Cellular Cancer Therapy, part 5

Chapter 4        Personal experience with insulin: First experiments

    Dr. Donato Perez Garcia (Sr.) suffered, during many years, from a gastrointestinal disturbance. For his own relief, he experimented with all the medical treatments known at the beginning of this century, without ever having achieved satisfactory results.

    At that tine, Banting and Best had just discovered insulin in Canada and it began to be used quite frequently in the treatment of diabetes mellitus. The pharmaceutical firm that produced it also recommended it for the treatment of obesity and emaciation.

    With the object of putting on weight, Dr. Perez Garcia gave himself daily intramuscular injections; from the first injections his digestion, appetite, and general state of being were sensibly better and he showed a gain in weight. This led him to give himself imprecise doses before each meal, producing hypoglycemias of variable duration and intensity.

    So as to be able to register more precisely the signs and symptoms of hypoglycemia, and to provoke a more intense reaction, he decided to inject a dose of insulin intravenously. His reasoning was that, if milk, which had more proteins, and a heavier molecular weight, could be given intravenously (as he had done with a friend), then insulin could as well, since it had a smaller molecular weight and was made up of only one protein, with 513 amino acids. Thus, in 1926, Dr. Perez Garcia had 10 IU of insulin injected intravenously. He initially felt no strong symptoms, but 20 minutes after the injection began to feel intense asthenia, a clouding of consciousness, hunger and thirst, which got progressively more intense with the passing of tine.

    This experiment led him to think that this had great possibilities for application in therapeutic medicine. If food is better digested and assimilated through the action of insulin, as his gain in weight had shown, then couldn’t it produce the same effect with drugs?

    In order to find an answer to this question, he began to experiment with dogs. He set up a control group and an experimental group. In the experimental group, he injected insulin intravenously and when the effects reached their peak, injected mercury and Neosalvarsan; proceeding then to extract their brains and spinal cords, washing them in isotonic saline solution. In the control group, the dogs were only injected with mercury and Neosalvarsan, without first being injected with insulin. In the experimental group, he found both substances in all of the sacrificed dogs. In the control group, on the other hand, he could not even find traces. With this experiment, he had shown, in 1930, that insulin increases the permeability of the cell membrane. After that, he intensified his research in this area, while treating patients with syphilis nervosa and schizophrenia with this technique.

    Dr. Perez Garcia concluded that if the hemato—encephalic [blood-brain] barrier could be crossed, then a therapeutic technique using insulin could be applied to all kinds of illnesses in which the major problem was getting the remedial drug into the cell interior. This was the basis for our treatment of all virus—produced illnesses and for cancer therapy.

    In the 50 years that followed that experiment, we have treated more than 30,000 patients with all kinds of diseases, with which experience we have come to know the exact moment in which to introduce a given drug into the cell, after it has been duly permeabilized with insulin.

Chapter 5        The Immunology of Cancer

    The possibility that immunological factors influence the development of tumors has been considered since many years ago, but only in the last decade has enough experimental and clinical evidence accumulated to support this point of view. Experimental investigation has revealed the presence of specific tumor antigens in laboratory animals. Given that tumors in animals can be prevented or cured with immunological methods, it is possible that a similar reaction in human cancer can be attributed to several things:

—— The phenomenon of spontaneous regression of the malign tissues has been observed by many investigators. The beginning of recurrences of metastasis after prolonged asymptomatic periods, which can last years, suggests the intervention of some immunological mechanisms in human cancer.

—— The presence of small infiltrations of lymphocytes in the primary tumor and of hystiocytosis in fistular pathways of the regional lymphatic ganglia, associated with good prognosis in cancer patients can be attributed, apparently, to immunological reactions, and

—— The presence of serum antibodies in patients with Burkitt’s cancer and cancer of the colon is indirect evidence of immunological reactions.

    In view of these observations, attempts are being made in immunotherapy and in the specific or inspecific alteration of the metabolism of neoplastic tissues. In a specific form, through the injection of irradiated leuc--ic cells; in an unspecified form, through massive doses of BCG vaccine. We will describe the molecular basis of neoplasias below since it is the foundation of the metabolic treatment which changes the condition of the tumor (the cancerous area) and destroys it.

