537

Ultraviolet Radiation and Cancer ofthe Skin

THE LANCET

As a cause of skin damage, especially skin

cancer, ultraviolet (u.v.) radiation is arousing ser-ious concern. Sun-induced skin injury is caused bythe u.v. part of the solar emission spectrum. Solaru.v. radiation can conveniently, but arbitrarily, bedivided into three zones-u.v.-A (long wavelengthu.v., 320-400 nm); u.v.-B (sunburn u.v., 290-320nm); and u.v.-C (short-wavelength "germicidal"u.v., below 290 nm). The intensity and wavelengthcut-off point of u.v. radiation at the earth’s surfaceis limited by the filtering action of the stratosphericozone layer, so that u.v.-C is prevented from reach-ing human skin. The increasing use of fluoro-carbon aerosol propellants and refrigerants, as

well as the advent of supersonic air travel, mayweaken the barrier function of the ozone layer,thus permitting more short-wavelength u.v. to

penetrate the earth’s atmosphere.’ Animal work byBLUM2 suggests that the carcinogenic effects of pro-longed exposure to u.v. are cumulative, the inci-dence of skin cancer being directly proportional tothe square root of the yearly dose. Thus a declineof atmospheric ozone can be expected to increasethe frequency of skin cancer, especially in lowerlatitudes.

At a molecular level, u.v. causes thymine dimerformation in D.N.A., the repair of which involvesenzymatic excision and repair of the damaged sec-tion of the D.N.A. strand.3 Failure of the repairmechanism is seen in its classic form in the rare

genodermatosis xeroderma pigmentosum.4 As a

result of a greatly increased incidence of mutationsand cell transformations in the skin, epitheliomasarise continually, with a predilection for light-exposed skin. A similar defect, in less florid form,may underlie the much commoner premalignantcondition of multiple solar keratoses. Patientsusually give a history of prolonged exposure to sun-light. Histologically the warty keratoses are charac-terised by dysplastic cells within the epidermis.

1. Johnston, H. Science, 1971, 173, 517.2. Blum, H. F. Photochem. Photobiol. 1976, 24, 249.3. Cleaver, J. E. Adv. Radiat. Biol. 1974, 4, 1.4. Cleaver, J. E. Proc. natn. Acad. Sci., U.S.A. 1969, 63, 428.

SwANBECK and his colleagues’ have shown thatleucocytes from patients with this condition havesignificantly reduced D.N.A. repair synthesis; andsimilar results have been reported from Glasgow6with lymphocyte cultures. Since D.N.A. repair is amulti-step process the precise nature of the defectremains uncertain. Nevertheless these findingsraise the interesting possibility that individualswith increased susceptibility to the mutageniceffects of u.v. may be identifiable.

’

Viewing the same problem from a pharmacologi-cal angle, GREAVES7 has proposed a link betweenthe acute and chronic responses of skin to u.v.radiation. exposure of human skin to u.v.-B causesincreased formation of the prostaglandin (P.G.) pre-cursor arachidonic acid and its prostaglandinmetabolites P.G.E2 and P.G.F2a, the levels reachinga maximum about 24 h after irradiation. Drawingfrom evidence of the inhibitory actions of prosta-glandins and cyclic A.M.P. on cell division in severalepithelial cell-culture systems, GREAVES suggeststhat u.v.-B-evoked prostaglandin formation plays aprotective role in skin by reducing the proliferativeactivity of the epidermis, and hence its vulnerabilityto the mutagenic actions of u.v. One difficulty withthis concept is that intradermal injection of P.G.Einto human skin causes an apparent increase in epi-dermal mitotic activity, but the doses used are athousand times higher than the amounts found inu.v.-B irradiated skin.

’

Notwithstanding the potentially harmful actionsof high-dosage u.v., phototherapy has been usedfor a least half a century in the treatment of in-flammatory, pigmentary, and proliferative dis-orders of skin. There is intense interest, in particu-lar, in long-term treatment of psoriasis by a com-bination of a systemically administered photo-sensitising psoralen and high-intensity long-wave-length (u.v.-A) irradiation (photochemotherapy,P.U.V.A.).9 This regimen is now used in many hospi-tals throughout the U.K. P.U.V.A. treatment is

usually effective in psoriasis and, despite the neces-sity in most patients for long-term maintenancetreatment, patients find it much more acceptablethan the conventional tar or dithranol regimens. Itis also an outpatient treatment, and seems to bealmost free of serious short-term side-effects. In

psoriasis the rate of epidermal cellular proliferationis increased, and the prevailing view is that resolu-tion of psoriatic lesions in response to P.U.V.A. isdue to production of D.N.A. damage which in turnleads to inhibition of epidermal D.N.A. synthesis. to

5. Lambert, B., Ringborg, U., Swanbeck, G. Acta dermatovener. 1976, 67, 594.6. Abo-Darub, J. M., Pitts, J. D., Mackie, R. M. Communication to British As-

sociation of Dermatologists Investigative Group, Jan. 27, 1978.7. Greaves, M. W. Lancet, 1978, i, 189.8. Eaglstein, W. H., Weinstein, G. D. J. invest. Derm. 1975, 64, 386.9. Parrish, J. A., Ftizpatrick, T. B., Tanenbaum, L., Pathak, M. A. New Engl.

