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Mechanism of action of FK 506 and cyclosporin
439
Mechanism of action of FK 506 and
cyclosporin SIR,-The mechanism of action of FK 506 and cyclosporin is still unclear, as discussed by Dr Macleod and Dr Thomson (Jan 5, p 25). Both FK 506 and cyclosporin bind to immunophilins, proteins with
peptidyl-prolyl cis-trans isomerase activity (PPIase), not phosphatidyl-prolyl isomerase, as erroneously stated by Macleod and Thomson. PPIase activity is inhibited by these drugs in vitro, but it is unknown whether PPIase has a physiological function and thus whether inhibition of this enzyme is important in
immunosuppression. PPIase accelerates otherwise slow, rate-limiting isomerisation steps in the in-vitro folding of proteins to their fmal conformation. We have studied the folding of procollagen in suspended chick embryo tendon fibroblasts,’ a system that allows monitoring of protein folding in intact cells. We have shown that procollagen folding is slowed by cyclosporin, in both chick embryos and cultured human fibroblasts.’ Besides indicating that PPIase has a function in living cells, these findings suggest that PPIase inhibition may be crucial for immunosuppression and support the hypothesis2 that cyclosporin, and probably also FK 506, inhibit the folding of an unidentified protein that is critical to T-lymphocyte activation. Division of Metabolism, Department of Paediatrics, University of Zurich, 8032 Zurich, Switzerland
BEAT STEINMANN ANDREA SUPERTI-FURGA
PETER BRUCKNER
1 Steinmann B, Bruckner P, Superti-Furga A. Cyclosporin A slows collagen triple-helix
vivo-indirect evidence for a physiologic role of J Biol Chem 1991; 266: 1299-303. 2. Kahan BD. Cyclosporine. N Engl Med 1989, 321: 1725-38. J
formation
m
ultraviolet-induced carcinogenesis than are central European patients. We would point out that our survey encompasses a considerable number of patients (39%) from Scandinavia who are also of skin types 1 and 2. We cannot explain the apparent discrepancy in tumour risk of continental European vs American and Scottish patients, apart from photobiological evidence that the American PUVA regimen is more carcinogenic than the European procedure. With respect to penile carcinomas it is noteworthy that in the USA many more men are circumcised than are in continental Europe, which would place these individuals in a higher risk group. Department of Dermatology I, University of Vienna Medical School,
K. WOLFF H. HÖNIGSMANN
A-1090 Vienna, Austria 1 Stem RS and Members of the
Photochemotherapy Follow-up Study. Genital
among men with psoriasis exposed to psoralens and ultraviolet A (PUVA) radiation and ultraviolet B radiation. N Engl J Med 1990; 322: 1093-97. rumours
2. Stem RS, Lange R.
Photochemotherapy: follow-up study. J Invest Dermatol 1988; 91:
120-24. 3
Honigsmann H, Wolff K, Gschnait F, et al. Keratoses and non melanoma skin tumours in long-term photochemotherapy (PUVA). J Am Acad Dermatol 1980; 3:
406-14. A, Reunala T, Idanpaan-Heikkila J, et al. PUVA treatment and skin cancer: a follow-up study. Acta Derm Venereol 1981; 61: 141-45. 5 Ros AM, Wennersten G, Lagerholm B. Long-term photochemotherapy for psonasis: a histopathological and clinical follow-up study with special emphasis on tumour incidence and behaviour of pigmented lesions. Acta Derm Venereol 1983; 63: 215-21. 6. Lindskov R. Skin carcinomas and treatment with photochemotherapy (PUVA). Acta Derm Venereol 1983; 63: 223-26. 7. Tanew A, Honigsmann H, Ortel B, et al. Nonmelanoma skin tumours in long-term photochemotherapy treatment of psoriasis. J Am Acad Dermatol 1986; 15: 980-85. 8 Henseler T, Christophers E, Honigsmann H, et al. Skin tumours in the European PUVA study. J Am Acad Dermatol 1987; 16: 108-16. 9. Gibbs NK, Honigsmann H, Young AR. PUVA treatment strategies and cancer risk. Lancet 1986; i: 150-51. 10. Henseler T, Wolff K, Hönigsmann H, et al. Oral 8-methoxypsoralen photochemotherapy of psoriasis. Lancet 1981; i: 853-57. 4. Lassus
Department of Biochemistry, Swiss Federal Institute of Technology, Zurich
However, Perkins et al feel that tar alone is not an additional risk factor; they ascribe the higher risk to the fact that their patients mostly have skin type 2 and thus are much more susceptible to
peptidyl-prolyl
cis-trans isomerase.
