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Chinese Medicine Pishuang and acute promyelocytic leukemia: from highly fatal to highly curable



Acute promyelocytic leukemia (APML, APL) is a subtype of acute myeloid leukemia (AML), a cancer of the white blood cells.In APL, there is an abnormal accumulation of immature granulocytes called promyelocytes. The disease is characterized by a chromosomal translocation involving the retinoic acid receptor alpha (RARA) gene and is distinguished from other forms of AML by its responsiveness to all-trans retinoic acid (ATRA; also known as tretinoin) therapy. Acute promyelocytic leukemia was first characterized in 1957 by French and Norwegian physicians as a hyperacute fatal illness, with a median survival time of less than a week.


APL is unique among leukemias due to its sensitivity to all-trans retinoic acid (ATRA; tretinoin), the acid form of vitamin A. Treatment with ATRA dissociates the NCOR-HDAC complex from RAR and allows DNA transcription and differentiation of the immature leukemic promyelocytes into mature granulocytes by targeting the oncogenic transcription factor and its aberrant action. Unlike other chemotherapies, ATRA does not directly kill the malignant cells. ATRA induces the terminal differentiation of the leukemic promyelocytes, after which these differentiated malignant cells undergo spontaneous apoptosis on their own. ATRA alone is capable of inducing remission but it is short-lived in the absence of concurrent "traditional" chemotherapy.


Arsenic compounds had been used as therapeutic agents for more than 2,000 years in Western and Eastern medicine, particularly in China. In Chinese medicine, its name is "Pishuang". Initial results on APL treatment with ATO were published in the late ’90s by Chinese investigators who observed striking responsiveness only in this subset among several leukemia types assessed. In particular, a study from Harbin Medical University reported CR rates with ATO as a single agent of up to 73% and 50% in newly diagnosed and relapsed APL patients respectively.


As of 2013 the standard of treatment for concurrent chemotherapy has become arsenic trioxide, which combined with ATRA is referred to ATRA-ATO; before 2013 the standard of treatment was anthracycline (e.g. daunorubicin, doxorubicin, idarubicin or mitoxantrone)-based chemotherapy. Both chemotherapies result in a clinical remission in approximately 90% of patients with arsenic trioxide having a more favorable side effect profile.


A clinical trial has found that the combination of all-trans retinoic acid, which is a metabolite of vitamin A, and arsenic trioxide is highly effective in children with standard- and high-risk acute promyelocytic leukemia, or APL. Nearly all patients in the trial survived for two years without experiencing a relapse. None of the children with standard-risk APL required conventional chemotherapy, and those with high-risk APL received just four doses of the chemotherapy drug idarubicin (Idamycin PFS). The results of the trial, conducted by the Children’s Oncology Group and funded by the National Cancer Institute, part of the National Institutes of Health, were published November 11, 2021, in JAMA Oncology.


“This is a remarkable achievement and will be the new standard of care,” said Malcolm A. Smith, M.D., Ph.D., of the Cancer Therapy Evaluation Program at the National Cancer Institute, which funded the multi-institutional, nonrandomized phase 3 cooperative group trial. “Twenty years ago, these patients would have been treated with intensive chemotherapy, including drugs that lead to heart problems later in life. By comparison, all-trans retinoic acid and arsenic trioxide have fewer acute or long-term side effects.”


My comments:

We need more researchers to join the team of investigating Chinese medicine to find a better solution of cancer.


References:

1. Kamran Alimoghaddam. A Review of Arsenic Trioxide and Acute Promyelocytic Leukemia. Int J Hematol Oncol Stem Cell Res. 2014 ; 8(3): 44–54.

2. Francesco Lo-Coco, and Laura Cicconi. History of Acute Promyelocytic Leukemia: A Tale of Endless Revolution. Mediterr J Hematol Infect Dis. 2011; 3(1): e2011067.

3. Zhen-Yi Wang 1, Zhu Chen. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 2008 ;111(5):2505-15. doi: 10.1182.








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