Tumoral Antigenicity in Man

    The search for antibodies that react specifically to cellular components of the tumor (antigens) is a very complex job. The most common type of analysis in use today is indirect immunofluorescence. This is the exposing of the tumor cells to the tested patient’s own serum. The tumor cells are washed and one can locate the presence of fixed immunoglobin through the addition of an antiimmunoglobin antibody, which has previously been marked with fluorescent colorant like fluorescaine isothiocianate In the malignant melanoma it has been possible to define characteristic antigens with this technique (Norton et al.; Lewis et al., 1969). Studies in melanoma cells, fixed with conventional methods, have revealed the presence of at least one common cytoplasmic antigen, not present in normal skin cells. In this same way, antigens have been described in sarcomas as well (Norton and Nalgreg, 1975).

    Experience has shown that the antigenetic similarities between normal cells and malignant cells are such that the habitual creation of efficient antibodies for the malignant cells by the host cells does not occur. This, of course, does not mean that there is an exact correspondence in the antigens of normal cells and cancerous ones, since in reality there is ample evidence that demonstrates the great difference in antigen structure between them. However, there is no explanation for the lack of immunological response to those tumoral antigens on the part of the host cell. This could he due to the fact that the specific tumoral antigen is not released by the tumoral cells because the host cell is subject to immunological paralysis or because a certain tolerance has been built up. Numerous attempts have been made at magnifying the antigenetic differences between normal coils and malignant cells through the use of immunologically competent cells and through the use of systems of stimulation of the immunological system to determine whether there is tolerance or immunological response (BCG, DPT and other vaccines). However, it should be said that in reality the attempts at using the immunological system in the treatment of malignant tumors in man has not shown very effective results, but when Donation Therapy is used, then a more effective stimulation of the immunological system is obtained.

Chapter 6         Permeabilization

    The cell membrane, according to Danielli and Robertson, is made up of two layers: one of proteins and another formed of lipids, where the lipid layer is the inner of the two. The exterior layer (the protein layer is in close contact with the vascular endothelium and thus with the circulation of the blood) takes in the necessary elements through active and passive diffusion.

    To permeabilize the membrane it is necessary to modify its surface tension, its osmotic pressure, its pH and the concentration of the ions, principally of potassium and sodium (bio—physico—chemical changes), so the elements indispensable to the cell metabolism can pass through.

    To make the cells permeable to drugs it is indispensable to change the osmotic pressure of the blood and of the same cells, as well as the interface tension between them. These two changes will cause modifications of a physico—chemical nature in both the blood and the cells, which will facilitate the absorption of drugs which normally would not be able to be absorbed because they don’t have selective permeability, as is the case with the elements that are necessary for the cells’ normal functioning, in which the permeability is physical.

    The incurability of some diseases is due to the fact that the necessary drugs cannot reach the bloodstream and with it the diseased cells. These, lacking the appropriate conditions for absorbing then, cannot take advantage of their therapeutic effects, and the drugs are therefore normally eliminated.

    Only in certain cases and at slightly elevated doses is it possible to obtain any therapeutic effect, but with the side effect of risking the integrity of the organs through which the drugs have to pass. Therefore, one of the fundamental conditions for achieving a cure in some pathological cases in which habitual therapy has failed, should be permeabilizing the cells to facilitate the absorption of the drug; as well, the specific substances that will least damage cellular life should be chosen and administered in very small doses, or at least in quantities smaller than those used today.

    We believe to have found a way to permeabilize cells through a procedure that the organism itself uses when it finds itself in certain physiological states, using one of its own hormones: insulin. Possibly corroborating this hypothesis, one can observe that diabetics are individuals that have little or no defense against infection, due to the lack of the humoral hormone par excellence. As a result of this deficit, a physico—chemical imbalance in the cells arises which favors the development of pathogenic microbes.

