189 eration has been stimulated, and transformation of cells has also been shown to be associated with lowered cellular concentrations of cyclic A.M.P.9-11 In psoriasis, a disorder in which epidermal-cell proliferation is excessive, epidermal adenyl-cyclase activity appears to be slug-
DOES ULTRAVIOLET-EVOKED PROSTAGLANDIN FORMATION PROTECT SKIN FROM ACTINIC CANCER? MALCOLM W. GREAVES Institute
St. John’s Hospital for Diseases Homerton Grove, London E9 6BX
of Dermatology, the Skin,
of
The role of increased prostaglandin activity which results from exposure of human skin to ultraviolet light is uncertain. Evidence from the effects of prostaglandins on epithelial cells in vitro suggests that prostaglandin E reduces proliferative activity in the epidermis, probably through a cyclicA.M.P.-dependent mechanism, thus reducing the vulnerability of epidermis to the mutagenic effects of ultraviolet exposure.
Summary
HYPOTHESIS
"WHITE" skin is not well adapted to strong sunlight, and the acute effects of over-long exposure to the sun can be unpleasant. Chronic, more insidious effects include the development of precancerous or cancerous warts and tumours of the epidermis. An upsurge of interest in the biological responses of skin to ultraviolet (u.v.) irradiation has also been prompted by the increasing use of long-wavelength u.v. radiation combined with systemic photosensitising psoralen administration (P.U.V.A.) in the treatment of psoriasis. The mutagenic action of P.U.V.A. on keratinocytes can be predicted from experiments in vitro.2,3 Concentrations of prostaglandins (P.G.s) and their precursors and metabolites are increased in exudate from human skin irradiated with "sunburn" (290-320 nm) u.v. in vivo,4-6 and this has led to the supposition that these vasoactive substances mediate sunburn erythema. Demonstrable suppression of sunburn erythema by indomethacin has strengthened this view. However, detailed studies of the appearance and disappearance of prostaglandins and their precursors and metabolites in the presence and absence of indomethacin suggest that inflammatory changes in irradiated skin cannot be satisfactorily explained by the actions of these agents alone.5,6 Of special interest is the finding that exudate from human skin irradiated with three times the minimum erythema dose of long-wavelength ultraviolet following psoralen pretreatment (P.U.V.A. erythema) shows 7 no increase in prostaglandin activity. Current views on the actions of prostaglandins emphasise their defensive roles. For example, in the lungs prostaglandins may regulate vascular perfusion, maintain bronchial-muscle tone, and prevent excessive bronchoconstriction. In the kidney they appear to modulate renal blood-flow, attenuate the action of pressor hormones, and amplify the vasodilator action of kinins. Interaction between two products of arachidonic-acid metabolism-thromboxane A2 and prostacyclin (P.G.1-2) - regulates platelet aggregation and maintains coronaryartery perfusion.8I suggest that evoked prostaglandin formation has a similar protective effect on the epidermis of sun-exposed skin. A fall in cellular cyclic A.M.P. and a rise in cyclic guanosine monophosphate (G.M.P.) have been reported in several cell-culture systems in which active prolif-
gish,’2 epidermal cyclic A.M.P. reduced,13 and cyclic G.M.P. increased,14 suggesting that a balance between these two nucleotides maintains epidermal homceostasis. Furthermore, prostaglandins, which are present in normal human
epidermis and which have been shown to inepidermal cyclic A.M.P. in normal skin in vitro, cause a significantly smaller increase in cyclic A.M.P. in psoriatic skin." Inhibition of epidermal tumour growth by prostaglandins has not yet been demonstrated, but prostaglandin E reduces the growth-rate of hela cells (possibly by a cyclic-nucleotide-dependent mechanism) and B-16 mouse melanoma cells in vitro,16,17 and prostaglandin E,reduces the damaging effect of ionising radiation on cells in vitro.18 On these grounds the presence of raised levels of P.G.E2 in u.v.-irradiated human skin would be expected to protect epidermal cells from the mutagenic effect of u.v. by increasing cyclic-A.M.P. formation, thus reducing the vulnerable pool of actively dividing cells. A number of important consequences might then be expected. Since we have been unable to demonstrate elevation of prostaglandins or related substances after long-wavelength u.v. irradiation in the skin of psoralen-treated subjects, the possibility of skin neoplasia developing in patients receiving this intense irradiation regularly needs careful consideration. It is also conceivable that long-term treatment with non-steroid anti-inflammatory prostaglandin-synthetase inhibitors (including indomethacin) and propionic-acid derivatives might be associated with increased incidence of skin carcinoma, especially in fair-skinned people in sunny climates. The prostaglandin synthesising and catabolising capacity of the skin of patients prone to develop multiple skin malignancy would also be worth investigating. However intriguing these possibilities appear, the first steps in substantiating the hypothesis presented here crease
must
be based
on
careful correlative studies of prosta-
glandin activity, epidermal-cell kinetics, and epidermal cyclic-A.M.P. levels in u.v.-irradiated human and animal skin. REFERENCES 1. 2.
