Imatinib

Correspondence from NEJM pointed out by Dr. Ruehlman...

Copyright 2002, Massachusetts Medical Society
N Engl J Med Volume 347:67-68, July 4, 2002
Correspondence

Imatinib and Chronic-Phase Leukemias
Boros, L. G., Cascante, M. Medline Citation To the Editor: Savage and Antman (Feb. 28 issue)¹ summarize the pathogenesis of BCR-ABL positive chronic-phase leukemias that are responsive to imatinib mesylate therapy. The authors point out that the mechanism of the antiproliferative action of imatinib lies in its effective control of BCR-ABL tyrosine kinase activity, thus interfering with the promotion of the phosphorylation of multiple substrates of mitogenic signaling pathways. The precise oncogenic mechanism of BCR-ABL is still unknown.

There are important changes in the metabolic profile of BCR-ABL positive cells after their reversion as a result of imatinib mesylate treatment. Hematopoietic cells transfected with BCR-ABL express the high-affinity GLUT-1 glucose transporter and increase their glucose uptake [~] the metabolic hallmark of their transformation.² This transformation also involves the activation of glucose-metabolizing enzymes, hexokinase type II and glucose-6-phosphate 1-dehydrogenase.³ Imatinib mesylate effectively controls these enzymes, which limits the uptake, phosphorylation, and use of glucose with respect to the synthesis of the nucleic acid precursor ribose as well as of NADP+ by means of the oxidative branch of the pentose cycle.⁴ This effect of imatinib is dose dependent and directed to the kinase activity of BCR-ABL, since negative control cells did not have a similar metabolic profile. The changes in metabolic-enzyme activity are also opposite to those induced by hydroxyurea, a potent inhibitor of DNA and RNA synthesis in patients with chronic myelogenous leukemia.

The control of glucose-substrate flux is an important mechanism of the antiproliferative action of imatinib mesylate and occurs downstream from the genetic and signaling effects of this drug, as described by Savage and Antman. The actions of imatinib on the genome, proteome, and metabolome may be used to identify direct enzyme targets, the inhibition of which would trigger similar metabolic modifications and thus control other cancers.⁵

Laszlo G. Boros, M.D.
Wai-Nang Paul Lee, M.D.
UCLA School of Medicine
Torrance, CA 90502-2910
boros@gcrc.rei.edu

Marta Cascante, Ph.D.
University of Barcelona
08028 Barcelona, Spain

References
1. Savage DG, Antman KH. Imatinib mesylate -- a new oral targeted therapy. N Engl J Med 2002;346:683-693.
2. Bentley J, Walker I, McIntosh E, Whetton AD, Owen-Lynch PJ, Baldwin SA. Glucose transport regulation by p210 Bcr-Abl in a chronic myeloid leukaemia model. Br J Haematol 2001;112:212-215.
3. Osawa H, Sutherland C, Robey RB, Printz RL, Granner DK. Analysis of the signaling pathway involved in the regulation of hexokinase II gene transcription by insulin. J Biol Chem 1996;271:16690-16694.
4. Boren J, Cascante M, Marin S, et al. Gleevec (STI571) influences metabolic enzyme activities and glucose carbon flow toward nucleic acid and fatty acid synthesis in myeloid tumor cells. J Biol Chem 2001;276:37747-37753.
5. Boros LG, Cascante M, Paul Lee W-N. Metabolic profiling of cell growth and death in cancer: applications in drug discovery. Drug Discov Today 2002;7:364-372.

Last update: 8/4/02; 4:38:32 PM.