    When an injection of insulin decreases the blood glucose level below half the normal concentration, the blood becomes hypotonic, the acid—base equilibrium breaks down in favor of H+; the blood loses its normal pH, that is, its constant H+/OH- iso—ionia which is an essential condition of life for the protoplasm and even more so than the osmotic isotonicity. These physico—chemical changes affect the cells causing a physico—chemical imbalance which is especially felt in the cell membrane.

    During acute hypoglycemia, the osmotic imbalance makes the cells give up the crystalloids and possibly part of the other substances in its protoplasm; thus an out—going current is formed, though it is not strong enough to make the blood isotonic and it remains hypotonic. This hypotonicity produces abundant sweating which, together with diuresis, helps increase the blood tonicity through the loss of water; this is accompanied by the release of heat, evident from the increased body temperature.

    The disturbance of the physico—chemical balance between blood and cells becomes even more accentuated when the surface tension is reduced because of the increase in temperature. Such physico—chemical modifications work within the cell making it permeable to all of the elements contained in the blood and facilitating the diffusion of normally not easily diffusible substances into the protoplasm. Therefore, any substance in the bloodstream (colloid or crystalloid) tends to pass into the cell protoplasm and does so, forced by a kind of suction which partially re—establishes the disturbed equilibrium. The cellular endosmosis, facilitated by the entrance of drugs in the bloodstream and by the blood’s hypertonicity, happens to a very high degree; the ions carried in the bloodstream, positive and negative, are forced into the cell protoplasm by the law of ionic equilibrium. In the same fashion, the other metabolic phenomena that govern cell life necessarily return part-way back to normal.

    As can be seen, hypoglycemia, disturbing in the described way all the cell constants, facilitated the passage of the medications from the blood to the cell, which normally would not occur.

    Such are the conditions that we have tried to reproduce to obtain a therapeutic effect that otherwise would not be possible. Without the aid of the phenomena of cell diffusion there can be no integral absorption of the medications, nor action against the microbes when they are in the tissue; on the other hand, there would be no favorable metabolic changes for the cell.

    It should be understood that the choice of the appropriate medication, dosage, and moment of application are very important. The conditions in which a cell is found is a state of high absorption, assimilation and physico—chemically able to carry out its metabolic functions should be maximal; only small quantities will then be necessary of both those elements necessary for normal functioning, and for therapeutic substances.

    Graphically we can represent this action by saying that we have made the equivalent of a sponge, whose interstices are in such condition as to be able to harbor new elements that happen to be near.

    We should point out that not only the cells have altered physico—chemical conditions, but the germs themselves, that for their proliferation require physico—chemical constants, seek those places in the organism that offer said constants; this is why we have the Treponema pallidum, for example, that looks for refuge in the nervous centers where it finds very favorable conditions that fulfill its requirements for proliferation, and where it can persist during an almost indefinite time, since the action of the medications cannot take effect because of insuperable barriers to their arrival in the cell.

    This protected environment where the microbes or viruses live has also been modified and has felt intensely the effect of the physico—chemical phenomena and, as a direct consequence, the microbes are in an unfavorable situation which can probably cause their death.

    We should remember how difficult it is to cultivate microbes or viruses when the conditions of the environment are not fixed, because of their extreme sensitivity. If the physico—chemical environment of the microbes has been modified (surface tension, osmotic pressure, isoelectric state, pH, etc.) these microbes have less resistance and are in precarious living conditions.

    After the hypoglycemia that so threatened their lives, the cells are ready to re—establish their equilibrium, which will depend on the substances that the blood contains; this is the most opportune moment for adapting them to a new way of life. This problem, of vital importance, should he resolved within a few seconds, it demands efficiency and rapidity, since otherwise there is the danger of general cytolysis.

    It is necessary, to give the cells the substances that their lives depend on in these few seconds; with these the production of cell energy continues, osmotic pressure is re—established in the blood and the cell, the protoplasmic molecules return to their normal situations, the respiratory functions become normal and, consequently, so does the cell temperature; in this same way, the isoelectric point is re—established and all Of the physico—chemical functions return to normal.

    At this moment the ideal would be to satisfy the cell’s physiological needs, and at the same time have them absorb the specific medication to be administered. When this can be done consistently, one of the major problems of therapy will be solved.

