CA: A Cancer Journal for Clinicians, Vol 23, 220-227, Copyright
© 1973 by American Cancer Society
L-Asparaginase for the Treatment of Cancer
Kenneth B. McCredie M.D.1,
Dah Hsi Wang Ho Ph.D.2, and
Emil J. Freireich M.D.3
1 Assistant Professor of Medicine and Assistant Internist, Developmental Therapeutics, University of Texas, M.D. Anderson Hospital and Tumor Institute at Houston, Houston, Texas.
2 Associate Professor of Biochemical Pharmacology, University of Texas, Houston, Texas.
3 Professor of Medicine, University of Texas, Houston, Texas.
The unique properties of L-asparaginase, including the ability to block incorporation of the nonessential amino acid L-asparagine into cancer cells, has made this agent a particularly exciting drug.
It is possible that depletion of L-asparagine from L-asparagine-dependent cells of patients could be enhanced by hemodialysis. Preliminary studies have shown that hemodialysis removed a large amount of L-asparagine, but homeostatic mechanisms prevented a decrease of L-asparagine in the plasma. Dietary deprivation of L-asparagine is another approach; L-asparagine is in the amino acid constituent of vegetables, fruits and most proteins. Since the deprivation of folic acid from the diet was not as successful as one would have hoped, L-asparagine deprivation may not be practical. L-asparagine analogs, 5-diazo-4-oxo-L-norvaline and 5-chloro-4-oxo-L-norvaline are effective inhibitors of asparagine synthetase, and the analogs of cofactors of asparagine synthetase might also be useful. L-glutamine is required for the biosynthesis of L-asparagine, and the analogs of glutamine, such as azaserine and 6-diazo-5-oxo-L-norleucine, were found to be the inhibitor of asparagine synthetase and were synergistic against tumors in experimental systems. The clinical trial of a combination of L-asparaginase and azaserine has been reported however, further studies are required to prove that combination therapy is significantly superior to L-asparaginase used alone.
The rapid development of resistance and its toxic side effects have limited use to single courses of L-asparaginase alone or in combination with other agents. The investigation of other enzymes with similar characteristics but with less toxic side effects may prove useful for the control of cancer.
