PREVENTIVE
4, 9-11 (1975)
MEDICINE
Immunology:
Its Vaiue in Cancer D.
Research
SCHMXHL'
The institute of Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg, Germany
Reports have appeared in recent months in both the scientific and popular press about the major financial efforts which have been made (particularly in the USA) to relate initiation, growth and therapy of cancer to the immunological competence of the whole organism or properties of the cancer cell. Expectations have been not infrequently aroused, particularly in newspapers, that it will be possible in the near future to overcome cancer through the latest findings in immunology. This kind of report naturally raises great hopes among the populace; of course, the critical reader asks whether these predictions can be fulfilled. Ever since cancer research has been scientificaIIy based there have been those who contended that, in particular, initiation and growth of cancer are controlled by immunologic surveillance mechanisms. The most prominent exponent of this view was Paul Ehrlich many decades ago; he attached the very greatest importance to immunologic studies in the area of cancer research. If one surveys what immunology has been able to contribute to understanding of the cancer process before the nineteen sixties, the final result is disappointing. Neither the mechanisms of carcinogenesis nor a scientifically based immunologic therapy for cancer has been derived. Only in recent years have observations of American colleagues at the large transplantation center in Denver, Colorado, given serious indications that both initiation and growth of cancer could be controlled by immunological mechanisms which are as yet unknown. It was observed that tumor incidence is significantly higher in recipients of organs than in normal populations of the same age. Malignant lymphomas in particular increase a relatively short time after the transplantation (a few months to three years) and solid carcinomas also appear. This raised incidence of cancer was associated, probably correctly, with the massive immunosuppressive-therapy required to prevent rejection of the organ. It would appear that tumors find better conditions for growth and initiation after reducing the effectiveness of the immune system of the body; this leads to the higher incidence of cancer in organ transplant recipients described above. However, it does not appear to me to be altogether clear whether, in addition to the immunosuppressive measures which may favour initiation of cancer, chemical carcinogenesis might be responsible for the tumors which have been observed. Alkylating cytostatics must frequently be used to achieve immunosuppression, and these agents are quite clearly to be viewed as carcinogens for man. Experimentally, carcinogenicity could be attributed to the ’ Director of the Institute of Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg, Germany. 9 Copyright
63 1975 by Academic
Press, Inc. All rights of reproduction
in any form reserved.
10
D. SCHM;iHL
alkylating agents; this also applies to some “occupational cancers.” Although the mechanism is quite different, one could similarly ask whether the “dormant” cancer cells which occur with high frequency in the prostate of older men are prevented from malignant proliferation by immunological surveillance. These indications of a possible relationship between immunosuppression, carcinogenesis and tumor growth justify the increased and more extensive immunological studies carried out in the field of cancer research. The object of these studies is to determine whether carcinogenesis, cancer growth and possibly also cancer therapy could be influenced by immunological measures. Every unprejudiced researcher will support and welcome these activities. We are also concerned with these questions in this institute, specifically whether or not the various currently known groups of chemical carcinogens (hydrocarbons, aromatic amines, nitroso compounds, alkylating agents) can be assigned immunosuppressive activity, i.e., whether chemical carcinogenesis is coupled with immunosuppression. These studies constitute about 10% of the activities of our institute. This is not the place to go into details of these investigations, but so far we have not been able to discover connections between immunosuppression and chemical carcinogenesis. Immunologic studies are expensive. As a rule, they call for a substantial expenditure on apparatus and personnel. The same applies to the media required for immunologic investigations. The strong emphasis on immunologic cancer research brings with it the danger (in my opinion) that other important areas of cancer research could be neglected. I am thinking in particular of studies in the chemical carcinogenesis area, since the most significant results of cancer research could without doubt be made here. These would also be important for the mass of the population and could be applied in the preventive medicine field and cancer prophylaxis. It should not be forgotten that today a large number of occupational cancers appear hardly at all or to a much smaller extent than formerly simply because the chemical carcinogens in the environment of the worker were recognized and could be removed. Further striking examples are the genesis of bronchial carcinomas in heavy smokers, particularly in those who inhale the tobacco smoke, and the contribution to this disease process in persons