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Antitumor Activity of Monomeric and Polymeric Cyclophosphamide Derivatives Compared with in Vitro Hydrolysis

Laboratory of Chemical Pharmacology, National Cancer Institute, NIH, Bethesda, Maryland 20205 [T. H., D. S. Z.], and Institute of Organic Chemistry, Mainz University, 6500 Mainz, Federal Republic of Germany [H. R.]

Relatively stable sulfhydryl derivatives of 4-hydroxycyclophosphamide and these same derivatives covalently bound to a polymeric carrier were studied in vitro and in vivo. The rate of release of 4-hydroxycyclophosphamide from monomeric and polymeric derivatives was examined under physiological conditions (pH 7.0, 37.0°) in vitro. Hydrophobicity and length of alkyl chain of substituents at the 4-position of the phosphamide ring decreased the rate of hydrolysis. The polymeric derivatives were more slowly hydrolyzed than were their corresponding monomers. Toxicity in mice indicated that the rate of hydrolysis in vitro is related to toxicity in vivo. The optimal antitumor activity (maximum 270% increase in life span in L1210-bearing mice) and effective dose range of each derivative of low molecular weight were similar to cyclophosphamide. The polymeric derivatives exhibited much less antitumor activity (maximum 50% increase in life span) than did cyclophosphamide. The short-alkyl-chain monomeric derivatives such as propanol and propionic acid caused acute lethal toxicity, which limited the upper dose usable for antitumor activity. Polymeric derivatives, when compared on a molar basis to their corresponding monomers, were relatively more toxic to the mice which limited their maximum dose.

¹ To whom requests for reprints should be addressed.

Received 11/13/79. Accepted 3/28/80.