Enzyme Therapy of Cancer by Max Wolf, M.D. (circa 1936).

Enzyme Therapy of Cancer by Max Wolf, M.D.

Proteolytic enzymes in the treatment of malignant tumors have been used in historical times already.  Long before the discovery of America by Columbus, medicine men of the Indians applied fruits and leaves of the papaya plant to malignant tumors, they used local enzyme therapy empirically.  It was known that fresh papaya fruits favorably influenced inflammations and edemas, that wounds, burns, bruises or infections healed faster and pains subsided sooner, also that malignant tumors responded sometimes to this therapy.

About the  year 1820, Physick  in Philadelphia was the first to use proteolytic enzymes in the form of stomach juice for surface cancer with good results.  In 1836 Schwann  isolated pepsin from stomach juice, in 1871 Purden and in 1888 Douglass  applied the enzyme pepsin to ulcerated cancerous lesions.  At the end of the 19th century the first attempts were made to give pepsin intramuscular and trypsin intravenous.

In the year 1902 the enzyme therapy of cancer received a decided impulse when John Beard  began cancer treatment with enzyme extracts of the pancreas.  His therapeutic successes caused great excitement.

By 1906 he had used trypsin, amylopsin and other unknown enzymes of the pancreas in treating different cancers.  His comprehensive book: The Enzyme treatment of Cancer  stirred up great interest among many scientists and clinicians who soon went about to develop further this therapy and to use it extensively.

Beard, the leading embryologist of his time, concluded from his studies for many years of the embryonal development of animals that during the progressive differentiation of the developing organs undifferentiated polyvalent “sex” cells wander from the trophoblast mainly through the mesoderm within the embryo to their goal of destination, the gonads.

Countless cells of them get stuck on this voyage between somatic cell aggregates. These everywhere dispersed embryonal trophoblast isles remain dormant, according to Beard , and do not multiply during the entire life span of the individual.

However, the one or the other cell can by specific irritants (cancerogens)  start a cell division and thus form a functionless tissue island, a tumor. Indeed, American scientists, like Hayflick, during recent years were able to identify in tissue cultures of the different organs sucr1 scattered cells, about 0.25 to 0.5% of the total, the least number in heart tissues.

They differ morphologically from the other cells by absorbing more dyestuff, but without mutagenic or cancerogenic irritations they remain dormant.  When their mitosis starts, they stain darker than the somatic cells, also typical characteristics of tumor cells appear.  Compared with normal cells, they are potentially immortal, i.e. they multiply without any restraint through hundreds of subcultures while all somatic cells in the cultures age, they lose their ability to further divide and die after not more than 50 mitoses.

Soon physicians all over the world were interested in the theoretical as well as the excellent therapeutic results.  The preparations used consisted mainly of freshly prepared pancreatic extracts (Campbell, Goeth, Duprey, Curtfield, Marsden, Meggit, Cleaves, Shaw­ McKenzie, Little, Bainbridge)

Hald, Pusey  and Blumenthal  reported before that intra-tumoral injections of trypsin would bring about a relatively fast softening of the tumor, with aseptic liquefaction.  However besides the therapeutic successes also side effects of a pyrogenic and toxic nature appeared.

Finally they began to produce pancreas extract industrially for a longer shelf life of the product.  But it was unknown at that time that after a few hours of storing at room temperature the enzyme activity of the liquid extracts was lost.  Their use resulted in a deterioration of therapeutic results obtained and led finally to the fact that the enzyme therapy of cancer was forgotten, or rather fell into hibernation.

Only much later the factors were recognized which ruined the confidence in Beard’s therapeutic development: the instability of the enzyme products, their antigenicity and the impurity of the extracts used that time as well as their contents of pyrogens and toxic admixtures.

When much later it became possible to produce crystalline and pure enzymes, the therapeutic application could be resumed again in larger amounts.  Sumner  crystallized in 1926

Urease, Northrop  in 1930 Pepsin, Northrop  and Kunitz, Trypsin.  Thus it became possible to stabilize the enzymes and to eliminate pyrogens and other toxic substances.

