EC Pharmacology And Toxicology

The mechanism of action of cyclophosphamide (CP), although successfully used in the clinic for more than 60 years, was unknown until a few years ago. The reason for this was that results from in vitro studies were uncritically transferred to in vivo conditions. In vitro, the alkylating metabolite phosphoramide mustard (PAM) is formed by β-elimination of acrolein from the CP metabolite aldophosphamide (ALD); in vivo, ALD is cleaved by phosphodiesterase with the formation of 3-hydroxypropanal (HPA) instead of acrolein. Three discoveries had to come together to elucidate the mechanism of action of CP and other oxazaphosphorine cytostatic (OX): namely that HPA is a CP metabolite, that HPA promotes p53-controlled apoptosis and that the cell death event following CP therapy is p53-controlled apoptosis triggered by DNA damage. Based on this, a simple model for the mechanism of action of OX was postulated. Based on this model and with the aim of reduced toxicity and improved antitumor efficacy, aldophosphamide thiazolidines and aldophosphamide perhydrothiazines were synthesized and tested in P388 tumor bearing mice. The toxicity of these compounds is 6-7 times lower in mice than the toxicity of the parent compounds CP and Ifosfamide (IF). Therapy experiments with p388 tumor bearing mice were carried out with SUM-IAP. SUM-IAP is an I-aldophosphamide perhydrothiazolidine with an alkylating function adapted to the mechanism of action whereby antitumor activity is increased 10⁴ to 10⁵ times. Formation of metastases resistant to SUM-IAP is prevented by combining SUM-IAP with cis platinum (CPT) and by combination with the apoptosis enhancer N-methylformamide (NMF). With SUM-IAP, the body's own immune defense against metastases can be activated by suppressing inhibitory regulatory T cells. All animals were cured in a corresponding experiment. In contrast to aldophosphamide perhydrothiazines, aldophosphamide thiazolidines crosses the blood-brain barrier and are candidates for the treatment of CNS tumors.

 Keywords: Mechanism of Action of Cyclophosphamide; Thiazolidines/Perhydrothiazines of Aldophosphamide; Apoptosis; Blood Brain Barrier; SUM-IAP; Anti-Metastatic Therapy

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