    With these studies we have managed to fulfill all of the necessary requirements for taking advantage of this process; the facts show us this more clearly with each passing day. Medications reach all the organism’s cells in an appropriate form, working at the same time in minimal quantities and synergistically, in such a way that they do not turn out to be harmful, since they are just acting to satisfy artificially created needs.

    The symptoms of thee hypoglycemia disappear completely within a few hours. We should remember that when the glycemia has been reduced by about 20%, the heart activates its functions, and consequently, the liver’s as well, and thus the transformation of glucogen into glucose is quicker. The same thing happens with the muscles and other organs that contain glucogen. When the circulation is activated, all of the mechanisms of excretion eliminate water, which conserves the blood isotonicity and assures that the physico—chemical phenomena that involve water (the majority) are not modified. This process is facilitated by the action of the sympathetic nervous system (which is especially affected by adrenaline), or by the specific pancreatic hormone that causes, among other things, cardiac acceleration. After a six to ten minute period, however, signs of cardiac asthenia appear, arterial blood pressure is reduced, the pulse rate is slower, etc. due to the lack of glucose, the energetic element of the heart; to the intoxication of the cardiac fibers produced by the initial period of hypoglycemia; to the probable depletion of adrenaline; to the lack of medullar and sympathetic stimulation as well as that of the particular cardiac ganglia, etc.

    In the elderly, arteriosclerosis can be another possible cause. In such patients, the application of tonocardiac substances or adrenaline is not sufficient, as they could die of a cardiac collapse preceded by respiratory phenomena like Cheyne—Stokes breathing.

    We have produced hypoglycemia in two subjects with large myocardial lesions and renal complications, without having observed cardiac asthenia. In sum, we can affirm that when the glycemia falls to below half of normal there is not imminent danger for the cardiovascular apparatus, except in case of sclerosis; in these cases and in those where the subject has a lesion in some part of the cardiovascular apparatus, the level of glycemia can fall to [by?] one—third of normal without danger. In addition, the simultaneous action of sweating and respiration, as well as an increase in diuresis, have a great influence on the increase in blood hypertonicity since by way of these mechanisms a great deal of water is eliminated

    The exciting action of insulin on the primary sympathetic nerve and afterwards on the vagus, have a large effect on the other internal secretions, but even without considering this direct action, we need to keep in mind the direct hormonal synergy of one hormonal secretion on another; besides these relations, the relations between hormones and vitamins are being given more and more importance.

    All of this explains why insulin has this therapeutic effect on endocrinological disturbances like metrorrhagias, hepatic insufficiency, Basedow’s disease, etc.

    The direct action of insulin on each and every one of the elements of the organism explains clearly the powerful effect that has been observed by many clinicians without being able to explain it, on diseases that have no relation with hormonal diffusion.

Recuperation from hypoglycemia

    After approximately six minutes, the glycemia rises to two—thirds normal; this fact shows that even after the violent change that insulin causes, the system still has some strength in reserve, and that the hemo—gluco—regulating apparatus, like other systems, with the goal of counteracting the pancreatic hormone, becomes hyperactive during this short period, which has to be taken advantage of to establish between the bloodstream and cells the opposite of what was observed during the period of increase. That is, the blood is hypertonic with relation to the cells, due to the presence of glucose and the loss of water (sweating and diuresis); the surface tension of the blood is, as well, higher. The iso—ionic/saline equilibrium, the blood pH, etc., try to return to their previous states of equilibrium.

    A current will necessarily have to be established from the outside to the inside of the cell, which will re—establish the equilibrium between the cell and the blood. The surface tension, diminished during hypoglycemia, begins, at this time, to return to its previous level; the cell pH, the iso—ionic and isotonic equilibria will return to their initial states, taking from the blood the elements indispensable to the re—establishing of the physico—chemical state of the cell.

