History of 6-Mercaptopurine (6MP)

George Hitchings and Gertrude Elion, who jointly obtained the Nobel Prize of medicine in 1988, figured that they could inhibit replication of rapidly dividing cells such as cancer cells and pathogens by making derivatives of the chemical bases constituting DNA (Hitchings G., Elion G. et al, 1950).

The concept they initially developed was to synthesize bases similar enough to the real ones in order to let them integrate metabolic pathways; however, they would be sufficiently different that once integrated they would inhibit de novo DNA synthesis. Hitchings and Elion also evidenced potential efficacy of antimetabolite drugs in the late 1940s as they performed systematic antitumor activity screening with purine and pyrimidine molecules at the Sloan-Kettering Institute. One of these purine analogue, the compound SK5357, or 6-Mercaptopurine (6MP), was discovered there.

Burchenal et al.(1949), Kiddeh et al.(1949), Gellhorn et al.(1950), Sugiura et al.(1950), Law et al.(1950) performed additional scientific work which supported this concept. The potential of 6MP for treatments of oncologic diseases such as Acute Lymphoblastic Leukæmia, Acute Myelogenous Leukæmia and Chronic Myelogenous Leukæmia was evidenced soon after.

In 1953, Clarke et al. performed single dose and multiple doses toxicology studies which allowed Burchenal et al. to perform the first clinical trial in human the same year (Burchenal et al. 1953). It is during this year that the US National Cancer Institute (NCI) was founded, that the DNA structure was discovered and that 6MP was approved by the Food and Drug Administration.

Despite the need for children of adapted suitable formulations, the authorized formulation of 6-Mercaptopurine is the adult scored tablets containing 50 mg of active substance also known as Puri-Nethol.