Paul A. Spagnuolo and Michael A. Rogers
In his Pulitzer Prize winning novel “The Emperor of all Maladies”, Dr. Siddhartha Mukherjee eloquently summarizes the history of rational drug design and its origins in understanding the impact of a food-derived bioactive compound (i.e., folic acid) in disease pathophysiology. Dr. Mukherjee reminds us that Sidney Farber's 1948 seminal paper in the New England Journal of Medicine set the framework for rational drug design. After observing that administration of folic acid in children with acute lymphoblastic leukemia (ALL) accelerated their disease, Farber and colleagues (notably Subbarao) developed anti-folate compounds to treat ALL. These drugs, aminopterin and later methotrexate, which is still used to this day as a cornerstone of several chemotherapy regimens, revolutionized cancer chemotherapy. In the 1980s, studies revealed that supplementation with all-trans retinoic acid (ATRA), a vitamin A derivative, forced differentiation of HL60 cells in culture. Later it was provided to a female patient with acute promyelocytic leukemia (APML) and she miraculously responded. She is alive and well today and ATRA remains a cornerstone of APML therapy.
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