Antineoplastic Activity of Highly Purified Bacterial Glutaminases

Abstract

SEVERAL lines of evidence motivated the treatment of neoplasms by glutaminase to cause glutamine deprivation. Certain tumour cells grown in tissue culture require glutamine at a level which is tenfold or greater than that of any other amino-acid^1,2. Glutamine participates in a wide variety of metabolic reactions in mammalian cells³. It has been suggested that one of the important functions of glutamine in the metabolism of certain tumours may be as a direct precursor of glutamic acid, which can then furnish the carbon for the partial operation of the tricarboxylic acid cycle from α-ketoglutarate to oxaloacetate⁴. Compared with other tissues, certain tumour cells seem to operate at a marginal level of glutamine availability because of slow synthesis⁵ and rapid utilization⁴. The glutamine antagonists, azaserine and 6-diazo-5-oxonorleucine (DON) have been shown to possess moderate antineoplastic activity, which may be enhanced by L-asparaginase^6–8. Greenberg et al.⁹ reported that a glutaminase-asparaginase preparation with a relatively high glutamine K_m (7 × 10⁻³M) decreased the initial rate of growth of a number of tumours, including an Ehrlich ascites carcinoma, but caused no significant increase in the survival time of tumour-bearing animals. In this study, more intensive therapy with three extensively purified glutaminase preparations with considerably lower K_m values resulted in marked inhibition of an Ehrlich ascites carcinoma and significant increases in the survival time of tumour-bearing animals.