living in regions of severe air pollution. By eliminating the cancer-producing agent, one can significantly reduce or completely remove the risk of developing the corresponding kind of cancer. There are further examples from the field of physical carcinogenesis, e.g. avoidance of skin cancer by appropriate protection of the skin from excessive ultraviolet irradiation or avoidance of radiation iatrogenically induced carcinomas of sarcomas. It was precisely in this field of chemical carcinogensis that research has been recently able to show that carcinogenic nitroso compounds are present in part of our food and that they can also arise in the stomach by contact of amines or amides with nitrite. It was further demonstrated in experimental animals that such carcinogens are active even in very small doses (less than 1 mg/kg) and only a few applications of these substances are not infrequently sufficient to produce cancer. It was also shown that these are among the most highly active carcinogens via the transplacental route. Combination studies in our own working group showed that very small doses of chemically very different carcinogens
EDITORIALS
11
which alone do not lead to cancer can together produce an additive effect if they act on the same organ. Nitroso compounds are equally carcinogenic in very different animal species (15 animal species have been studied up to now, including birds, fish and monkeys). It was demonstrated in in vitro metabolic studies that man metabolizes nitroso compounds in a similar way to experimental animals, so it can be assumed that man is sensitive to the carcinogenic action of nitroso compounds. The same may well apply to other chemical carcinogens, e.g. mycotoxins, hydrocarbons or some pharmaceuticals. Studies in the field of chemical carcinogenesis have yielded a large number of tangible findings, application of which might alford appropriate active prophylactic measures against cancer. In contrast to some of the reflections of the immunologists, these findings are available today and are of high scientific and, in particular, practical relevance. In enthusiasm for the new vistas which immunology might possibly open up in cancer research, one should not forsake the old and proved approaches, especially since they promise to be most useful in cancer prevention. REFERENCE Schmkihl, D. “Entstehung, Wachstum und Chemotherapie maligner Tumoren,” 2nd Edition, Editio Cantor, Aulendorf, 1970.
4, 9-11 (1975)
MEDICINE
Immunology:
Its Vaiue in Cancer D.
Research
SCHMXHL'
The institute of Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg, Germany
Reports have appeared in recent months in both the scientific and popular press about the major financial efforts which have been made (particularly in the USA) to relate initiation, growth and therapy of cancer to the immunological competence of the whole organism or properties of the cancer cell. Expectations have been not infrequently aroused, particularly in newspapers, that it will be possible in the near future to overcome cancer through the latest findings in immunology. This kind of report naturally raises great hopes among the populace; of course, the critical reader asks whether these predictions can be fulfilled. Ever since cancer research has been scientificaIIy based there have been those who contended that, in particular, initiation and growth of cancer are controlled by immunologic surveillance mechanisms. The most prominent exponent of this view was Paul Ehrlich many decades ago; he attached the very greatest importance to immunologic studies in the area of cancer research. If one surveys what immunology has been able to contribute to understanding of the cancer process before the nineteen sixties, the final result is disappointing. Neither the mechanisms of carcinogenesis nor a scientifically based immunologic therapy for cancer has been derived. Only in recent years have observations of American colleagues at the large transplantation center in Denver, Colorado, given serious indications that both initiation and growth of cancer could be controlled by immunological mechanisms which are as yet unknown. It was observed that tumor incidence is significantly higher in recipients of organs than in normal populations of the same age. Malignant lymphomas in particular increase a relatively short time after the transplantation (a few months to three years) and solid carcinomas also appear. This raised incidence of cancer was associated, probably correctly, with the massive immunosuppressive-therapy required to prevent rejection of the organ. It would appear that tumors find better conditions for growth and initiation after reducing the effectiveness of the immune system of the body; this leads to the higher incidence of cancer in organ transplant recipients described above. However, it does not appear to me to be altogether clear whether, in addition to the immunosuppressive measures which may favour initiation of cancer, chemical carcinogenesis might be responsible for the tumors which have been observed. Alkylating cytostatics must frequently be used to achieve immunosuppression, and these agents are quite clearly to be viewed as carcinogens for man. Experimentally, carcinogenicity could be attributed to the ’ Director of the Institute of Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg, Germany. 9 Copyright
63 1975 by Academic
Press, Inc. All rights of reproduction
in any form reserved.
