Acute Promyelocytic Leukaemia, vitamin A acid (ATRA) and Arsenic (ATO)

Acute leukaemias are the most aggressive (fast dividing cancer cells) forms of human cancers which makes them life-threatening with high mortality rate but on the other hand, very susceptible to cytotoxic chemotherapy with curative intent.

Acute promyelocytic leukaemia (APL) was once considered the most malignant human leukemia as well as the one associated with the worst prognosis but has been transformed in the past few decades into the most curable leukemia with the best prognosis.

Cytotoxic chemotherapy always has been the standard-of-care for acute leukaemia and for most subtypes it still is. It’s very effective but causes a lot of collateral damage because it also kills normal cells in the body and has got some unique organ toxicities like hair loss, mucositis (sore mouth and gut), hand-foot syndrome, nausea and vomiting, diarrhoea, bone marrow suppression, lung, heart and nerve toxicity to name a few.

However, this millennium has brought us many types of targeted therapy (mainly small molecules and antibodies), which are not cytotoxic (non-chemo) and have got much fewer side-effects mentioned above.

The paradigm of targeted (small molecule) therapy is imatinib for chronic myeloid leukaemia (CML) with more than 90% overall survival if molecular remission has been achieved compared with only half of all patients surviving previously.

In the early 70ties, APL was successfully treated with cytotoxic chemotherapy but with considerable toxicity.

In the mid 80’s a series of unrelated circumstances led to the first experiences with vitamin A (retinoic) acid in China that revolutionized APL and cancer treatment

In vitro (“in the test tube”) studies on leukemic cell differentiation (“maturation”).
The need for of anticancer drugs less expensive than chemotherapy due to the economic constraints experienced at that time in China.
A philosophical lesson derived from Confucius who believed in the rehabilitation of criminals 

The unusual combined results of experimental evidence, philosophical tradition and politico-economic circumstances led to the first attempts in medicinal treatment to convert criminals (leukemic blasts) into good citizens (mature white blood cells) through the differentiating (“maturing”) agent ATRA or All-Trans-Retinoic Acid and subsequently ATO or Arsenic Trioxide.

APL is characterized by the following (as per above illustrations):

Severe bleeding in the skin due to over-consumption of clotting factors.
Bone marrow and blood smear with characteristic abnormal promyelocytes (leukaemia cells)
Demonstration of translocation chromosome 15 and 17 with fluorescent dye.
Formation of chromosome 15 and 17 translocation and subsequent fusion transcript PML-RARα which blocks the promyelocytic maturation to normal, mature, functioning white cells.

“TAMING AN EVIL WITH A TOXIC AGENT” or ONE MAN’s POISON IS ANOTHER’s MAN MEAT!

Although Arsenic was only identified in 1250 it was already used medicinally for over 2000 years.  Arsenic was therapeutically used as medicine in 1786 to treat psoriasis and later for syphilis and even chronic myeloid leukaemia (vide supra) in the 19th century with unacceptable side-effects.

In the early 1970’s a group from Harbin Medical University in North-eastern China identified Arsenic Trioxide (ATO) as an active anti-cancer ingredient.

ATO in conjunction with ATRA both kill directly leukaemic cells at high concentration and encourage normal cells to develop properly at low concentration and longer treatment course.

Both Arsenic and ATRA are examples of targeted therapy, which is the first non-chemo combo ever used for a subtype of acute leukaemia and has become the standard-of-care with acceptable side-effects

because it lacks the usual side-effects of conventional cytotoxic chemotherapy mentioned above and offers great overall survival exceeding 90 %, which is the best survival known to any type of acute leukaemia.

“If you use laws to direct the people, and punishments to control them, they will merely try to evade the laws, and will have no sense of shame. But if by virtue you guide them, and by the rites you control them, there will be a sense of shame and of right.” (Confucian Analects. Republished by Zhong-Hua-Shu-Ju, Beijing, 2005.) The translation of the essence of Confucius' philosophy into cancer therapy could be, if cancer cells are considered elements with “bad” social behavior in our body, “educating” rather than killing these elements might represent a much better solution.