Immunosuppression, Skin Cancer, and Ultraviolet A Radiation
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《新英格兰医药杂志》
Skin cancer is a serious problem in immunosuppressed patients. In these patients, cutaneous cancers are common in areas of the skin that are exposed to the sun, are more aggressive than in patients who are not immunosuppressed, are sometimes fatal, and often require multiple surgical procedures.1 Although the absolute risk of squamous-cell carcinoma after renal transplantation is highest in sunny climates, the risk of these tumors is also greatly elevated in less sunny areas. For example, a study of more than 700 renal-transplant recipients in the Netherlands disclosed that the overall incidence of squamous-cell carcinoma was 250 times that in the general Dutch population.2 The reasons for the dramatic increase in these tumors among immunosuppressed patients is not completely understood, although it is often attributed to decreased cancer surveillance owing to panimmunosuppression that results from drug therapy and exposure to ultraviolet B (UVB) radiation. A recent study by O'Donovan and colleagues, however, points a finger elsewhere: they show that azathioprine, an immunosuppressant used in organ transplantation, sensitizes DNA to ultraviolet A (UVA) radiation.3
UVA radiation comprises more than 90 percent of incident midday solar ultraviolet radiation and is present for more hours of each day and throughout the year than UVB radiation. It penetrates more deeply into skin than UVB, and it passes through glass. O'Donovan et al. showed that treatment with azathioprine causes 6-thioguanine (the active metabolite of azathioprine) to be incorporated into the DNA of patients' skin cells. On exposure to low levels of UVA radiation, this metabolite is converted in an oxygen-dependent reaction into two products that are bad news for DNA: reactive oxygen species and guanine-6-sulfonate (G-6-SO3). A sudden increase in reactive oxygen species causes oxidative stress, which in turn produces DNA lesions. O'Donovan et al. also showed that G-6-SO3 itself is mutagenic (Figure 1).
Figure 1. How UVA Radiation Damages DNA.
A recent experiment by O'Donovan et al.3 suggests a mechanism by which azathioprine may sensitize DNA to UVA radiation. It was previously demonstrated that 6-thioguanine, a metabolite of azathioprine, is incorporated into the DNA of skin cells of patients who take the drug. O'Donovan et al. showed that 6-thioguanine is converted into guanine-6-sulfonate (G-6-SO3) on exposure to UVA and that G-6-SO3 blocks the action of a polymerase with strict fidelity (leading to deletions) and facilitates the insertion of a noncomplementary residue by an error-prone polymerase (leading to point mutations).
These observations are consistent with the results of another experiment this group conducted to evaluate the extent to which exposure to a low level of UVA radiation, cell culture with 6-thioguanine, and the two combined to increase the number of mutations in a reporter gene. They found that neither agent on its own detectably increases the number of mutations, but the two combined result in a threefold increase, as compared with the control. Thus, 6-thioguanine photosensitizes cells to UVA radiation.
Whether these findings are relevant to the incidence of squamous-cell carcinoma in patients treated with azathioprine has yet to be determined, although the authors provided a relevant finding. They compared the minimal erythema dose (the minimal amount of radiation required to elicit erythema) in patients before and three months after the initiation of therapeutic doses of azathioprine and found that with treatment, the skin became more sensitive to UVA but not UVB radiation.
Several observations indicate that multiple factors may be involved in the accelerated rate of appearance of tumors. For instance, organ-transplant recipients who are receiving azathioprine have an increased incidence of cancer on areas of the skin and mucous membranes that have not been exposed to the sun. In addition, patients receiving cyclosporine alone also have an increased risk of squamous-cell carcinoma, and there is no evidence that cyclosporine is a photosensitizer.
There is, however, a precedent for drug-induced sensitivity to UVA radiation and increased susceptibility to skin cancers. A 20-year prospective study showed that multiple aggressive squamous-cell carcinomas developed in UVA-exposed sites in patients with psoriasis treated with an oral psoralen and UVA radiation from high-intensity lamps (PUVA).4 Psoralens are intercalated into DNA and, in the doses used for therapy, increase the sensitivity of the skin to UVA radiation by a factor of 10 to 100. By comparison, the skin of the azathioprine-treated patients studied by O'Donovan et al. was no more than three times as sensitive to UVA radiation (as determined by experiments involving the minimal erythema dose). However, psoralen-induced photosensitization lasts only hours and is used only two or three times per week, whereas azathioprine treatment is usually continuous.
The known carcinogenic and immunosuppressive effects of ultraviolet radiation are caused predominantly by exposure to UVB radiation, the strongest risk factor for skin cancer in the general population. Although continued exposure to UVB radiation is likely to be a major risk factor for squamous-cell carcinoma in azathioprine-treated patients, the most important determinants of risk in transplant recipients are probably prior exposure to cutaneous carcinogens such as UVB radiation and PUVA. When substantial exposure to PUVA is followed by immunosuppressive therapy, the risk of squamous-cell carcinoma is further increased and exceeds one case per year among those using immunosuppressive therapies for at least three months.5
Regardless, we should heed the implications of the study by O'Donovan et al.3 Measures to reduce the risk of skin cancer should include the use of a so-called broad-spectrum sunscreen that protects against UVA as well as UVB radiation. That said, the Food and Drug Administration might consider adopting standards for UVA testing and using "broad spectrum" as a label.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Dermatology, Massachusetts General Hospital, Boston.
References
Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol 2002;47:1-17.
Hartevelt MM, Bavinck JN, Kootte AM, Vermeer BJ, Vandenbroucke JP. Incidence of skin cancer after renal transplantation in The Netherlands. Transplantation 1990;49:506-509.