10
D. SCHM;iHL
alkylating agents; this also applies to some “occupational cancers.” Although the mechanism is quite different, one could similarly ask whether the “dormant” cancer cells which occur with high frequency in the prostate of older men are prevented from malignant proliferation by immunological surveillance. These indications of a possible relationship between immunosuppression, carcinogenesis and tumor growth justify the increased and more extensive immunological studies carried out in the field of cancer research. The object of these studies is to determine whether carcinogenesis, cancer growth and possibly also cancer therapy could be influenced by immunological measures. Every unprejudiced researcher will support and welcome these activities. We are also concerned with these questions in this institute, specifically whether or not the various currently known groups of chemical carcinogens (hydrocarbons, aromatic amines, nitroso compounds, alkylating agents) can be assigned immunosuppressive activity, i.e., whether chemical carcinogenesis is coupled with immunosuppression. These studies constitute about 10% of the activities of our institute. This is not the place to go into details of these investigations, but so far we have not been able to discover connections between immunosuppression and chemical carcinogenesis. Immunologic studies are expensive. As a rule, they call for a substantial expenditure on apparatus and personnel. The same applies to the media required for immunologic investigations. The strong emphasis on immunologic cancer research brings with it the danger (in my opinion) that other important areas of cancer research could be neglected. I am thinking in particular of studies in the chemical carcinogenesis area, since the most significant results of cancer research could without doubt be made here. These would also be important for the mass of the population and could be applied in the preventive medicine field and cancer prophylaxis. It should not be forgotten that today a large number of occupational cancers appear hardly at all or to a much smaller extent than formerly simply because the chemical carcinogens in the environment of the worker were recognized and could be removed. Further striking examples are the genesis of bronchial carcinomas in heavy smokers, particularly in those who inhale the tobacco smoke, and the contribution to this disease process in persons living in regions of severe air pollution. By eliminating the cancer-producing agent, one can significantly reduce or completely remove the risk of developing the corresponding kind of cancer. There are further examples from the field of physical carcinogenesis, e.g. avoidance of skin cancer by appropriate protection of the skin from excessive ultraviolet irradiation or avoidance of radiation iatrogenically induced carcinomas of sarcomas. It was precisely in this field of chemical carcinogensis that research has been recently able to show that carcinogenic nitroso compounds are present in part of our food and that they can also arise in the stomach by contact of amines or amides with nitrite. It was further demonstrated in experimental animals that such carcinogens are active even in very small doses (less than 1 mg/kg) and only a few applications of these substances are not infrequently sufficient to produce cancer. It was also shown that these are among the most highly active carcinogens via the transplacental route. Combination studies in our own working group showed that very small doses of chemically very different carcinogens
EDITORIALS
11
which alone do not lead to cancer can together produce an additive effect if they act on the same organ. Nitroso compounds are equally carcinogenic in very different animal species (15 animal species have been studied up to now, including birds, fish and monkeys). It was demonstrated in in vitro metabolic studies that man metabolizes nitroso compounds in a similar way to experimental animals, so it can be assumed that man is sensitive to the carcinogenic action of nitroso compounds. The same may well apply to other chemical carcinogens, e.g. mycotoxins, hydrocarbons or some pharmaceuticals. Studies in the field of chemical carcinogenesis have yielded a large number of tangible findings, application of which might alford appropriate active prophylactic measures against cancer. In contrast to some of the reflections of the immunologists, these findings are available today and are of high scientific and, in particular, practical relevance. In enthusiasm for the new vistas which immunology might possibly open up in cancer research, one should not forsake the old and proved approaches, especially since they promise to be most useful in cancer prevention. REFERENCE Schmkihl, D. “Entstehung, Wachstum und Chemotherapie maligner Tumoren,” 2nd Edition, Editio Cantor, Aulendorf, 1970.
