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Synergistic Antileukemic Effect of Theophylline and 1,3-Bis(2-chloroethyl)-1-nitrosourea¹

Clinical Investigations Branch, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20205 [W. D. D.], and Section of Medical Oncology, Department of Medicine, Northwestern University School of Medicine, Chicago, Illinois 60611 [S. H. B.]

A series of experiments evaluated the antileukemic effect of an agent which elevates cellular cyclic adenosine 3':5'-monophosphate levels by inhibiting phosphodiesterase. When administered alone, theophylline had only modest antileukemic effects, but it had synergistic effects when administered with 1,3-bis(2-chloroethyl)-1-nitrosourea. This synergism produced an improved therapeutic index in a dose-response study and in a comparison between antileukemic effects and effects on white blood cell nadirs. Uptake of 1,3-bis(2-chloroethyl)-1-nitrosourea and studies of timing of treatment support the hypothesis that elevation of cyclic adenosine 3':5'-monophosphate levels is the mechanism of the observed synergistic effect.

¹ Supported by USPHS Grants CA15145 and CA17145 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Landow Building, Room 8C17, National Cancer Institute, Bethesda, Md. 20205.

Received 8/31/78. Accepted 4/ 3/80.