O'Donovan P, Perrett CM, Zhang X, et al. Azathioprine and UVA light generate mutagenic oxidative DNA damage. Science 2005;309:1871-1874.
Stern RS, Laird N, Melski J, Parrish JA, Fitzpatrick TB, Bleich HL. Cutaneous squamous-cell carcinoma in patients treated with PUVA. N Engl J Med 1984;310:1156-1161.
Marcil I, Stern R. Squamous-cell cancer of the skin in patients given PUVA and ciclosporin: nested cohort crossover study. Lancet 2001;358:1042-1045.(John A. Parrish, M.D.)
UVA radiation comprises more than 90 percent of incident midday solar ultraviolet radiation and is present for more hours of each day and throughout the year than UVB radiation. It penetrates more deeply into skin than UVB, and it passes through glass. O'Donovan et al. showed that treatment with azathioprine causes 6-thioguanine (the active metabolite of azathioprine) to be incorporated into the DNA of patients' skin cells. On exposure to low levels of UVA radiation, this metabolite is converted in an oxygen-dependent reaction into two products that are bad news for DNA: reactive oxygen species and guanine-6-sulfonate (G-6-SO3). A sudden increase in reactive oxygen species causes oxidative stress, which in turn produces DNA lesions. O'Donovan et al. also showed that G-6-SO3 itself is mutagenic (Figure 1).
Figure 1. How UVA Radiation Damages DNA.
A recent experiment by O'Donovan et al.3 suggests a mechanism by which azathioprine may sensitize DNA to UVA radiation. It was previously demonstrated that 6-thioguanine, a metabolite of azathioprine, is incorporated into the DNA of skin cells of patients who take the drug. O'Donovan et al. showed that 6-thioguanine is converted into guanine-6-sulfonate (G-6-SO3) on exposure to UVA and that G-6-SO3 blocks the action of a polymerase with strict fidelity (leading to deletions) and facilitates the insertion of a noncomplementary residue by an error-prone polymerase (leading to point mutations).
These observations are consistent with the results of another experiment this group conducted to evaluate the extent to which exposure to a low level of UVA radiation, cell culture with 6-thioguanine, and the two combined to increase the number of mutations in a reporter gene. They found that neither agent on its own detectably increases the number of mutations, but the two combined result in a threefold increase, as compared with the control. Thus, 6-thioguanine photosensitizes cells to UVA radiation.
Whether these findings are relevant to the incidence of squamous-cell carcinoma in patients treated with azathioprine has yet to be determined, although the authors provided a relevant finding. They compared the minimal erythema dose (the minimal amount of radiation required to elicit erythema) in patients before and three months after the initiation of therapeutic doses of azathioprine and found that with treatment, the skin became more sensitive to UVA but not UVB radiation.
Several observations indicate that multiple factors may be involved in the accelerated rate of appearance of tumors. For instance, organ-transplant recipients who are receiving azathioprine have an increased incidence of cancer on areas of the skin and mucous membranes that have not been exposed to the sun. In addition, patients receiving cyclosporine alone also have an increased risk of squamous-cell carcinoma, and there is no evidence that cyclosporine is a photosensitizer.
There is, however, a precedent for drug-induced sensitivity to UVA radiation and increased susceptibility to skin cancers. A 20-year prospective study showed that multiple aggressive squamous-cell carcinomas developed in UVA-exposed sites in patients with psoriasis treated with an oral psoralen and UVA radiation from high-intensity lamps (PUVA).4 Psoralens are intercalated into DNA and, in the doses used for therapy, increase the sensitivity of the skin to UVA radiation by a factor of 10 to 100. By comparison, the skin of the azathioprine-treated patients studied by O'Donovan et al. was no more than three times as sensitive to UVA radiation (as determined by experiments involving the minimal erythema dose). However, psoralen-induced photosensitization lasts only hours and is used only two or three times per week, whereas azathioprine treatment is usually continuous.
The known carcinogenic and immunosuppressive effects of ultraviolet radiation are caused predominantly by exposure to UVB radiation, the strongest risk factor for skin cancer in the general population. Although continued exposure to UVB radiation is likely to be a major risk factor for squamous-cell carcinoma in azathioprine-treated patients, the most important determinants of risk in transplant recipients are probably prior exposure to cutaneous carcinogens such as UVB radiation and PUVA. When substantial exposure to PUVA is followed by immunosuppressive therapy, the risk of squamous-cell carcinoma is further increased and exceeds one case per year among those using immunosuppressive therapies for at least three months.5
Regardless, we should heed the implications of the study by O'Donovan et al.3 Measures to reduce the risk of skin cancer should include the use of a so-called broad-spectrum sunscreen that protects against UVA as well as UVB radiation. That said, the Food and Drug Administration might consider adopting standards for UVA testing and using "broad spectrum" as a label.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Dermatology, Massachusetts General Hospital, Boston.
References
Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol 2002;47:1-17.
Hartevelt MM, Bavinck JN, Kootte AM, Vermeer BJ, Vandenbroucke JP. Incidence of skin cancer after renal transplantation in The Netherlands. Transplantation 1990;49:506-509.
O'Donovan P, Perrett CM, Zhang X, et al. Azathioprine and UVA light generate mutagenic oxidative DNA damage. Science 2005;309:1871-1874.
Stern RS, Laird N, Melski J, Parrish JA, Fitzpatrick TB, Bleich HL. Cutaneous squamous-cell carcinoma in patients treated with PUVA. N Engl J Med 1984;310:1156-1161.
Marcil I, Stern R. Squamous-cell cancer of the skin in patients given PUVA and ciclosporin: nested cohort crossover study. Lancet 2001;358:1042-1045.(John A. Parrish, M.D.)