Whether one accepts, on the basis of the survey just made, the view that alterations in enzyme activities are directly or indirectly connected with the development, establishment and progress of malignancy or not, in any case one should consider the possibilities of how such activity levels can be influenced under in vivo conditions by various means or agents (cf. reference 248), then assess the ensuing biological effects, if any, and finally retrace one's steps back to the basic thesis of this monograph, that of metabolic and enzymic abnormalities as a cause or a characteristic of cancer. There exist four main ways leading theoretically in a predesigned manner to an alteration of enzymic activities which could involve EFS, or holo-, apo-, co-enzymes and metal activators, or substrates or products. The four ways are: (i) Enzyme adaptation and induction; (ii) metabolic antagonism and inhibition; (iii) restitution and replacement; (iv) increase of catabolism or degradation. Looking at these processes in turn one finds the following:

1. Adaptation and Induction

In difference to adaptation of a biological system in response to environmental changes in a general sense, metabolic adaptation rests on changes in enzyme biosynthesis, mainly induced by the corresponding substrate or a related inductor. This phenomenon has been observed in many instances in microbiological systems 182 but much less frequently in animals and man. However, reports have been accumulating which were admirably reviewed by Knox et a'.148 These authors came to the conclusion that changes in the concentration or activity levels of extra- or intra-cellular enzymes in animals can be brought about by a great variety of agents and conditions. In addition to substrates, a number of hormones have been found which in most cases increase certain enzymes, while changes of functional proteins generally, either up or down, may depend on diet and age. The latter condition could have an important bearing on the cancer problem. The questions arise whether the active agents produce their effects on their own or in combination with what may be called co-inducers, forming 'organizers,'182 and whether this affects enzyme forming systems (EFS). Work in the microbiological field, as carried out by various laboratories (cf. reference 175), has provided evidence that the biosynthetic systems together with small-molecular inducers and suppressors are involved. This includes, therefore, also those cases in which not stimulation but suppression has been noted, such as demonstrated by Gorini and Maas 107 with arginine, acting as a suppressor of its own synthesis, or by Yates and Pardee 288-269 with uracil in E. colt hindering the de novo formation of uridylic acid, although this might be caused by negative feedback, as pointed out by Potter.199 If so, these examples should come under the heading of inhibitors (see below). There remains another point to be settled, namely whether these changes in enzyme activity levels could be due to liberation of inactive conjugated enzymes or the binding of active ones (see catalase) or even to a sudden outpour or disappearance of co-factors.

Here are a few illustrations from studies in mammals: Feigelson et al.90 claimed an increase of liver xanthine oxidase (-f- 44%) and adenosine deaminase (+ 85%) in mice after short-term administration of xanthine. It is of some importance in this connection to recall the observation by Haddow (see Bergel et al.29) that in long-term experiments xanthine injected in larger amounts into the rat, gave rise to granulomas of which a proportion developed into malignant sarcomas. Increases in β-galactosidase in the dog pancreas or arginase in rat liver, as quoted by Knox et al., have to be further examined as to their being true adaptation phenomena or due to other circumstances. But there seems to be little doubt that tryptophane acts as an inducer for tryptophane peroxidase in the rat liver (+ 450%) ,147 149 a finding which was recently confirmed by Auerbach and Waisman 16 for the healthy liver adjacent to a Novikoff hepatoma which itself did not respond at all to this adaptive process. One can therefore deduce that the tumor had lost its EFS, or at least its co-inducer. Referring to the effects of hormones, androgens, such as testosterone, increase beta-glucuronidase activity in the kidney of male mice according to Fishman and Lipkind,97 and estrogens do the same with serine aldolase in the uteri of castrated female rats.187 A claim which deserves attention, although further studies have to confirm it, was made by Barnard and Danielli.24 It followed an investigation of Hebborn and Danielli128 on the reactivation of acylated N,N-di- (2-chloro-ethyl) -p-phenylenediamine and -p-aminophenol and attempts to link cancer chemotherapy to an adaptive process. When a course of injections of an inert phenylurethane was given to rats carrying the Walker carcinoma 256 prior to their treatment with the corresponding p-mustard derivative, the anti-tumor effects were more pronounced than with the phenylurethane mustard alone. The authors concluded from these results that a latent mustard derivative could be activated in vivo by enzymic degradation, with liberation of the cytotoxic moiety, and that this was due to an induced formation of an enzyme, specific in the case described for the removal of the urethane portion.

At this moment the question remains open: can alterations of enzyme activity levels, differing in neoplasms from those in healthy tissues, be brought about by agents and processes of adaptation (induction or suppression) and, if so, effect a 'normalization' of certain metabolic irregularities?