Enzyme Alterable Alkylating Agents. VI. Synthesis, Chemical Properties, Toxicities, and Clinical Trial of Haloacetates and Haloacetamides Containing Enzyme-Susceptible Bonds<xref ref-type="fn" rid="FN2">2</xref>

Abstract

In a chemotherapy program designed to take advantage of possible hydrolytic enzyme deficiency in tumor cells, a series of esters and amides containing haloacetyl groups were synthesized, and their chemical properties and toxicities determined. The iodoacetyl derivatives are potent alkylating agents extremely stable in water. The bifunctional iodo esters are readily attacked enzymatically, as shown by the rapid splitting of the ester link in the presence of human, dog, or mouse serum, various tissue homogenates of the mouse and dog, and commercially available enzymes. The acid formed on hydrolysis of the bifunctional iodoacetates is less toxic than the parent compound. If cytotoxicity is involved, this is consistent with the biochemical requirement that enzymatic detoxification occurs in certain normal cells more readily than in some tumor cells. Two of 31 patients with gastrointestinal carcinoma showed objective evidence of an effect of agent S-10 on their tumors. This agent has little toxicity and may be given for long periods without cumulative effects or bone marrow toxicity.