Some effects of two drugs on lysosomal enzymes and their potential value as antimetastatic agents in the treatment of cancer

Abstract

The case for the involvement of lysosomal enzymes in the metastatic spread of cancer has been examined. A study of the effects of two potentially inhibitory compounds on a selection of these enzymes has been made both in vivo and in vitro. The two compounds, glucosaccharo-1,4-lactone (GSL) and the sodium salt of 1-(3-benzamino-4-methylbenzamido)-naphthalene-4,6,8-trisulphonic acid (Suramin), have been tested for their effects on hydrolytic lysosomal enzymes. GSL is a very powerful and specific inhibitor of beta-glucuronidase (BGD), (E.C.3.2.1.31): The Ki of this inhibitor was found to be in the order of 10 to 10 M, depending on the enzyme source. Suramin, though a less powerful inhibitor, has been shown to inhibit BGD, acid phosphatase (APT) (E.C.3.1.3.2) and N-acetylneuraminidase (E.C.3.2.1.18), while showing a less marked effect on aryl sulphatase (E.C.3.1.6.1.).

In order to determine the effects of these compounds in vivo, experiments were made to observe the effect of GSL and Suramin on lysosomal enzyme activity and the composition of liver after 24-hour and 4-week administrations. Suramin, which appeared to have the more profound influences on the lysosomal enzymes and which, according to the literature, is metabolically inert, was also tested for its effects on the Ehrlich ascites tumour (EAT) and on involution of the rat uterus. The drug's effect on EAT was dramatic: tumour development was markedly inhibited and levels of BGD, APT and N-acetyl-neuraminidase activity were reduced to those found in normal, healthy animals. The influence of these enzymes on EAT cell surfaces is discussed in relation to surface electrical charges and intercellular binding of malignant cells. The effect of Suramin on rat uterus involution was also marked: the rate of involution was reduced, BGD and APT activities were lowered, and the rate of change found in tissue proteins was modified.

The significance of these findings is discussed and further relevant studies are suggested which might contribute to a clearer understanding of the process of metastasis and to a prediction of the usefulness of these compounds as antimetastatic agents.