[Distribution studies of alpha-L-arabinofuranosidase already unstable at pH 7.0 (37 degrees C) in tumor-bearing mice in connection with its possible use to enhance the selectivity of the chemotherapy of malignant tumors].

Abstract

Graffi et al. (1-3) had proposed the use of exogenous enzymes to toxify inactive transport forms of cancerostatic substances. For this purpose, the pH difference between normal tissues and the tumor was to be exploited, which can be essentially increased by the application of glucose and inorganic phosphate (5-7). Earlier studies using alpha-L-arabinofuranosidase obtained from Aspergillus niger have shown that the selectivity of tumor chemotherapy can be increased in this way (4). The alpha-L-arabinofuranosidases known to date are stabile in a wide pH range (9). However, in some moulds we found pH-labile enzymes of this kind that become irreversibly inactivated in the weakly alkaline or neutral pH range (10, 11). Studies on the distribution of the activity of a pH-labile alpha-L-arabinofuranosidase from Glomerella myabana in tumor-bearing mice have shown that this enzyme is rapidly eliminated from the organism, in contrast to the pH-stable alpha-L-arabinofuranosidase from A. niger. Apart from its excretion via kidney and liver, of importance is the inactivation of the enzyme in the normal tissues. The additional application of glucose strongly increased the activity of this enzyme both in the tumor and in normal tissues (12). By injecting alkaline solutions, stronger inactivation in normal tissues than in the tumor was achieved (13). In the present paper, distribution of an alpha-L-arabinofuranosidase from Fusarium species I 50 (11), inactive already at pH 7.0 (37 degrees C), was studied in tumor-bearing mice. The activity of this enzyme could be enriched under various conditions in the tumor, and especially favorable proved to be the additional application of a combination of glucose and inorganic phosphate. Under these conditions, a higher activity than in the tumor was demonstrable only in the kidney, which can possibly be eliminated in larger experimental animals by diuretics or an appropriate alkaline administration. The investigations have shown that the pH-labile alpha-L-arabinofuranosidases, especially those of Fusarium sp., due to their pharmacokinetic behavior are better suited for use in our therapy concept than the hitherto employed enzyme from A. niger. More recently, Tietze (16) has proposed a similar therapy concept, in which also the glucose-increased pH difference between tumor and normal tissue using tumor-own enzymes, exogenous enzymes as well as transport forms of cancerostatic agents spontaneously hydrolysing under weakly acidic pH conditions is to be exploited.