sanz et al, 2005;Soignet et al, 2005), and as a first line drug for the treatment of late stage human African trypanosomiasis (HAT; http:// www.sti.ch/scih/africa2.htm; http://www.icp.ucl.ac.be/$ opperd/parasites/drugs1.htm; http://www.who.int/tdr/dw/ tryp2004htm). While differences in the concentration and duration of exposure to arsenic must account at least in part for the different biological outcome as the dose of arsenic used in chemotherapy is 1-2 log units higher than the level of arsenic found as an environmental carcinogen, the molecular basis of these divergent effects of arsenic is not well understood.…”

Long-term cardiac-specific mortality among 44,292 acute myeloid leukemia patients treated with chemotherapy: a population-based analysis

“…The treatment of APL has developed dramatically over the past three decades due to the elucidation of the PML/RAR fusion gene, from anthracycline monotherapy to arsenic-based therapy to a combinatorial therapy of arsenic and all-trans retinoic acid [13]. However, arsenic agents have been proven to impair cardiac electrophysiology and ultimately increase cardiacspecific mortality [14,15]. Therefore, it is thought that chemotherapy is of high risk for AML patients, a population with many senior citizens [16].…”