DIVISION OF MICROBIOLOGY: L‐ASPARAGINASE: THE EVOLUTION OF A NEW TUMOR INHIBITORY AGENT*

Abstract

All accounts of the finding that L-asparaginases have tumor inhibitory properties must begin in the same way: with the observations of Kidd, r eported in 1953, that when normal guinea pig serum is injected into mice and rats bearing certain transplanted lymphomas a striking regression, even of established tumors, was produced.1,a This significant discovery was made during the course of studies in which the serum was used as a source of complement in an attempt to enhance the activity of heterologous antiserum made against the tumor. The combination of guinea pig serum and antibody was highly effective, but a strong tumor inhibitory activity was found in controls given guinea pig serum alone. From this beginning Kidd established a number of fundamental points about the activity of guinea pig serum which, although now subjected to reexamination on a larger scale, remain essentially unmodified. First, he showed that tumor inhibition was produced only by guinea pig serum; s e r a of several other species, namely, the horse, the rabbit, and the human, were without effect. Secondly, he showed that although three different lymphomas, 6C3HED and Lorenz's Lymphoma 2 in mice, and the Murphy-Sturm lymphosarcoma of rats were highly sensitive, and with the first two complete regression of large established tumors could be regularly obtained, others were totally insensitive. Indeed, later work with 20 different lymphomas, most of them recently induced, did not reveal a single sensitive line.3 Thirdly, it was found that animals treated with guinea pig serum in doses which completely inhibited their tumors, o r even over prolonged periods with larger amounts, were not made toxic. The animals appeared in every way normal, and gross and microscopic examination of their tissues revealed no pathological changes.Because of the way in which the discovery was made and because at f i r s t it appeared that only long transplanted tumors were sensitive, guinea pig serum was generally thought to act through its high complementary activity, in augmenting an immunological reaction between the host and the implanted tumor, Kidd, I believe, was never convinced of this explanation and a number of findings were hard to reconcile with it.

L-Asparagine degradation in saccharomyces cerevisiae: Genetic control and biochemical properties of yeast L-asparaginase

“…Interest in asparaginases was stimulated when it was found to be the tumor-suppressing agent in guinea pig serum (2, 6~ 7, 8,10,14,63,113). …”

“…Many types of malignant cells have been shown to be deficient in the enzyme asparag:i.n.e synthetase, which, in mammalian t.:ells, catalyzes the synthesis of asparagine from aspartate and glutamine (10,12,40,86,87,92). To grow, the deficient cells require as exogenous supply of asparagine (35,85,110).…”

Overview on L-Asparaginase

“…[30] suggests thst by measuring the L-aspartic acid, after separating it from L-asparaginses by paper electrophoresis or by chromatograpgy on ion exchange paper, greater sensistivity can be achieved. Although the method provides good reproducibility results are inconsistent from different labs with the same sample.…”

“…The major advantage of fungal asparaginase over bacterial asparaginase is the existence of a mechanism called nitrogen catabolic repression which represses the synthesis of unneeded catabolic enzyme during enzyme production. [29,30] Fungal sources were found to produce higher enzyme yield with submerged fermentation.…”

Glutamate Oxidation in 6C3HED Lymphoma: Effects of L-Asparaginase on Sensitive and Resistant Lines

“…The resulting deficiency is ultimately seen as a general reduction of macromolecular syntheses (3)(4)(5)(6). However, asparaginase has diverse effects that may not be completely explained on this basis: cells lacking asparagine synthetase, when cultured in asparagine-deficient tissue culture media, show a marked delay in proliferation, but do not die (7); asparaginase inhibits lectin-induced blast transformation of lymphocytes, and addition of exogenous asparagine does not prevent this effect (5,8); asparaginase has immunosuppressive properties that are not consistently reversed by asparagine (4,5); tumor cells in culture show marked cytotoxic changes within an hour of exposure to asparaginase (9), and it seems unlikely that deprivation of asparagine alone would have such a rapid effect on cell structure; asparaginase delays mitotic events in regenerating rat liver, a tissue in which asparagine synthetase deficiency has not been demonstrated (10).…”