Hepatotoxicity profile of single agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia, its impact on clinical outcome and the effect of genetic polymorphisms on the incidence of hepatotoxicity

Mathews, Vikram; Desire, Salamun; George, Biju; Lakshmi, Kavitha M; Rao, Jayandharan Giridhara; Viswabandya, Auro; Bajel, Ashish; Srivastava, Vivi M.; Srivastava, Alok; Chandy, Mammen

doi:10.1038/sj.leu.2404165

Cited by 42 publications

(25 citation statements)

References 9 publications

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“…Seven of these patients were successfully re-challenged with ATO and there were no cases of acute hepatic failure or mortality attributable to hepatic toxicity 14 .…”

Section: Discussionmentioning

confidence: 99%

“…This observation matches with an international study that noted 7 (63.33%) of 11 newly diagnosed patients developed hepatotoxicity and 2 of them failed to recover, with liver dysfunction contributing to their death 13 . In the Indian Trial, Grade 1, 2, 3 and 4 hepatotoxicity (NCICTC v 2.0) was seen in 14 (18.4%), 7 (9.2%), 4 (5.3%) and 4(5.3%) patients, respectively 14 . Transient elevation of liver enzymes were the prominent abnormality in these patients.…”

Section: Discussionmentioning

confidence: 99%

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A Prospective Study on the Effectiveness of Arsenic Trioxide (ATO) in Remission Induction of Acute Promyelocytic Leukemia (APL)

Anis

Khan

Afrosa

et al. 2015

Chatt Maa Shi Hosp Med Coll J

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Background: Arsenic Trioxide (ATO) as a single agent, has proven efficacy in inducing molecular remission in patients with Acute Promyelocytic Leukemia (APL). It is commonly used to treat relapsed APL. But there is Limited study on ATO in the management of newly diagnosed cases of APL. The concerned study was done to evaluate the effectiveness and outcome of ATO in remission induction of new cases of APL in the context of a limited resource hospital in Bangladesh. Methods: From March 2008 to March 2010, 20 patients with Promyelocytic Leukemia (PML) / Retinoic Acid Receptor α (RAR α) + newly diagnosed APL were enrolled. All patients were treated with a regimen of single-agent arsenic trioxide till remission at our center. After remission the regimen was administered on outpatient basis. Results: Overall 15 (75%) patients achieved complete hematological remission. 12 (80%) patients achieved molecular remission after induction phase and 3 (20%) after completion of consolidation phase. At a median follow up of 36 months (Range 25 -44 months), Disease Free Survival (DFS) and Overall Survival (OS) 86.6% and 85.3% respectively. Relatively young patients with long form of t (15;17) had shown good response with this response. However, the response is slower than All Trans Retinoic Acid (ATRA). Patients presenting with high White Blood Cell (WBC) count, low platelet count, variable form of t (15;17) are found to respond poorly. The toxicity profile, in the majority, was mild and reversible. Treatment cost was also reduced than that of conventional regimen. Conclusion: Single-agent arsenic trioxide as used in this study in the management of newly diagnosed cases of APL is safe, cost beneficent and is associated with durable responses. But additional interventions as combining ATRA with ATO would probably required in high risk cases.

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“…Seven of these patients were successfully re-challenged with ATO and there were no cases of acute hepatic failure or mortality attributable to hepatic toxicity 14 .…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Prospective Study on the Effectiveness of Arsenic Trioxide (ATO) in Remission Induction of Acute Promyelocytic Leukemia (APL)

Anis

Khan

Afrosa

et al. 2015

Chatt Maa Shi Hosp Med Coll J

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“…V-PYRRO/NO facilitated arsenic induction of MT, which may be important in NO-induced arsenic tolerance. The highly effective use of inorganic arsenic against certain leukemias is well established [2,3,5] and it's utility against solid tumors is under study. A limiting side effect, a least in some subpopulations, could be hepatotoxicity [4,5].…”

Section: Discussionmentioning

confidence: 99%

“…The highly effective use of inorganic arsenic against certain leukemias is well established [2,3,5] and it's utility against solid tumors is under study. A limiting side effect, a least in some subpopulations, could be hepatotoxicity [4,5]. Thus, a liver specific prodrug that reduces inorganic arsenic hepatotoxicity could have significant utility as an adjuvant in arsenical chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…Although very effective clinically, concerns have been raised about the potential for fatal hepatotoxicity in patients undergoing arsenical chemotherapy for cancer [4]. The individual susceptibility to arsenical hepatotoxicity varies widely in humans, possibly due to differences in arsenic methylation [5]. Thus, an agent or agents that would effectively limit arsenical hepatotoxicity may be a valuable adjunct to arsenical chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

