EC Pharmacology and Toxicology

Although cyclophosphamide (CP) has been clinically proven in the treatment of cancer for over 60 years, until recently nothing was known about its mechanism of action. The reason for this was that results from in vitro experiments were not critically questioned, but were uncritically transferred to in vivo conditions. In vitro, the formation of the alkylating metabolite phosphoreamide mustard (PAM) produces acrolein as a by-product, whereas in vivo the proapoptotic metabolite 3-hydroxypropanal (Reuterin) is formed, which enhances p53-controlled apoptosis caused by DNA alkylation by PAM. CP was found by a happy coincidence. It is not tailor-made for the mechanism of action. The present article describes the development of new cyclophosphamides adapted to the mechanism of action, which in animal experiments are less toxic and orders of magnitude more effective than the cyclophosphamides used clinically today.

Keywords: Cyclophosphamide; Mechanism of Action; 3-Hydroxypropanal (Reuterin); Alkylating Function; Aldophosphamide-Thiazolidine-Perhydrothiazine; Apoptosis-Enhancer

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