Experimental Chemotherapy Studies. Iv. the Protective Action of Mercaptoalkylamines against Alkylating Agents.

SUMMARY The protective action of mercaptoalkylamines has been examined. Anticipated protection against HN2 has been observed, l-mercapto-2-aminobutane being slightly more effective than cysteamine. Protection failed in the case of L-phenylalanine mustard and chloroquine mustard, but significant post-protection was obtained with Cytoxan. Results obtained with various combinations of intraperitoneal and sub cutaneous administration showed equal effectiveness, arguing against a generalized direct reaction between the thiol compound and the alkylating agent. The data for Cytoxan also suggest that protection involves specific interactions at sensitive sites. It was also shown that the protection of the host was accompanied by potentiation of the anti-leukemic activity of the HN2 and that this effect was not significantly altered by the subcutaneous administration of l-mercapto-2-aminobutane (MAB). The quantitative results strongly suggest preferential destruction of tumor cells after administration of MAB, as compared with HN2 doses which produce equivalent lethality to the host. The effectiveness of chloroquine mustard against L1210 was not increased by pre-administration of MAB, whereas the MAB effects on Cytoxan activity were equivocal. Similarly, MAB protection produced much smaller effects on N-mustard activity when tested against the HN2-sensitive Gardner lymphosarcoma. The protective action of cysteamine (MEA)1 and other aminosulfhydryl compounds (e.g., S-AET, cysteine) against nitrogen mustard and other N-bis(|3-chloro-ethyl) alkylating agents is now well established (2, 4, 14, 25). Our purpose in this study was to examine this protective action in greater detail and to investigate the extent to which it could be used to potentiate the chemo-therapeutic action of alkylating agents. The first portion of this study deals with the effects of MEA and, in par-Grant CY-5295-C1. 1The following abbreviations have been used in this paper: MEA, l-mercapto-2-aminoethane MAB, l-mercapto-2-aminobutane AET, 2-aminoethylisothiouronium bromide HN2, methyl-N-bis (/3-chloroethy lamine) PAM,p-(bis-(/3-chloroethyl)amino)-L-phenylalanine (L-phenyl alanine mustard) CTX, cyclophosphoamide mustard (Cytoxan or endoxan) CQM,