Clinical evaluation of a new alkylating agent: Cytoxan (cyclophosphamide)

Abstract

to obtain a cytotoxic drug with I an enhanced chemotherapeutic index for use in the treatment of advanced cancer, Arnold and co-workers in 19571 synthesized a cyclic phosphamide ester of nitrogen mustard with the following structure: A B As found in earlier work,4 the attachment of a phosphoryl group (B) to nitrogen mustard (A) reduces the chemical activity of the parent compound by diminishing the basic properties of the central nitrogen atom and thus in turn decreasing the ionizability of the chlorine atoms in the chloroethyl groups. For the activation of cyclophosphamide, phosphamidases or phosphatases are theoretically needed to break the cycle group at the phosphorous-nitrogen or the phosphorous-oxygen bonding respectively: thus, the compound is relatively inert until it is incorporated into cells containing these enzymes.