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Drug-induced Stimulation of Transport of Hydrolyzed Nitrogen Mustard and Choline by Normal and Leukemic Human Cells in Vitro¹

Department of Medicine, University of Manitoba, and the Manitoba Institute of Cell Biology, Winnipeg, Manitoba, R3E OV9, Canada

The effect of morphine and cocaine on the transport of hydrolyzed nitrogen mustard (HN2-OH) and choline by peripheral blood cells of normal subjects and patients with chronic lymphocytic leukemia, acute lymphoblastic leukemia, and acute myeloblastic leukemia was determined. Transport of HN2-OH by lymphocytes from normal individuals and patients with chronic lymphocytic leukemia was stimulated by morphine and cocaine and, in each case, the effect was statistically significant (p < 0.05 or greater). However, choline transport by normal lymphocytes was not altered by cocaine and was only slightly stimulated by morphine; choline transport by lymphocytes from patients with chronic lymphocytic leukemia was not stimulated by either morphine or cocaine.

HN2-OH and choline transport by cells from patients with either acute lymphoblastic or myeloblastic leukemia was stimulated to a comparable degree by both drugs. Stimulation of HN2-OH transport by morphine and cocaine was greater in normal lymphocytes than in acute leukemic cells and the differences were highly significant (p < 0.001). Conversely, stimulation of choline transport was more marked in acute leukemic cells than in normal lymphocytes, and these differences were also highly significant (p < 0.001). It was previously shown that transport of nitrogen mustard by normal and leukemic human cells was biphasic in nature, consisting of a choline-independent component at "high" drug concentrations and a choline-dependent system at "low" substrate concentrations. The preferential stimulation of the low-dose, choline-dependent system by morphine and cocaine in acute leukemic cells relative to that observed in normal lymphocytes suggests a possible mechanism of increasing the therapeutic index of nitrogen mustard.

¹ This work was supported by a grant from the National Cancer Institute of Canada.

² Clinical Research Associate of the National Cancer Institute of Canada.

Received 7/14/75. Accepted 11/21/75.