In 1934 in Vienna Freund discovered that in the serum of people or animals free of cancer chemical substances existed which were able to dissolve cancer cells, while the blood of cancer patients was lacking this ability.

Besides that, the Freund- Kaminer  team also found that the serum and urine of cancer patients not only was lacking in cancerolytic property but that cancer cells were even protected by it against dissolution by normal serum and produce a cancer-protection substance in the serum.

If, for instance, to normal serum half the amount of cancer serum is added, the former loses its proteolytic capacity against cancer cells.  Freund  isolated this water-soluble, thermolabile substance from the serum and urine of men and horses free of cancer; he called it “Normal Substance” and used it with partly good results as parenteral therapy on inoperable cancer cases.

Furthermore, this phenomenon  led to the development of the Freund-Kaminer  reaction. This test indicated that the serum of cancer-free people and animals dissolves a large percentage of cancer cells in a fresh cancer suspension {later he used for this test heat-killed necrotic cells) or it changed them markedly.

However, cancer serum hardly affected them, it even protected them against disintegration by normal serum.  Kretz  and Benda  could verify these facts, also Klein  and Lustig. Freund  had found 30 years earlier that cancer serum possesses  these cancer­ protective qualities which are derived from abnormal fatty acids found in the intestinal tract.

His directions to fight the cancer disease by diet {total elimination of animal fats afermentative foods and by elimination, as much as possible, of the abnormal {acid-fast) colibacteria, which live in the colon of cancer patients, by intestinal antiseptics like menthol, or by enemas) are based upon these investigations.

Freund and Lustig showed in 1993 on tar cancers of mice that a cancerophile diet hastens the tumor development and the animals died earlier, while a cancerophobe diet protects 50% of the mice.

On account of the beginning World War, Freund  and Kaminer  were forced to discontinue their activity in Vienna and therefore hadno chance anymore to identify chemically the isolated Normal Substance.  By Christiani  in Vienna it was later identified as a cytolytic enzyme and, independently shortly before, by us (Wolf) as a proteolytic-lypolytic enzyme.

Christiani  worked on the problem of closer examination of the cancerolytic enzymes and could demonstrate that the “normal substance” is in fact a hydrolytic enzyme which he called “solving enzyme”.  He proved 1938 that this solving enzyme is bound to the albumin fractions and is thermolabile.

It is present in the serum and urine of healthy people and animals (horses), but absent in the serum and urine of cancer patients.  Later on Christiani  found in the serum of cancer patients some of the inhibitors of the solving enzyme.

They protect cancer cells against the solving enzyme and are produced by the cancer cells.  Also Freund  knew about such inhibitors which were named “protective substances”. Cholesterol esters, e.g. cholesterol-butyrate or cholesterol-succinate have this protective action and indeed are identical with those formed by the cancer cells.

Christiani  also could show that inhibitors, identified by him, could themselves be inactivated by a number of substances, like oxydation products of ergosterol or the?­ dehydrocholesterol.   Such substances have acidic character.  He called them deactivators. In vitro they were able to prevent the attachment of the inhibitor-the protection of the cancer cell-to the solving enzyme, as well as to free again an already blocked enzyme.

Further investigations proved that the de-activator present in healthy people is bound to the globulin fraction of the serum.  The de-activator is synthesized from ?-dehydrocholesterol by means of the enzyme ergosteroloxydase, which cannot be demonstrated in cancer tissues.

Since then numerous scientists were able to prove that the serum of healthy men and animals is rich in proteolytic, lypolytic and amylolytic enzymes.  Patients with more or less active inflammations or infections have in general a lower enzyme potential, but by far the lowest enzyme content as a rule is found in cancer cases (32,33).

Since in precancerous  and in earliest stages of beginning cancers the enzyme niveau in the serum appears very reduced, it seems most probable that low enzyme values represent a predisposition or condition for the malignant process.  Sometimes the low level is inherited, in some cases it may be caused by chronic infections, damage to the pancreas or other diseases, possibly also faulty nutrition.

