EFFECTS OF NITROGEN MUSTARDS ON THE INCORPORATION OF AMINO ACIDS INTO THE PROTEINS OF TISSUES OF TUMOR-BEARING RATS. I. AMINO ACID MUSTARDS AND HN2

¹ Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland

The effects of methyl-bis-(2-chloroethyl) amine (HN2) and the nitrogen mustard derivatives of alanine and phenylalanine on the incorporation of amino acids into proteins have been studied using isotopically labeled amino acids in rats bearing the Walker 256 carcinosarcoma. Carcinostatic doses of these compounds were found to produce an inhibition of the incorporation of amino acids into the protein of the tumor. Following administration of the amino acid mustards inhibition was noted only in the tumor, while the administration of HN2 was followed by effects on amino acid incorporation in a number of nontumor tissues. In the tumor, the mustard derivatives of alanine and phenylalanine were as effective in inhibition of the incorporation of structurally unrelated amino acids, such as lysine and methionine, as of the corresponding amino acids, alanine and phenylalanine. These observations suggest that these compounds act not as analogue inhibitors but as alkylating agents with altered tissue specificity.

These compounds inhibited the incorporation of amino acids into all of the cellular proteins of the tumor. However, inhibition of amino acid incorporation was found to a greater degree in nuclear proteins than in cytoplasmic proteins, and, in kinetic studies, inhibition occurred earlier in the acid-insoluble proteins of the nucleus than in any other fraction. These observations suggest that the sites of formation of the acid-insoluble proteins of the tumor nucleus are primary sites for the action of these compounds and that the synthesis of these proteins may be of particular importance for the growth process.