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

Based on the findings that the pH in malignant tumors can be preferentially decreased by stimulation of their aerobic glycolysis, acid-sensible prodrugs, which are nearly nontoxic at physiological pH, were synthesized. At lower pH, however, these compounds are cleaved with liberation of a cytotoxic...

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Published inCancer research (Chicago, Ill.) Vol. 49; no. 15; pp. 4179 - 4184
Main Authors TIETZE, L. F, NEUMANN, M, MÖLLERS, T, FISCHER, R, GLÜSENKAMP, K.-H, RAJEWSKY, M. F, JÄHDE, E
Format Journal Article
LanguageEnglish
Published Philadelphia, PA American Association for Cancer Research 01.08.1989
Subjects
Animals
Antineoplastic agents
Antineoplastic Agents - metabolism
Biological and medical sciences
Biotransformation
Cell Survival - drug effects
General aspects
Glycolysis
Hydrogen-Ion Concentration
Medical sciences
Pharmacology. Drug treatments
Phosphoramide Mustards - metabolism
Prodrugs - metabolism
Rats
Tumor Cells, Cultured - drug effects
Antineoplastic agent
Rat
Rodentia
Cytotoxicity
Prodrug
Extracellular
In vitro
Vertebrata
Mammalia
Animal
PH
Active ingredient
Mammary gland
Chemical synthesis
Tumor cell
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Summary:Based on the findings that the pH in malignant tumors can be preferentially decreased by stimulation of their aerobic glycolysis, acid-sensible prodrugs, which are nearly nontoxic at physiological pH, were synthesized. 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 M1R 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 hyperglycemic hosts, the colony-forming fraction of M1R 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 the 2-hexenopyranoside of aldophosphamide is described in detail.
ISSN:0008-5472
1538-7445