3. 4. 5. 6. 7. 8.
T.
Parrish, J. A., Fitzpatrick, B., Tanenbaum, L., Pathak, M. A. New Engl. J. Med. 1974, 291, 1207. Igali, S., Bridges, B. A., Ashwood Smith, M. J., Scott, B. R. Mutation Res. 1970, 9, 21. Ashwood Smith, M. J., Grant, E. Br. med. J. 1976,i, 342. Greaves, M. W., Sondergaard, J. S. J. invest. Derm. 1970, 54, 365. Black, A ,K., Greaves, M. W., Hensby, C. N., Plummer, N. A. Br. J. clin. Pharmac. (in the press). Black, A. K., Greaves, M. W., Hensby, C. N., Plummer, N. A., Warm, A. P. ibid. (in the press). Hensby, C. N., Plummer, N. A., Warin, A. P., Greaves, M. W. Unpublished. Moncada, S., Gryglewsksi, R., Bunting, S., Vane, J. R. Nature, 1976, 263, 663.
9. 10.
Sheppard, J. R. Nature new Biol. 1972, 236, 14. Hadden, J. W., Hadden, E. M., Haddox, M. K., Goldberg, N. Acad. Sci. U.S.A.
11. 12. 13. 14. 15. 16. 17. 18.
D. Proc. natn.
1972, 69, 3024. Seifert, W. E., Rudland, P. S. Nature, 1974, 248, 138. Wright, R. K., Mandy, S. H., Halprin, K. M., Hsia, S. L. Archs Derm. 1973, 107, 47. Voorhees, J. J., Duell, E. A., Bass, L. J., Powell, J. A., Harrell, E. R. ibid. 1972, 105, 695. Voorhees, J. J., Stawiski, M., Duell, E. A., Haddox, M. K., Goldberg, N. D. Life Sci. 1973, 13, 639. Aso, K., Orenberg, E. K., Farber, E. M. J. invest. Derm. 1975, 65, 375. Thomas, D. R., Philpott, G. W., Jaffe, B. M. Exp. Cell. Res. 1974, 84, 40. Santoro, M. G., Philpott, G. W., Jaffe, B. M. Nature, 1976, 263. 777. Eisen, V., Walker, D. I. Br. J. Pharmac. 1976, 57, 527.
DOES ULTRAVIOLET-EVOKED PROSTAGLANDIN FORMATION PROTECT SKIN FROM ACTINIC CANCER? MALCOLM W. GREAVES Institute
St. John’s Hospital for Diseases Homerton Grove, London E9 6BX
of Dermatology, the Skin,
of
The role of increased prostaglandin activity which results from exposure of human skin to ultraviolet light is uncertain. Evidence from the effects of prostaglandins on epithelial cells in vitro suggests that prostaglandin E reduces proliferative activity in the epidermis, probably through a cyclicA.M.P.-dependent mechanism, thus reducing the vulnerability of epidermis to the mutagenic effects of ultraviolet exposure.
Summary
HYPOTHESIS
"WHITE" skin is not well adapted to strong sunlight, and the acute effects of over-long exposure to the sun can be unpleasant. Chronic, more insidious effects include the development of precancerous or cancerous warts and tumours of the epidermis. An upsurge of interest in the biological responses of skin to ultraviolet (u.v.) irradiation has also been prompted by the increasing use of long-wavelength u.v. radiation combined with systemic photosensitising psoralen administration (P.U.V.A.) in the treatment of psoriasis. The mutagenic action of P.U.V.A. on keratinocytes can be predicted from experiments in vitro.2,3 Concentrations of prostaglandins (P.G.s) and their precursors and metabolites are increased in exudate from human skin irradiated with "sunburn" (290-320 nm) u.v. in vivo,4-6 and this has led to the supposition that these vasoactive substances mediate sunburn erythema. Demonstrable suppression of sunburn erythema by indomethacin has strengthened this view. However, detailed studies of the appearance and disappearance of prostaglandins and their precursors and metabolites in the presence and absence of indomethacin suggest that inflammatory changes in irradiated skin cannot be satisfactorily explained by the actions of these agents alone.5,6 Of special interest is the finding that exudate from human skin irradiated with three times the minimum erythema dose of long-wavelength ultraviolet following psoralen pretreatment (P.U.V.A. erythema) shows 7 no increase in prostaglandin activity. Current views on the actions of prostaglandins emphasise their defensive roles. For example, in the lungs prostaglandins may regulate vascular perfusion, maintain bronchial-muscle tone, and prevent excessive bronchoconstriction. In the kidney they appear to modulate renal blood-flow, attenuate the action of pressor hormones, and amplify the vasodilator action of kinins. Interaction between two products of arachidonic-acid metabolism-thromboxane A2 and prostacyclin (P.G.1-2) - regulates platelet aggregation and maintains coronaryartery perfusion.8I suggest that evoked prostaglandin formation has a similar protective effect on the epidermis of sun-exposed skin. A fall in cellular cyclic A.M.P. and a rise in cyclic guanosine monophosphate (G.M.P.) have been reported in several cell-culture systems in which active prolif-