Gaschler  et al. determined the proteolytic activity in the serum of a great number of people.  They found that healthy men in general have a high protease index, while this was reduced with sick people, particularly patients with chronic inflammations or infections, also in old age.  The serum of cancer patients, of those with precanceroses and patients who later developed malignancies  showed a significantly decreased proteolytic enzyme level.

The Gaschler  test is very simple.  It is not dependable, but in our experience with over 1000 tests, it gave some valuable information, particularly as a negative exclusion test for malignancies.

It was clinically applied that time to cancer patients with tumors of all different types, even in advanced stages.  With the oral application of his enzyme mixture Gaschler could accomplish only some slight local beneficial effects.  Therefore he confined his therapy exclusively to parenteral application.

In several clinics of the Charita  in Berlin, encouraging results were accomplished. Elevation of general well-being, improved appetite, gain in weight and other subjective improvements were registered.  With a number of patients regressions could be determined.

All these results were taken in consideration during our own developments and experiments.  We developed in numerous animal experiments and trials at the Biological Research Institute in N.Y. individual enzymes and enzyme combinations with and without activators which had selectively a lytic action on cancer cells.

In the experimental groups, on the other hand, the following events could be observed: first the cancer cel s.grew without restraint into all directions, fastest in the direction against the normal tissue.  Almost suddenly the cancer cells stopped growing further.

They changed partly into a spindle shape, also ball-like form, some shriveled, became enucleated and finally dissolved, while the normal tissues showed hardly any influence by the enzymes added to the cultures.  They rather pushed back the front rows of the tumor cells. The cell damages were much more pronounced than those seen in damage to normal tissues observed in the controls.

These characteristic pictures of cell cultures show the reaction of normal and malignant cells under influence by proteolytic enzymes.  While fibroblasts remain uninfluenced, cancer tissue undergoes lysis after a short period of time.

The enzymes tested in these experimental groups were solutions of trypsin, chymotrypsin, plasmin, kathepsin, pepsin, liver catalase, papain, ficin, bromelin, and enzyme extracts of lens esculenta, pisum sativum, aspergillus oryzae, spleen, thymus (mainly nucleases), liver and primarily the enzyme combination finally determined by us as optimal.*

During our investigation it was necessary to develop new tests for assaying the proteolytic and fibrinolytic activity in body fluids.  The specificity and sensibility of the plate tests were not high enough (methods after Astrup and Mullertz ).

In extensive animal experiments on rats we tested the proteolytic activity of the serum after taking the proteolytic enzymes mixture.  It was given to the animals in gradually increasing amounts orally, intramuscular, intraperitoneal or by rectum.  After 90 minutes the proteolytic activity of the serum was determined by the plate method mentioned.  A significant relation between the proteolytic potential and the concentration of the enzyme mixture given was shown.

Some authors discuss the importance of general membrane defects in cancer. (Hoelzi-Wallach ).  They distinguish between:

  1. plasma membrane (cell contact, cell surface, immunological changes),
  2. mitochondrial membrane (protein and lipid synthesis),
  3. lysosomal membrane,
  4. nuclear membrane and
  5. the endoplasmatic reticulum, responsible for enzymatic changes and enzyme biosynthesis

It concluded that the membrane hypothesis of tumors postulates that an oncogenic agent acts to introduce an inappropriate protein into or through cell membranes-either in replacement of or in addition to normal components.

*Proteolytic enzymes of fractionated hydrolysates of beef pancreas, calf thymus, pisum sativum, lens esculenta, papayotin, mannit.

Sagiroglu  could show in his experiments that in stained malignant tissues many epitheloid cancer cells show smaller or larger membrane defects near the nucleus. Through these tears the cytoplasma leaked out producing the picture of a “nucleus halo” after staining. Such damages of the cell membrane of malignant cells could give a natural explanation for their selective destruction by enzymes.

