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Methods for studying the in vivo incorporation of radioactive amino acids by leukocytes are described. The incorporation of S35 L-cystine into normal and leukemic leukocytes was studied and compared with the utilization of S35 L-methionine, S35 sodium sulfate, and C14 sodium formate. Radioactive L-cystine is rapidly absorbed and rapidly incorporated into the proteins of leukocytes. There are distinctive differences in rates and levels of utilization of S35 L-cystine by normal leukocytes and by leukocytes of acute and chronic leukemia. The leukocytes of acute leukemia and of chronic myeloid leukemia have a greater avidity for L-cystine than normal leukocytes. This rapid utilization of an amino acid by immature leukocytes is not limited to L-cystine and is probably a manifestations of the rapid metabolic turnover characteristic of immature cells in general. However, in view of the observations on the specificity of L-cysteine and related compounds in modifying the leukotoxic effects of nitrogen mustard, the avidity of immature leukocytes for L-cystine may have greater significance than the utilization of other metabolites. The data indicate that the life span of normal leukocytes is approximately 13 days. The life span of leukocytes in chronic myeloid leukemia is slightly less than that of normal leukocytes whereas the life span of acute leukemic leukocytes is much shorter than that of normal leukocytes. The life span of lymphocytes in chronic lymphatic leukemia appears to be much longer than that of normal leukocytes. Although L-cystine and L-methionine are readily utilized its acute leukemia, there is marked impairment in the utilization of sodium sulfate in vivo. By comparison, normal leukocytes readily utilize sodium sulfate in vivo. This discrepancy may be due to the rapid turnover of sulfur in acute leukemia or to an intrinsic metabolic defect of acute leukemic leukocytes.

Administration of L-cysteine hydrochloride to animals prior to the injection of nitrogen mustard (HN2) modifies the severe leukopenia characteristically induced by HN2 (1). However, if the L-cysteine hydrochloride is administered after HN2, even immediately, the leukopenia is not modified. It has not been demonstrated whether the effect of L-cysteine depends upon the presence of certain groups or groupings in the molecule or whether it is the result of non-specific chemical inactivation of HN2. Accordingly, the specificity as well as the mechanism of L-cysteine protection was investigated by correlating the chemical structure of related compounds with their ability to prevent HN2-induced leukopenia. METHODSSeveral amino acids and sulfhydryl-containing compounds structurally closely related to cysteine, as well as compounds containing various combinations of functional sulfhydryl, amino and carboxyl groups were investigated. Ascorbic acid was also tested because, like the other compounds, it is a strong reducing agent.In addition to L-cysteine, the compounds investigated were glutathione, D,L-homocysteine, D,L-methionine, L-alanine, D,L-serine, thioglycolic acid, dithiopropanol (BAL), thiomalic acid, thiourea, beta mercapto-ethylamine and ascorbic acid (Table I and Figures 1-4).Except for dithiopropanol (BAL), amounts molecularly equivalent to, or greater than the amounts of L-Cysteine which have been found to be effective in preventing HN,-induced leukopenia in rabbits were used (Table I).Larger amounts of BAL were not used because of their toxicity. Solutions of these substances were adjusted to pH 6.5 to 7.0 with sodium hydroxide and, with the exception of BAL, were injected either intravenously or intraperitoneally. Dithiopropanol (10 per cent solution of BAL in oil) was administered by intramuscular or intraperitoneal injection.