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The nitric oxide prodrug, V-PYRRO/NO, mitigates arsenic-induced liver cell toxicity and apoptosis

Liu

Fuquay

et al. 2007

Cancer Letters

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Arsenite is an important cancer chemotherapeutic. The liver is a major target tissue of arsenic toxicity and hepatotoxicity may limit its chemotherapeutic efficacy. O 2 -vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO) is a liver-selective nitric oxide (NO)-producing prodrug metabolized by hepatic P450 enzymes to release NO locally. V-PYRRO/NO protects against various organic or inorganic hepatotoxicants but any role in arsenic hepatotoxicity is undefined. Thus, we studied the effects of V-PYRRO/NO (0-1000 μM) pretreatment on inorganic arsenic-induced toxicity in cultured rat liver (TRL 1215) cells. These cells metabolized the prodrug to release NO, producing extracellular nitrite levels to 41.7-fold above control levels (7.50 ± 0.38 μM) after 24 h V-PYRRO/ NO (1000 μM) exposure. The effect of pretreatment with V-PYRRO/NO (24 h) on the cytolethality of arsenic (as NaAsO 2 ) exposure (24 h) was assessed. Arsenic was markedly less toxic in V-PYRRO/ NO pretreated cells (LC 50 = 30.3 μM) compared to control (LC 50 = 20.1 μM) and the increases in LC 50 showed a direct relationship to the level of NO produced (measured as nitrite). Consistent with the cytolethality data, V-PYRRO/NO pretreatment markedly reduced arsenic-induced apoptosis as assessed by DNA fragmentation. Activation of the c-Jun N-terminal kinase (JNK) pathway can be critical to apoptosis and pretreatment with V-PYRRO/NO suppressed arsenic-induced JNK activation. V-PYRRO/NO pretreatment modestly increased metallothionein (MT), a metal-binding protein, but greatly enhanced arsenic induction of MT. Thus, V-PYRRO/NO pretreatment directly mitigates arsenic toxicity in cultured liver cells, reducing cytolethality, apoptosis and related JNK pathway activation, apparently through generation of NO. The role of NO in reducing the hepatotoxicity of arsenical chemotherapeutics in vivo deserves additional study.

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Current awareness: Pharmacoepidemiology and drug safety

2006

Pharmacoepidemiology and Drug

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In order to keep subscribers up‐to‐date with the latest developments in their field, John Wiley & Sons are providing a current awareness service in each issue of the journal. The bibliography contains newly published material in the field of pharmacoepidemiology and drug safety. Each bibliography is divided into 20 sections: 1 Books, Reviews & Symposia; 2 General; 3 Anti‐infective Agents; 4 Cardiovascular System Agents; 5 CNS Depressive Agents; 6 Non‐steroidal Anti‐inflammatory Agents; 7 CNS Agents; 8 Anti‐neoplastic Agents; 9 Haematological Agents; 10 Neuroregulator‐Blocking Agents; 11 Dermatological Agents; 12 Immunosuppressive Agents; 13 Autonomic Agents; 14 Respiratory System Agents; 15 Neuromuscular Agents; 16 Reproductive System Agents; 17 Gastrointestinal System Agents; 18 Anti‐inflammatory Agents ‐ Steroidal; 19 Teratogens/fetal exposure; 20 Others. Within each section, articles are listed in alphabetical order with respect to author. If, in the preceding period, no publications are located relevant to any one of these headings, that section will be omitted.

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Hepatotoxicity profile of single agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia, its impact on clinical outcome and the effect of genetic polymorphisms on the incidence of hepatotoxicity

Cited by 42 publications

References 9 publications

A Prospective Study on the Effectiveness of Arsenic Trioxide (ATO) in Remission Induction of Acute Promyelocytic Leukemia (APL)

A Prospective Study on the Effectiveness of Arsenic Trioxide (ATO) in Remission Induction of Acute Promyelocytic Leukemia (APL)

The nitric oxide prodrug, V-PYRRO/NO, mitigates arsenic-induced liver cell toxicity and apoptosis

Current awareness: Pharmacoepidemiology and drug safety

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