Genital carcinomas in psoriasis patients treated with photochemotherapy SIR,-Dr Perkins and colleagues (Nov 17, p 1248) report from Glasgow 3 male patients with psoriasis from a cohort of only 130 patients in whom genital malignant disease had developed after fairly high doses of photochemotherapy (PUVA). Stern et all showed an alarming increased risk of genital tumours in PUVAtreated men, with an incidence of invasive squamous cell carcinoma 286 times that of the general population in those exposed to high-dose PUVA. A US multicentre study noted a significant overall increased cancer risk in PUVA patients 5--10 years after their first treatment,’ but European epidemiological surveys uniformly found an increased risk only in patients previously treated with other potential carcinogens and failed to reveal any direct correlation between increased risk and PUV A. 3-8 This discrepancy has so far not been explained, but it has been. suggested that the disparity in cancer risk between the US and European surveys could be attributable to differences in the therapeutic strategies used.9 Although a long-term follow-up study of about 3000 patients with psoriasis in the European multicentre PUVA studyl° is continuing, the striking increase in risk of genital tumours reported by Stern_ 1 and by Perkins et al prompted us to look at the prevalence of genital tumours in male patients in continental Europe. A total of 32 599 patients have been treated in eleven European University centres in the past 13-16 years with systemic and topical (bath) PUVA. About 10-15% of these patients have received intermittent PUVA over 15 years. The highest cumulative UVA doses ranged from 1698 to 5580 J/cm. No genital tumours were observed in any of these patients. Although this analysis is uncontrolled and has not been tested statistically, the absence of genital tumours is remarkable. In view of the large number of patients and the risk of genital tumours postulated by Stern et al,9 we would expect to have found at least a few patients with such lesions. None of the American patients had had concomitant or previous herpesvirus infections but all had been treated, as had Perkins and colleagues’ Scottish patients, with tar and shortwave ultraviolet radiation before PUVA was initiated.
How does tamoxifen interact with
chemotherapy? SiR,—The Early Breast Cancer Trialists’ Collaborative Group has recently published a systematic overview of randomised trials of tamoxifen that began before 1985, concentrating on follow-up during the first five years.1 The results contain interesting data on a possible interaction of tamoxifen with chemotherapy. The trials were of two types-tamoxifen versus nil ("T alone trials") or tamoxifen plus chemotherapy compared with the same chemotherapy alone ("T plus C trials"). There is no evidence of a difference in the effect of tamoxifen in the two types of trial when the results are considered as a whole. However, the results can be divided into four categories on the basis of trial type-namely, with or without chemotherapy and age below 50 or 50 or more. When the endpoints of both mortality and recurrence (or prior death) are examined the magnitude of the odds reductions (and SD) favouring the tamoxifen-treated patients differs only in the T plus C, age less than 50 group: Trial type
T only T plus C
Mortality Age < 50 Age 3 50 21(14)% 19(4)% -9 (9)% 22(6)%
Recurrence
Age < 50 32(10)% 8
(7)%
Age 50 32(3)% 35(5)%
Two arguments that this is not a real effect are that comparisons of odds reductions from different trials are not randomised and may be biased by patient selection, and that subgroup analyses such as this can easily generate spurious results. Statistically, this is a second-order interaction, and may therefore be difficult to believe. (The differential effect of tamoxifen in the < 50 and 50 age groups is first order. The suggestion that within this interaction there is also a difference in the effect dependent on whether or not chemotherapy is given is therefore second-order.) The plausibility of this effect is strengthened, however, by the fact that it appears for both the mortality and recurrence endpoints. Despite these reservations, we believe that the apparent reduction in the effect of tamoxifen in the presence of chemotherapy in patients less than 50 is
