The impulse toward the use and production of this type of preparation is directly traceable to a series of scientific experiments on the tumors of animals, which date back no farther than the year 1911. In that year Wassermann and his co-workers[267] published a report on the treatment of rat tumors by means of the intravenous injection of selenium compounds. This paper received wide notoriety through its enthusiastic diffusion by the lay press. Shortly afterward Neuberg and his co-workers[268] published their observations upon the therapeutic effects of certain metallic compounds. The clinical application of the encouraging results obtained by these authors in animal tumors followed rapidly, and up to the present time a number of papers have appeared in which the claim is made that human tumors also may be favorably influenced through the constitutional use of substances similar to those used by Wassermann or Neuberg. In some cases, use has been made of colloidal solutions of the heavy metals, such as copper; in others, selenium compounds have been used, while in a third set of observations the therapeutic agent represents an attempt to combine the virtues of these two types of therapy by employing selenium in colloidal form. As an example of the first class, may be cited the cuprase of Gaube du Gers;[269] of the second, the seleniovanadic ointment of Roemer and the sulpho-selene of Walker; of the third, seleniol and electro-selenium.
Inasmuch as this new type of cancer therapy derives its origin, its justification and its support, in very large measure, from the laboratory results obtained in animals, it is a matter of considerable importance to examine those results with care, in order to determine whether they furnish a satisfactory basis for human therapy, and whether they justify the hopes to which they have given rise.
It is safe to assert that the application of chemotherapy to the treatment of tumors practically dates from the publications of Wassermann. He stated the principle that a rational therapy of tumors must be based on constitutional treatment. It appears evident that local treatment can have only local effects. The lymphatic extensions of tumorous growths, and the often unsuspected metastases in distant organs must of necessity escape the effects of purely local treatment. Hence, Wassermann reached the conclusion that all treatment of cancer which was to be effective, and not merely palliative, must be carried to all parts of the body by means of the blood stream. He therefore introduced the use of intravenous injections in the experimental therapy of rat and mouse tumors. An accidental observation led him to believe that selenium was a substance possessing a high degree of affinity for tumor cells.
In order to insure the penetration of the tumor in the live animal by this substance, however, he considered it essential to combine it with some other highly diffusible substance. This type of substance, which was to act as a carrier of the selenium, he described under the name “cytotrochin,” from the Greek word τροχιά {trochia}, meaning road. For this purpose he selected eosin. The eosin and the selenium were then combined by a method and in a form the details of which have never been published. All that we know of this preparation is contained in the statement that it is very difficult to produce, and that it is extremely unstable and difficult to keep. Mice can be given amounts of from 2 to 3 mg. of this substance in solution. Wassermann experimented with mice inoculated with transplanted tumors of the types of carcinoma and sarcoma. After from three to five intravenous injections of the drug, he noted that the tumors become softer and fluctuate. After still further injections the fluid mass undergoes absorption, and the tumor gives the impression of an empty sac. If it is possible to carry the injections up to the number of ten or twelve, recovery ensues. In such cured animals there remain only the unabsorbed portions of the fibrous capsule. Recurrences were not observed in the cured animals. Wassermann further stated that two spontaneous tumors in mice which had been treated by this method presented favorable results.
Wassermann’s original presentation gave few experimental details, and has not been followed by the promised scientific report. From his article it is impossible to determine what proportion of his animals were cured and what proportion failed to survive the treatment. From a later paper by Keysser[270] we learn that by far the larger portion of the animals perished during the treatment in the stage of softening, so that a cure was accomplished in from only 3 to 5 per cent. of the animals. This is a point of great importance, inasmuch as it furnishes an indication of the highly dangerous character of this mode of treatment. Fatal results are attributed by Keysser to the absorption of toxic products from the tumor. This contention, however, is supported by no observations, and it is certainly equally fair to assume that death results from the toxic effects of the compound. A microscopic study of tumors taken from animals undergoing treatment was made by Hansemann. He found that the death of the cells was the result of nuclear destruction.
Within a very few months after Wassermann’s publication, Neuberg and Caspari[268] published a paper which was the first of a series of studies on the therapeutic effects of the heavy metals on the animal tumors. They used zinc, platinum, tin, selenium, copper, silver and cobalt in the form of certain complex organic compounds, the composition of which is not revealed. Owing to the fact that intravenous injections of these compounds produced a specific effect on the tumors, they are described as “tumoraffin” substances. Immediately after the intravenous injection of these preparations, there followed a marked hyperemia of the tumor, whereas the remainder of the mouse’s body appeared markedly anemic. The hyperemia was often attended by hemorrhage into the tumor. This first stage was succeeded by liquefaction and absorption followed by recovery in favorable cases. The authors failed to state in what proportion of their experiments the animals died, and in what proportion recovery ensued.
The second paper on this subject is by Neuberg, Caspari and Löhe,[268] in which further details are vouchsafed. They state that with the compounds used by them the toxic and the therapeutic doses approximate very closely, from which it follows that the treatment, as with the Wassermann method, results in a very high mortality. Smaller doses produce no therapeutic effect; on the contrary, they seem to act as a stimulus to the tumor, accelerating the normal rate of growth. Spontaneous tumors show similar effects, but no cures are recorded. Only in tumors in which autolysis is active intra vitam does the method exert any effect. Consequently the benign primary tumors of animals, such as fibromas, are not influenced by it.
Neuberg and Caspari are to a great extent responsible for the colloidal theory of treatment in tumors. Accepting the observations of Petri and others that the autolytic ferments in tumors are quantitatively greater and qualitatively different from those present in the normal tissues of the body, they venture the assumption that the process of recovery in the experimental tumors of animals is due to the self-digestion of the tumor by these ferments. Ascoli and Izar[271] had shown that such ferments are materially stimulated by the presence of metals, and more especially of metals in colloidal form. This contention is apparently in harmony with the well-established fact that certain colloidal metals of themselves are capable of acting under certain circumstances as ferments. Neuberg and Caspari were at first of the belief that the compounds produced by them circulate in colloidal form. Subsequently they stated that these compounds were crystalline substances, but they assumed, under the influence of the theoretical consideration mentioned above, that these substances are broken up in the tumor and there undergo transformation into the colloid state.
In connection with the preceding observations there are certain other experimental results which require mention. Izar[271] succeeded in curing rat tumors by means of injection of colloidal sulphur. C. Lewin[272] cured subcutaneous mouse tumors with various preparations of gold. Werner and Szécsi[273] produced similar results through a combination of selenium-vanadium with cholin-borate; in these experiments the selenium-vanadium was supposed to be present in colloidal form.