Exact observations of the cancer cells made it probable  that their cell membrane, in contrast  to that of fibroblasts and other normal cells, is permeable for the proteolytic and lypolytic enzymes in our mixture. Thus the catabolic  enzymes penetrate into the inner cell and are able to dissolve the cytoplasma.

The fact that normal cells are more protected against lysis than cancer cells through enzyme inhibitors certainly also plays a part. But since the enzyme mixture used by us contains also lipolytic enzymes against which no inhibitors have been found so far, the cancer cell membrane seems to be insufficiently protected against these enzymes; a factor which therapeutically is very important.

All cell membranes consist mainly of phospholipids and mucopolysaccharides.  They cannot normally be attacked by the specific enzymes present in small concentration in the blood, since no sufficiently wide pores exist which would allow the entrance of the macromolecules of the enzyme.

The protective cell wall becomes, however, penetrable for lytic enzymes when marked irritations lead to cell damages or to necrobiotic or necrotic processes.  In such cases the penetration succeeds easily, also enzymes are set free from the lysosomes, thus bringing about an endogenous lysis.

Electron microscopic and isotopic investigations showed that catabolic  enzymes penetrate also through membranes  of malignant cells.  Possibly this is brought about by the fact that the cell membrane  shows defects and that it is incomplete during the rapid mitosis.

In further comprehensive experiments we investigated the effects of the enzyme combination besides in vitro tests, upon the different tumor implants, in rats and mice on chemically induced rat tumors and on spontaneous mamma carcinomas of dogs. The preparation Carzodelan®  of Gaschler was part of in the investigations.

In both cases definite significant damages of the cancer cells could be demonstrated without influencing normal tissues.

The de-activator is present in all tissues except the thymus.  With cancer patients this de­ activator is not found in the tumor and in tumor-bearing organs, but in tumor-free organs in the form of a lactone.  In this form it cannot de-activate the applied protective substance (inhibitor); it is biologically inert.

In the solid Ehrlich- carcinoma of the mouse, after intratumoral injection of Carzodelan® or of our mixtures, statistically significant tumor regression took place.  The tumors partly ulcerated or necrotized, in other cases a partial shrinking in size appeared.  Later on the disease process lead to death but the prolongation of life was significant

During the examination of calf pancreas extract it was found that pure trypsin and chymotrypsin are to a great extent inhibited by the cancer serum, but their inhibition is blocked or is absent if amylases and lipase, but also certain other substances of the pancreas extraction are present.

The cytolytic  effect of our enzyme  mixture was demonstrated by animal experiments of several investigators. The enzymes administered via various  routes to hamsters  with cheek pouches of hetero-transplantable human tumors showed this anti tumor effect (Goldenberg , personal communications).

One interesting model for the selective  effect of proteolytic  enzymes  upon tumor cells is the spontaneous mamma  adenoma of the sprague-Dawly rat.  In all female animals of this certain strain a spontaneous fibroadenoma resp. adenofibroma develops in advancing age. These tumors develop  subcutaneously and can grow into all regions  of the body.

They may reach a size twice the size of the whole rat.  If the proteases  are injected intratumorally in these rats, necrosis resp. liquefication  of the tumor takes place till the entire tumor has disappeared.  With tumors  up to the size of a hens egg, these results are always reproducible, with tumors beyond the size of a man’s fist the success  is not always constant.

As an explanation it may be mentioned that the tumor necrotises rapidly in rats and the death of the rat is caused  by the overwhelming floodings  of the organism  with the catabolic products of the tumor.

It is remarkable that the enzyme activity stops causing  necroses  as soon as all tumor tissue is dissolved, the surrounding healthy tissues (connective and muscular  tissues) are not affected.  Also the necrotized skin over the tumor heals during enzyme therapy  without complications.  Mostly not even noticeable scar tissue remains  (Weigelt )

Especially  clearly the protective effect of the enzyme mixture  can be shown with the sarcoma  180 of the mouse.   Tl1is sarcoma  has a taking rate of over 95%.   But in mice which received  4 days before  and during transplantation 5 mg of the enzyme mixture, in only 20% of the animals  tumors  were formed.

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