The Distribution of Radioactivity in Tissues of the Rat Following the Administration of a Nitrogen Mustard Derivative

Abstract

AMINO ACIDS bearing the "nitrogen mustard" di-(2-chloroethyl)amino-side chain have been found to be effective inhibitors of the Walker carcinoma (Haddow, private communication; cf. Bergel and Stock, 1953). Their biological and chemotherapeutic behaviour is similar to that of other "nitrogen mustards" such-as di-(2-chloroethyl)methylamine itself. But special interest attached to one of these substituted amino acids, p-di-(2-chloroethyl)aminophenylalanine (Bergel and Stock, 1954), because its L-isomer was observed to be more active against the experimental tumour than the D-isomer (Haddow, private communication; cf. Bergel and Stock, 1953;Koller and Veronesi, 1956). This difference indicated that the configuration of the amino acid portion of the molecule might play a part in determining the mode of action of p-di-(2-chloroethyl)aminophenylalanine.The particular activity of the L-isomer, furthermore, suggested the possibility that this compound might influence protein formation or actually be incorporated into proteins. In the present investigation experiments were initially designed to test the occurrence of such incorporation with the aid of p-di-(2-chloroethyl)amino-DL-phenyl[fi-14C]alanine (PAM;Bergel, Burnop and Stock, 1955). In order to obtain precise information as to the origin of the different behaviours of the Dand L-forms it would clearly be desirable to do similar experiments with these forms. Unfortunately, the resolution of the DL-compound has not been achieved with the radioactively-labelled material. However, the work gave information in general on the distribution in the rat of a therapeutically effective nitrogen mustard derivative. MATERIALS AND METHODSAnimals and administration of PAM.-Male Wistar albino rats kept on a standard diet were injected intraperitoneally with PAM either suspended in arachis oil (8 mg./ml.) or as the sodium salt. This was freshly prepared by dissolving the acid in slightly less than the theoretical quantity of NaOH in methanol. The methanol was removed under slightly reduced pressure and NaCl

Hydrolysis and Protein Binding of Melphalan

“…Because the quantification of I11 and IV by HPLC was not performed due to background interference, the chemical nature of unrecovered I remained undetermined. There is evidence that I undergoes extensive alkylation and physical adsorption to plasma proteins (1)(2)(3)(4). Thirty percent of the initial carbon-14 was not extracted from plasma proteins at 37" after 8 hr (Fig.…”