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Protonmediated liberation of aldophosphamide from a nontoxic prodrug: a strategy for tumor-selective activation of cytocidal drugs

By Lutz F. Tietze, Manfred Neumann, Thomas Möllers, Et Al, Contact The Aacr Publications, Lutz F. Tietze, Manfred Neumann and Manfred F. Rajewsky


Based on the findings that the pH in malignant tumors can be prefer entially decreased by stimulation of their aerobic glycolysis, acid-sensible prodrugs, which are nearly nontoxic at physiological pH, were synthe sized. At lower pH, however, these compounds are cleaved with liberation of a cytotoxic species. The prototypic drug compound 2-hexenopyranoside of aldophosphamide was prepared, which releases aldophosphamide by acid-catalyzed hydrolysis. Exposure of cultured MIR rat mammary carcinoma cells to this agent at pH 7.4 only resulted in slight toxicity. However, when drug treatment was performed at pH 6.2, the mean pH in malignant tumors of hyperglycémie hosts, the colony-forming fraction of MIR cells decreased to 0.05 and 0.0001 of controls treated at pH 7.4 after exposure for 24 h and 48 h, respectively. The synthesis of th

Year: 1989
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