The Newer Nitrogen Mustards in the Treatment of Leukemia

Abstract

Since the discovery by Gilman, Goodman, Lindskog, and Dougherty (1) of the chemotherapeutic effect of the nitrogen mustards on lymphosarcoma, and their application to the treatment of Hodgkin's disease by Jacobson (2), these agents have been widely used in the treatment of leukemia and the lymphomas (3-7). Because the effect of the nitrogen mustards originally employed in the therapy of neoplastic disease, although definite, was only palliative, a search for related compounds which might exert a more beneficial and more prolonged effect was instituted. In the studies of cancer chemotherapy at the Sloan-Kettering Institute certain nitrogen mustard derivatives have been shown to be effective in prolonging the survival time of mice with transmitted leukemia (8). One of these derivatives has now been examined extensively for its therapeutic value against leukemia in man, and the results are herewith reported. This new nitrogen mustard derivative, 1:3 propane diamine N N N′ N′ tetrakis-(2-chloroethyl)dihydrochloride, more commonly known as SK 136, is of about the same order of toxicity as methyl bis(2chloroethyl)amine hydrochloride, the more widely used nitrogen mustard known as HN2, in that the leukotoxic and LD50 doses were approximately the same in mice and in larger animals. It was noted, however, in rats, that with SK 136 convulsions were produced by smaller multiples of the lethal dose than with HN2. When given clincally in a dosage of 0.1 mg. per kilogram of body weight daily for four to eight doses, SK 136 usually caused much less nausea and vomiting than did HN2, but a slight degree of dizziness was experienced by most patients. This relative lack of nausea and vomiting seemed to be particularly noticeable with cases of chronic myelogenous leukemia, whereas patients with Hodgkin's disease occasionally had as much or more nausea and vomiting than they did with HN2. The dizziness generally was not severe and disappeared in one to twenty-four hours after injection. An occasional patient complained of nervousness and bad dreams following the injections, but no true hallucinations of toxic psychoses were noted. As with HN2, leukopenia and thrombocytopenia were occasionally noted. In contrast to HN2, in which increase of the amount given in a single injection to 0.2 mg. per kilogram of body weight caused no marked increase in the nausea and vomiting, doubling the dose of SK 136 caused the appearance of nausea and vomiting and severe dizziness. A closely allied derivarive, SK 137, 1:3 propane diamine-2-chloro N N N′ N′ tetrakis (2-chloroethyl) dihydrochloride, in which a chlorine was substituted for a hydrogen in the 2-position of the propane moiety, was also tested clinically. The chemotherapeutic activity of the two drugs appeared to be approximately equal, but the appearance of occasional transient toxic psychoses of twelve to seventy-two hours' duration with SK 137 caused its use to be discontinued.