Mechanism of action of FK 506 and
cyclosporin SIR,-The mechanism of action of FK 506 and cyclosporin is still unclear, as discussed by Dr Macleod and Dr Thomson (Jan 5, p 25). Both FK 506 and cyclosporin bind to immunophilins, proteins with
peptidyl-prolyl cis-trans isomerase activity (PPIase), not phosphatidyl-prolyl isomerase, as erroneously stated by Macleod and Thomson. PPIase activity is inhibited by these drugs in vitro, but it is unknown whether PPIase has a physiological function and thus whether inhibition of this enzyme is important in
immunosuppression. PPIase accelerates otherwise slow, rate-limiting isomerisation steps in the in-vitro folding of proteins to their fmal conformation. We have studied the folding of procollagen in suspended chick embryo tendon fibroblasts,’ a system that allows monitoring of protein folding in intact cells. We have shown that procollagen folding is slowed by cyclosporin, in both chick embryos and cultured human fibroblasts.’ Besides indicating that PPIase has a function in living cells, these findings suggest that PPIase inhibition may be crucial for immunosuppression and support the hypothesis2 that cyclosporin, and probably also FK 506, inhibit the folding of an unidentified protein that is critical to T-lymphocyte activation. Division of Metabolism, Department of Paediatrics, University of Zurich, 8032 Zurich, Switzerland
BEAT STEINMANN ANDREA SUPERTI-FURGA
PETER BRUCKNER
1 Steinmann B, Bruckner P, Superti-Furga A. Cyclosporin A slows collagen triple-helix
vivo-indirect evidence for a physiologic role of J Biol Chem 1991; 266: 1299-303. 2. Kahan BD. Cyclosporine. N Engl Med 1989, 321: 1725-38. J
formation
m
ultraviolet-induced carcinogenesis than are central European patients. We would point out that our survey encompasses a considerable number of patients (39%) from Scandinavia who are also of skin types 1 and 2. We cannot explain the apparent discrepancy in tumour risk of continental European vs American and Scottish patients, apart from photobiological evidence that the American PUVA regimen is more carcinogenic than the European procedure. With respect to penile carcinomas it is noteworthy that in the USA many more men are circumcised than are in continental Europe, which would place these individuals in a higher risk group. Department of Dermatology I, University of Vienna Medical School,
K. WOLFF H. HÖNIGSMANN
A-1090 Vienna, Austria 1 Stem RS and Members of the
Photochemotherapy Follow-up Study. Genital
among men with psoriasis exposed to psoralens and ultraviolet A (PUVA) radiation and ultraviolet B radiation. N Engl J Med 1990; 322: 1093-97. rumours
2. Stem RS, Lange R.
Photochemotherapy: follow-up study. J Invest Dermatol 1988; 91:
120-24. 3
Honigsmann H, Wolff K, Gschnait F, et al. Keratoses and non melanoma skin tumours in long-term photochemotherapy (PUVA). J Am Acad Dermatol 1980; 3:
406-14. A, Reunala T, Idanpaan-Heikkila J, et al. PUVA treatment and skin cancer: a follow-up study. Acta Derm Venereol 1981; 61: 141-45. 5 Ros AM, Wennersten G, Lagerholm B. Long-term photochemotherapy for psonasis: a histopathological and clinical follow-up study with special emphasis on tumour incidence and behaviour of pigmented lesions. Acta Derm Venereol 1983; 63: 215-21. 6. Lindskov R. Skin carcinomas and treatment with photochemotherapy (PUVA). Acta Derm Venereol 1983; 63: 223-26. 7. Tanew A, Honigsmann H, Ortel B, et al. Nonmelanoma skin tumours in long-term photochemotherapy treatment of psoriasis. J Am Acad Dermatol 1986; 15: 980-85. 8 Henseler T, Christophers E, Honigsmann H, et al. Skin tumours in the European PUVA study. J Am Acad Dermatol 1987; 16: 108-16. 9. Gibbs NK, Honigsmann H, Young AR. PUVA treatment strategies and cancer risk. Lancet 1986; i: 150-51. 10. Henseler T, Wolff K, Hönigsmann H, et al. Oral 8-methoxypsoralen photochemotherapy of psoriasis. Lancet 1981; i: 853-57. 4. Lassus
Department of Biochemistry, Swiss Federal Institute of Technology, Zurich
However, Perkins et al feel that tar alone is not an additional risk factor; they ascribe the higher risk to the fact that their patients mostly have skin type 2 and thus are much more susceptible to
peptidyl-prolyl
cis-trans isomerase.
