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ULTRAVIOLET RADIATION, T LYMPHOCYTES, AND SKIN CANCER
530 hazards ofaparticular drug or incapable of making a reasoned judgment concerning its risks and benefits. Most of us will have witnessed instances of illogical, inappropriate, or dangerous prescribing numerous enough to excuse the attitude of the Committee; and the remarkable efficacy of the marketing of benoxaprofen seems to confirm that medical men and women are highly susceptible to advertisements. What, then, are the lessons to be learned from the benoxaprofen debacle? It has shown us, yet again, that new drugs can have new and serious unwanted effects; it has confirmed the importance of reporting "events" rather than merely "adverse effects"; it has shown that doctors will prescribe a drug with novel pharmacological properties in the absence of evidence from clinical trials that these properties confer any benefit upon the recipients;1 it has demonstrated that intensive marketing methods are effective even when directed at a highly sophisticated consumer; and it implies that the Committee on Safety of Medicines has formed an unflattering, but perhaps realistic, opinion of the prescribing abilities of doctors. Most of these lessons should have been learned from the experience with practolol. No radical changes are needed in the rules for assessment and marketing of new drugs. The existing system strikes- a reasonable balance between the hazards of exposure of patients to a new compound, and the benefits to be gained from its early use. Patients seem to be learning that no drug treatment can be entirely without risk; doubtless they will also accept that new treatments are riskier, for some years after their introduction, than old ones. What we really need is an improvement in the. standard of prescribing by doctors.
ULTRAVIOLET RADIATION, T LYMPHOCYTES, AND SKIN CANCER THE involvement of the immune system in the genesis of skin malignancy has long excited interest. These investigations have been given added impetus by reports of aggressive Kaposi’s sarcoma and opportunistic infections in male homosexuals,2 and by the suggestion that phototherapy of skin disease might cause increase in incidence of skin cancer
through immunosuppression.3 The ability of long-continued ultraviolet (UV) to cause skin cancer is generally held to be due to its mutagenic effect on epidermal cell DNA. However, the possibility that the carcinogenic actions of UV might be more complex were suggested by the studies of Fisher and Kripke,4 who found that prolonged UV exposure resulted in failure of mice to reject highly antigenic UV-induced transplanted skin tumours. The inability to reject these tumours was passively transferable to normal mice via lymphocytes from irradiated animals. Subsequent studies by the same group5 implicated the suppressor T lymphocyte subset in this process. New findings now implicate the suppressor T lymphocytes in the6 regulation of development of UV-evoked skin cancers.6
Lethally X-irradiated mice repopulated with lymphoid tissue from UV-irradiated mice were grafted with skin from syngeneic mice which had been irradiated for 16 weeks by UV. These grafts were monitored weekly for skin cancer. This method enabled the local mutagenic effects ofUV on the skin to be distinguished from the systemic actions ofUV. The frequency of tumours which developed in the previously irradiated grafts placed on recipients of lymphocytes from UV-irradiated individuals was higher than in mice treated in an otherwise identical way which had received lymphocytes from healthy unirradiated animals. Thus the frequency of tumours in the irradiated skin depended not only upon the dose of irradiation (which was equal in the two experimental groups) but also on the presence in the grafted mice of lymphoid cells from irradiated animals. In further studies the same group showed that mice which had previously been injected intravenously with suppressor-cell-enriched lymphocyte preparations from UV-irradiated mice showed a higher rate of skin tumour development after UV irradiation than comparable mice which had received cells from nonirradiated animals. The tumours evoked in the above experiments were mainly cutaneous fibrosarcomas; in man UV characteristically leads to squamous and basal cell carcinomas and melanomas, and fibrosarcomas are rare in sun-damaged skin. Nevertheless Fisher and Kripke’s findings strongly support the view that UV carcinogenesis involves both a direct mutagenic effect on skin cells and a "pseudopromotor" action through induction of suppressor T lymphocytes. Burnet proposed that foci of transformed cells might be held in check by a normally functioning immune system.7 These findings suggest that his immunosurveillance theory can be applied to ultraviolet carcinogenesis. They should prompt a thorough evaluation of the immune status of individuals receiving recreational, cosmetic, or therapeutic UV irradiation. An epidemiological survey of individuals with extensive solar skin changes for frequency of non-cutaneous neoplasia would also be of interest.
