Year: 2025
Type: article
Abstract: This paper does not describe the results of a systematic search for the mechanism of action of cyclophosphamide and the consequences and possible indications arising from this mechanism. Rather, it describes a puzzle in which own results, some of them very old, were re-evaluated with the latest biochemical knowledge and supplemented by results from the scientific literature. The mechanism of action of cyclophosphamide, indispensable in clinical practice for 60 years, was unknown until recently simply because biochemical knowledge was lacking and because results from in vitro experiments were uncritically extrapolated to in vivo conditions. In vitro, the DNA alkylating metabolite phosphoramide mustard (PAM) is formed from the CP metabolite aldophosphamide (ALD) by phosphate and bicarbonate ion-catalyzed β-elimination of acrolein; In vivo, however, ALD is cleaved by phosphoesterases or DNA polymerase δ and ε associated 3'-5' exonucleases into the complementary meabolites PAM and 3-hydroxypropanal (HPA). The following describes the mechanism of action of CP, namely the complementary interaction of alkylating PAM and apoptosis-enhancing HPA, and it is shown how by optimizing the complementary effects of PAM and HPA the antitumor efficacy in the P388 mouse tumor model can be increased by more than ten thousandfold. Further experiments show that by optimizing the interaction of DNA alkylation and enhancing the resulting apoptosis by HPA, the formation of resistant metastases can be prevented and low toxicity chemotherapy can be achieved.
Source: Drugs and Drug Candidates
DOI: 10.3390/ddc4040048
Author: Georg Voelcker
Institution: Goethe University Frankfurt
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,207
OpenAlex ID: W4415819763