Just as nutritional deficiencies which in the long run reflect unfavorably on metabolic and hence enzymic events in the body have been treated with vitamins, amino-acids, etc., and, as just noted, with metals, and hormonal imbalances with hormones, such as insulin, thyroxine, tri-iodothyronine, estrogens, androgens, progesterones, pituitary preparations, corticosteroids, and so forth, the question arises whether cells suffering from a permanent insufficiency of enzymes or their co-factors could be, so to speak, nursed back to a more normal state by providing them with either holo-, apo-, coenzymes or model systems with a specific enzymic activity. t does not necessarily mean that with a tumor cell one should expect to convert this pathological cell into a completely healthy one. As in the case of insulin versus diabetes, where dietary controls and maintenance doses of the hormone have to be applied during the whole life time of a diabetic individual, it would be a major achievement to keep the neoplasm under control and, if inoperable, to live with it. This might be a status, so it is believed, acceptable to the clinician and the patient, as long as the growth of the cancer, its spreading and dissemination or the formation of metastases are stopped during the period of prolonged replacement therapy. Enzymes have been employed clinically, as discussed by Richterich 218 in his interesting book on enzymopathology, and from time to time reports, particularly on the use of proteolytic enzymes and a bacterial DNase on patients, have appeared in the medical literature. So far no reliable practical experiences in the treatment of cancer have been reported. Yet it is just this group of pathological states which requires urgently new and further trials. It was mentioned above that many tumors on biochemical analysis showed a lack of catabolic enzymes in nucleic acid metabolism and of anabolic enzymes in carbohydrate-energy processes. Both deficiencies led to a permanent 'misuse' of metabolic intermediates and end-products, such as an irrepressible DNA-synthesis and carbohydrate breakdown coupled with decreased glycogen storage, hence to a relatively high rate of growth and cell division and an increasing de-differentiation. Replacement therapy could, therefore, provide catabolic catalysts where catabolism is blocked and where there is too much of a tendency for building units to be polymerized to macromolecules, or anabolic catalysts when anabol-ism is hindered and degradative processes manufacture excess of energy, misdirected towards abnormal biological events.

The use of purified or crystalline enzyme preparations for such restitution therapy may, of course, come up against a number of serious difficulties. First, there is the problem of availability of sufficient quantities for prolonged courses of treatment, and if these preparations derive from a different species (bovine, equine, bacterial, fungal), the question of immunological compatibility comes to the fore. But even if all this could be straightened out, there remains the problem of transport to the cell and the often active, enzyme-catalysed, transport into the cell. With regard to the former, a number of materials are diverted to the liver or to the kidney and, treated as an interloper, excreted in a conjugated or degraded form. As to the latter, the study of permeability of the cell membrane and perhaps the nuclear membrane has occupied the minds and hands of many workers in cytology. While heavily charged compounds will react mainly with the cell surface, the penetration of oligo- and macro-molecules into the cell interior is still a subject of speculation and research.49-5177 Most of the enzymes of relevance to the subject under discussion have considerable molecular weights and could perhaps enter the cell by a process of pinocytosis. It is at present largely a matter of guesswork, whether at least some of the tumor cells, which under the microscope frequently show pseu-dopod formation, behave like amoebae and are capable of swallowing big chunks of proteins. Under any circumstances, unless one deals with a specific coenzyme deficiency, it would be much better from every point of view—availability, compatibility and permeability—to look for model systems which, simple in themselves, would under biological conditions act like the enzyme to be restituted. In other words a more intensive search should be made for synthetic biocatalystswhich ought to exert a specific activity and stimulate desirable reactions with a rate comparable to that of the corresponding natural enzyme.

*This includes, in the long run, also attempts at 'repairing' the RNA-containing EFS and the faulty DNA, an approach which is outside the scope of this monograph (see chapter Conclusions and Outlook).

4. Postulate for Increase of Catabolism

All these considerations apply also to attempts at fortifying or boosting catabolic processes in the cell or perhaps in the intercellular fluid, full with substances and material to be taken up by the cell for its survival, of substrates on which the tumor depends slightly or decidedly more than normal tissues or the healthy parts of the tumor-bearing host. It has been noted before that neoplastic or leukemic cells can have a greater avidity for, say, glutamine,217 cysteine/cystine 262 or for starting materials or intermediates in nucleic acid syntheses. It is a fact that such dependence on building units could be and is disturbed by antimetabolites and inhibitors, as discussed in a preceding sub-chapter. But it should be practically feasible to introduce into the neoplastic tissues, enzymes or model systems which would destroy a compound, more essential for the tumor, either before it penetrates the abnormal cell or after it has joined the pool in the cytoplasm or nucleus. Relatively little is known about such possibilities, but if one looks at ribonuclease as a catabolising enzyme and at cysteine desulfhydrase as an enzyme which could diminish the availability of this amino-acid for the formation of glutathione and sulfhydryl compounds, that is cysteine containing functional proteins, it rests with experimental results whether this postulate is sound or not. A number of results are given in the following chapter which, with its examples, provides some illustration of what was said particularly under the heading of the last two sub-chapters. It must be remembered however that this field is a relatively new one and that most of the findings are of a preliminary nature. Nevertheless, provocative speculation and working hypotheses have never done any harm. If not producing straightforward answers through experimentation based on them, they have opened up at least new vistas.