DIABETES MELLITUS AND SOCIOECONOMIC FACTORS THE epidemiology of insulin-dependent diabetes (IDD) has been compared to that of poliomyelitis and Hodgkin’s disease in that all three show a peak age of onset in childhood, considerable differences in geographic prevalence, seasonal variation, and some evidence of clustering.l-4 Polio and Hodgkin’s disease are also related positively to social class. Whether there is any social class relationship with IDD, however, is uncertain. Thus two recent North American studies, using a similar method for classifying socioeconomic status (median income of census tracts), have yielded different results. In Montreal5 the incidence of IDD below age 17 was Immunological factors in the process of carcinogenesis. Br Med Bull 1964, 20: 154-58. 1. Hillis A. Does insulin-dependent diabetes mellitus (IDDM) follow the poliomyelitis pattern? Am JEpidemiol 1980; 112: 452. 2. Dauer CG The changing distribution of paralytic polio Ann NY Acad Sci 1955; 61: 943-55. 3. Correa P, O’Connor GT. Epidemiologic patterns of Hodgkin’s disease. Int J Cancer 7. Burnet FM
1. 2. 3.
Anonymous. Benoxaprofen (Opren). Drug Therap Bull 1981; 19: 95-96 Hymes KB, Cheung T, Green JB Kaposi’s sarcoma in homosexual men: a report of eight cases. Lancet 1981; ii 598-600. Strauss GH, Greaves M, Price M, Bridges BA, Hall Smith P, Vella Briffa D. Inhibition of delayed hypersensitivity reaction in skin (DNCB test) by 8-methoxypsoralen
photochemotherapy. Lancet 1980, ii 566-59. 4 Fisher MS, Kripke ML Systemic alteration induced in mice by ultraviolet light irradiation and its relationship to ultraviolet carcinogenesis Proc Natl Acad Sci USA 1977; 74: 1688-92 ML. Immunologic mechanisms in UV radiation carcinogenesis. Adv Cancer Res 1981, 34: 69-106. 6.Fisher MS, Kripke ML. Suppressor T lymphocytes control the development of primary skin cancers in ultraviolet irradiated mice. Science 1982, 216: 1133-34
5.
Kripke
1971; 8: 192-201 4 Gamble DR. The
epidemiology of insulin dependent diabetes, with particular reference to the relationship of virus infection to its etiology Epidemiol Rev 1980, 2: 49-70. 5 Colla E, Siemiatycki J, West R, Belmonte MM, Crepau MP, Poirier R, Wilkins J Incidence of juvenile onset diabetes in Montreal: Demonstration of ethnic differences J Chron Dis 1981; 34: 611-16.
ULTRAVIOLET RADIATION, T LYMPHOCYTES, AND SKIN CANCER THE involvement of the immune system in the genesis of skin malignancy has long excited interest. These investigations have been given added impetus by reports of aggressive Kaposi’s sarcoma and opportunistic infections in male homosexuals,2 and by the suggestion that phototherapy of skin disease might cause increase in incidence of skin cancer
through immunosuppression.3 The ability of long-continued ultraviolet (UV) to cause skin cancer is generally held to be due to its mutagenic effect on epidermal cell DNA. However, the possibility that the carcinogenic actions of UV might be more complex were suggested by the studies of Fisher and Kripke,4 who found that prolonged UV exposure resulted in failure of mice to reject highly antigenic UV-induced transplanted skin tumours. The inability to reject these tumours was passively transferable to normal mice via lymphocytes from irradiated animals. Subsequent studies by the same group5 implicated the suppressor T lymphocyte subset in this process. New findings now implicate the suppressor T lymphocytes in the6 regulation of development of UV-evoked skin cancers.6