    Observation of the patients shows that permeability is not selective, at least at this moment, but that it is simply a physico—chemical phenomenon. Today it is accepted that the same thing happens in the normal metabolic changes in the cell. The facts show that during the period of increasing glycemia the crystalloids that the blood contains pass into the cell, which can be deduced from the physico—chemical considerations as well as from the clinical signs, for about 30 minutes after the administration of the medications some of the symptoms that motivated the treatment begin to disappear. This leads us to believe that therapeutic action begins when the glycemia falls to one—third below normal; and that it is proportional to the degree of hypoglycemia, the lowest level of which still compatible with life is 15 mg of glucose per 100 cc of blood.

    So as not to expose the patient to the dangers of a very intense hypoglycemia, we can say, as a rule of thumb, that maximal therapeutic action results when the glycemia reaches 50% below normal. This degree of hypoglycemia is not dangerous, since in some patients the glucose level rises spontaneously. In this case, the physician still has enough time to initiate the therapy appropriate for each patient. However, this hypoglycemic state can be a delicate one in some patients, especially when it is the first treatment, in which case the doctor should be sure to have the previously selected medications at hand.

    It should be kept in mind that, except at the moment of the hypoglycemia(s), the figure representing the habitual glucose level of the individual always returns to normal, in spite of the amount of insulin required in each case to produce the sane degree of hypoglycemia, which can vary; that is, to force the glucose level to 50% of normal in the first treatment, it is necessary to use larger doses of insulin than in subsequent treatments, even if the individual is always observed to be in the same state of glycemia before treatment; it seems that the organism becomes more sensitive as the number of hypoglycemic states becomes larger.

    It would be important to investigate whether this increased facility for provoking repeated hypoglycemias is due to a disturbance of tine function of the storage of glucogen by the appropriate organs, which do not provide glucose after the injection of insulin, or whether it has other causes.

    Hypoglycemia, as we have described it, is that which corresponds to individuals with an approximate age of 35 years and weigh 60 kg, with an average glycemia of 82 mg/100 ml; when these factors are different, the characteristics of the hypoglycemia vary as well.

    Modifications of insulinic hypoglycemia vary according to differences in the following factors:

Age. We have used insulin with patients from two years old on, having observed invariably that the younger the patient, the quicker the action of the hormone. Infants and children show the most intense reaction to insulin. Up to 35 years of age, the manifestations are always proportional to the quantity of insulin that is injected, varying according to the mode of application; intravenously the hypoglycemic effects are produced more quickly and ostensibly.

    The return of normal glycemia is seen in a very short time, for the symptoms disappear the same day of the provoked hypoglycemia. In reacting, these individuals feel extraordinarily quickly the therapeutic action of the medications. The age at which the therapeutic effects are most favorable ranges from 20 to 40, on the average. From 40 on, the reactions to insulin are rapid, as in the child, but the appearance of the symptoms is variable: in some, tachycardia appears first, in others sweating, drowsiness or another symptom, probably revealing some lesion not discovered before administering insulin. In general, this is dangerous in the elderly because of the variability of the symptoms, and especially because they do not normalize quickly and easily their glycemia. When in these subjects the glycemia has managed to return to normal, it quickly fails again, and so the physician should be duly prepared to combat the symptoms that can appear differently either in terms of time of appearance or in terms of their variability. This requires sufficient practice in the application of the method, so as to avoid any danger.

Weight. One of the most important factors for dosification is the weight of the individual, which is directly proportional to the quantity of insulin necessary for provoking hypoglycemia.

    The medication—intoxications produced by previous treatments, autointoxication of intestinal origin and others, of varying causes, make individuals hypersensitive. This proves that in the intensity of the hypoglycemic shock the accumulated toxins or the lesions produced by them have an effect, as well as the decreased level of glucose in the blood and tissues. When these factors arc found , together or in isolation, in a subject, the organism will respond hypersensitively.

    Normal glycemia and age are secondary factors, except from 40 on. As for the time in which the symptoms appear, we will say that a minimum is 10 minutes and a maximum would be 50 minutes after the injection.

    As proof of the little influence that normal glycemia has on dosage, we can say that we have treated diabetics with more than 200 mg/100 ml of blood (to whom we gave insulin), and made the glycemia fall to 50% of normal; that is to say that the same quantity of insulin causes, in normal or hyperglycemic patients, the same decrease in glycemia.

part 6