Genital carcinomas in psoriasis patients treated with photochemotherapy SIR,-Dr Perkins and colleagues (Nov 17, p 1248) report from Glasgow 3 male patients with psoriasis from a cohort of only 130 patients in whom genital malignant disease had developed after fairly high doses of photochemotherapy (PUVA). Stern et all showed an alarming increased risk of genital tumours in PUVAtreated men, with an incidence of invasive squamous cell carcinoma 286 times that of the general population in those exposed to high-dose PUVA. A US multicentre study noted a significant overall increased cancer risk in PUVA patients 5--10 years after their first treatment,’ but European epidemiological surveys uniformly found an increased risk only in patients previously treated with other potential carcinogens and failed to reveal any direct correlation between increased risk and PUV A. 3-8 This discrepancy has so far not been explained, but it has been. suggested that the disparity in cancer risk between the US and European surveys could be attributable to differences in the therapeutic strategies used.9 Although a long-term follow-up study of about 3000 patients with psoriasis in the European multicentre PUVA studyl° is continuing, the striking increase in risk of genital tumours reported by Stern_ 1 and by Perkins et al prompted us to look at the prevalence of genital tumours in male patients in continental Europe. A total of 32 599 patients have been treated in eleven European University centres in the past 13-16 years with systemic and topical (bath) PUVA. About 10-15% of these patients have received intermittent PUVA over 15 years. The highest cumulative UVA doses ranged from 1698 to 5580 J/cm. No genital tumours were observed in any of these patients. Although this analysis is uncontrolled and has not been tested statistically, the absence of genital tumours is remarkable. In view of the large number of patients and the risk of genital tumours postulated by Stern et al,9 we would expect to have found at least a few patients with such lesions. None of the American patients had had concomitant or previous herpesvirus infections but all had been treated, as had Perkins and colleagues’ Scottish patients, with tar and shortwave ultraviolet radiation before PUVA was initiated.
How does tamoxifen interact with
chemotherapy? SiR,—The Early Breast Cancer Trialists’ Collaborative Group has recently published a systematic overview of randomised trials of tamoxifen that began before 1985, concentrating on follow-up during the first five years.1 The results contain interesting data on a possible interaction of tamoxifen with chemotherapy. The trials were of two types-tamoxifen versus nil ("T alone trials") or tamoxifen plus chemotherapy compared with the same chemotherapy alone ("T plus C trials"). There is no evidence of a difference in the effect of tamoxifen in the two types of trial when the results are considered as a whole. However, the results can be divided into four categories on the basis of trial type-namely, with or without chemotherapy and age below 50 or 50 or more. When the endpoints of both mortality and recurrence (or prior death) are examined the magnitude of the odds reductions (and SD) favouring the tamoxifen-treated patients differs only in the T plus C, age less than 50 group: Trial type
T only T plus C
Mortality Age < 50 Age 3 50 21(14)% 19(4)% -9 (9)% 22(6)%
Recurrence
Age < 50 32(10)% 8
(7)%
Age 50 32(3)% 35(5)%
Two arguments that this is not a real effect are that comparisons of odds reductions from different trials are not randomised and may be biased by patient selection, and that subgroup analyses such as this can easily generate spurious results. Statistically, this is a second-order interaction, and may therefore be difficult to believe. (The differential effect of tamoxifen in the < 50 and 50 age groups is first order. The suggestion that within this interaction there is also a difference in the effect dependent on whether or not chemotherapy is given is therefore second-order.) The plausibility of this effect is strengthened, however, by the fact that it appears for both the mortality and recurrence endpoints. Despite these reservations, we believe that the apparent reduction in the effect of tamoxifen in the presence of chemotherapy in patients less than 50 is