gish,’2 epidermal cyclic A.M.P. reduced,13 and cyclic G.M.P. increased,14 suggesting that a balance between these two nucleotides maintains epidermal homceostasis. Furthermore, prostaglandins, which are present in normal human
epidermis and which have been shown to inepidermal cyclic A.M.P. in normal skin in vitro, cause a significantly smaller increase in cyclic A.M.P. in psoriatic skin." Inhibition of epidermal tumour growth by prostaglandins has not yet been demonstrated, but prostaglandin E reduces the growth-rate of hela cells (possibly by a cyclic-nucleotide-dependent mechanism) and B-16 mouse melanoma cells in vitro,16,17 and prostaglandin E,reduces the damaging effect of ionising radiation on cells in vitro.18 On these grounds the presence of raised levels of P.G.E2 in u.v.-irradiated human skin would be expected to protect epidermal cells from the mutagenic effect of u.v. by increasing cyclic-A.M.P. formation, thus reducing the vulnerable pool of actively dividing cells. A number of important consequences might then be expected. Since we have been unable to demonstrate elevation of prostaglandins or related substances after long-wavelength u.v. irradiation in the skin of psoralen-treated subjects, the possibility of skin neoplasia developing in patients receiving this intense irradiation regularly needs careful consideration. It is also conceivable that long-term treatment with non-steroid anti-inflammatory prostaglandin-synthetase inhibitors (including indomethacin) and propionic-acid derivatives might be associated with increased incidence of skin carcinoma, especially in fair-skinned people in sunny climates. The prostaglandin synthesising and catabolising capacity of the skin of patients prone to develop multiple skin malignancy would also be worth investigating. However intriguing these possibilities appear, the first steps in substantiating the hypothesis presented here crease
must
be based
on
careful correlative studies of prosta-
glandin activity, epidermal-cell kinetics, and epidermal cyclic-A.M.P. levels in u.v.-irradiated human and animal skin. REFERENCES 1. 2.
3. 4. 5. 6. 7. 8.
T.
Parrish, J. A., Fitzpatrick, B., Tanenbaum, L., Pathak, M. A. New Engl. J. Med. 1974, 291, 1207. Igali, S., Bridges, B. A., Ashwood Smith, M. J., Scott, B. R. Mutation Res. 1970, 9, 21. Ashwood Smith, M. J., Grant, E. Br. med. J. 1976,i, 342. Greaves, M. W., Sondergaard, J. S. J. invest. Derm. 1970, 54, 365. Black, A ,K., Greaves, M. W., Hensby, C. N., Plummer, N. A. Br. J. clin. Pharmac. (in the press). Black, A. K., Greaves, M. W., Hensby, C. N., Plummer, N. A., Warm, A. P. ibid. (in the press). Hensby, C. N., Plummer, N. A., Warin, A. P., Greaves, M. W. Unpublished. Moncada, S., Gryglewsksi, R., Bunting, S., Vane, J. R. Nature, 1976, 263, 663.
9. 10.
Sheppard, J. R. Nature new Biol. 1972, 236, 14. Hadden, J. W., Hadden, E. M., Haddox, M. K., Goldberg, N. Acad. Sci. U.S.A.
11. 12. 13. 14. 15. 16. 17. 18.
D. Proc. natn.
1972, 69, 3024. Seifert, W. E., Rudland, P. S. Nature, 1974, 248, 138. Wright, R. K., Mandy, S. H., Halprin, K. M., Hsia, S. L. Archs Derm. 1973, 107, 47. Voorhees, J. J., Duell, E. A., Bass, L. J., Powell, J. A., Harrell, E. R. ibid. 1972, 105, 695. Voorhees, J. J., Stawiski, M., Duell, E. A., Haddox, M. K., Goldberg, N. D. Life Sci. 1973, 13, 639. Aso, K., Orenberg, E. K., Farber, E. M. J. invest. Derm. 1975, 65, 375. Thomas, D. R., Philpott, G. W., Jaffe, B. M. Exp. Cell. Res. 1974, 84, 40. Santoro, M. G., Philpott, G. W., Jaffe, B. M. Nature, 1976, 263. 777. Eisen, V., Walker, D. I. Br. J. Pharmac. 1976, 57, 527.