Lethally X-irradiated mice repopulated with lymphoid tissue from UV-irradiated mice were grafted with skin from syngeneic mice which had been irradiated for 16 weeks by UV. These grafts were monitored weekly for skin cancer. This method enabled the local mutagenic effects ofUV on the skin to be distinguished from the systemic actions ofUV. The frequency of tumours which developed in the previously irradiated grafts placed on recipients of lymphocytes from UV-irradiated individuals was higher than in mice treated in an otherwise identical way which had received lymphocytes from healthy unirradiated animals. Thus the frequency of tumours in the irradiated skin depended not only upon the dose of irradiation (which was equal in the two experimental groups) but also on the presence in the grafted mice of lymphoid cells from irradiated animals. In further studies the same group showed that mice which had previously been injected intravenously with suppressor-cell-enriched lymphocyte preparations from UV-irradiated mice showed a higher rate of skin tumour development after UV irradiation than comparable mice which had received cells from nonirradiated animals. The tumours evoked in the above experiments were mainly cutaneous fibrosarcomas; in man UV characteristically leads to squamous and basal cell carcinomas and melanomas, and fibrosarcomas are rare in sun-damaged skin. Nevertheless Fisher and Kripke’s findings strongly support the view that UV carcinogenesis involves both a direct mutagenic effect on skin cells and a "pseudopromotor" action through induction of suppressor T lymphocytes. Burnet proposed that foci of transformed cells might be held in check by a normally functioning immune system.7 These findings suggest that his immunosurveillance theory can be applied to ultraviolet carcinogenesis. They should prompt a thorough evaluation of the immune status of individuals receiving recreational, cosmetic, or therapeutic UV irradiation. An epidemiological survey of individuals with extensive solar skin changes for frequency of non-cutaneous neoplasia would also be of interest.
DIABETES MELLITUS AND SOCIOECONOMIC FACTORS THE epidemiology of insulin-dependent diabetes (IDD) has been compared to that of poliomyelitis and Hodgkin’s disease in that all three show a peak age of onset in childhood, considerable differences in geographic prevalence, seasonal variation, and some evidence of clustering.l-4 Polio and Hodgkin’s disease are also related positively to social class. Whether there is any social class relationship with IDD, however, is uncertain. Thus two recent North American studies, using a similar method for classifying socioeconomic status (median income of census tracts), have yielded different results. In Montreal5 the incidence of IDD below age 17 was Immunological factors in the process of carcinogenesis. Br Med Bull 1964, 20: 154-58. 1. Hillis A. Does insulin-dependent diabetes mellitus (IDDM) follow the poliomyelitis pattern? Am JEpidemiol 1980; 112: 452. 2. Dauer CG The changing distribution of paralytic polio Ann NY Acad Sci 1955; 61: 943-55. 3. Correa P, O’Connor GT. Epidemiologic patterns of Hodgkin’s disease. Int J Cancer 7. Burnet FM
1. 2. 3.
Anonymous. Benoxaprofen (Opren). Drug Therap Bull 1981; 19: 95-96 Hymes KB, Cheung T, Green JB Kaposi’s sarcoma in homosexual men: a report of eight cases. Lancet 1981; ii 598-600. Strauss GH, Greaves M, Price M, Bridges BA, Hall Smith P, Vella Briffa D. Inhibition of delayed hypersensitivity reaction in skin (DNCB test) by 8-methoxypsoralen
photochemotherapy. Lancet 1980, ii 566-59. 4 Fisher MS, Kripke ML Systemic alteration induced in mice by ultraviolet light irradiation and its relationship to ultraviolet carcinogenesis Proc Natl Acad Sci USA 1977; 74: 1688-92 ML. Immunologic mechanisms in UV radiation carcinogenesis. Adv Cancer Res 1981, 34: 69-106. 6.Fisher MS, Kripke ML. Suppressor T lymphocytes control the development of primary skin cancers in ultraviolet irradiated mice. Science 1982, 216: 1133-34
5.
Kripke
1971; 8: 192-201 4 Gamble DR. The
epidemiology of insulin dependent diabetes, with particular reference to the relationship of virus infection to its etiology Epidemiol Rev 1980, 2: 49-70. 5 Colla E, Siemiatycki J, West R, Belmonte MM, Crepau MP, Poirier R, Wilkins J Incidence of juvenile onset diabetes in Montreal: Demonstration of ethnic differences J Chron Dis 1981; 34: 611-16.