J. Med. 1974, 291, 1207.10. Walter, J. F., Voorhees, J. J., Kelsey, W. H., Duell, E. A. Archs Derm. 1973,

107, 861.

538

Psoralens form photoadducts and interstrand cross-links with D.N.A. in the presence of u.v.-A and

mounting evidence indicates that these events aremutagenic. We have known for some time that, inEscherichia coli cultures, 8-methoxypsoralen pro-duces mutations in the presence of u.v.-A." Morerecently extensive chromosome damage has beenproduced by long wavelength u.v. in Chinese ham-ster cell cultures containing 8-methoxypsoralen.12In man, P.U.V.A. may well give rise to similar chro-mosomal damage. Although sister chromatid

exchange studies after p.u.v.A. treatment in vivohave revealed no evidence of chromosome lesions, 13in-vitro irradiation of human lymphocytes byu.v.-A in the presence of 8-methoxypsoralen signifi-cantly increased the frequency of chromosomalaberrations. 14, 15 Evidence of chromosomal damagedoes not by itself prove that P.U.V.A. treatment iscarcinogenic in the skin, but there is certainlycause for disquiet in the ability of parenteral8-methoxypsoralen combined with u.v.-A to pro-mote skin cancer in mice16-18 and to increase therate of squamous epithelioma in patients with xero-derma pigmentosum.19 The large majority of pa-tients with common chronic plaque psoriasis re-spond satisfactorily to topical dithranol or tar

therapy, and a two-centre M.R.C. supported clini-cal trial is now comparing the efficacy of P.U.V.A.and dithranol in psoriasis. This information shouldhelp clinicians select patients for P.U.V.A. treat-

ment. Meanwhile the prudent course is to use

P.U.V.A. routinely only in patients unresponsive toor intolerant of conventional topical regimens andin elderly patients unlikely to live long enough tobe at risk of P.u.v.A.-induced skin cancer. In addi-tion, a case for P.U.V.A. treatment can doubtless bemade in individual adults with "routine" exten-sive psoriasis in whom dithranol or tar treament is,for one reason or another, impractical. In these pa-tients the dosage of radiation must be kept to theabsolute minimum which brings about and main-tains resolution of the psoriasis.

ANTITHROMBIN III AND HEPARIN

HEPARIN is still the most versatile and useful drug forprophylaxis and treatment of venous thromboembol-ism.’ It is also widely used to prevent or delay clottingon foreign surfaces. The prime action of heparin is toenhance the rate at which antithrombin III (At III), an

11. Igali, S., Bridges, B. A., Ashwood-Smith, M. J., Scott, B. R. Mutation Res.1970, 9, 21.

12. Ashwood-Smith, M. J., Grant, E. Br. med. J. 1976, i, 342.13. Zaynoun, S., Konrad, K., Gschnait, F., Wolff, K. Acta dermatoverner. 1977,

57, 431.14. Carter, D. M., Wolff, K., Schnedl, W. J. invest. Derm. 1976, 67, 548.15. Swanbeck, G., Thyresson-Hok, M., Bredberg, A., Lambert, B. Acta derma-

tovener. 1975, 55, 367.16. Griffin, A. C., Hakim, R. E., Knox, J. J. invest. Derm. 1958, 31, 289.17. Griffin, A. C. ibid. 1959, 32, 367.18. Hakim, R. E., Griffin, A. C., Knox, J. M. Archs Derm. 1960, 82, 572.19. Reed, W. B., Sugarman, G. I., Mathis, R. A. ibid. 1977, 113, 1561.1. Thomas, D. P. Semin. Hemat. 1978, 15, 1.

a2 globulin proteinase inhibitor, neutralises certain im-portant clotting enzymes .2 The complex formed betweenAt III and heparin is particularly effective in neutralis-ing activated factor Xa and thrombin, thus preventingfibrin formation.3,4The plasma At III concentration is about 0 mg/ml,

with a fractional catabolic rate of 55% of the plasmapool per day. Collen et al. reported a normal turnoverof At III in 3 patients with venous thrombosis nottreated with heparin, but in 3 further patients who weregiven heparin there was a significantly enhanced At IIIturnover. They suggested that - this rather surprisingresult may be due to higher physiological turnover of theAt 111/heparin complex. Their preliminary conclusionswere soon strikingly confirmed by Marciniak and Goc-kerman,6 who studied 26 patients receiving continuousor intermittent intravenous heparin therapy. All pa-tients showed a progressive reduction in At III, as mea-sured by both functional and immunological At III

assays. The maximum decreases were to about one-thirdof the normal plasma At III level, but this happenedonly when the heparin had been continuously present inthe blood for long periods; single heparin injections hadno effect on plasma At III levels. Marciniak and Gocker-man made the interesting suggestion that, as long asheparin is circulating, the increased rate of binding in-duced by heparin will compensate even for low concen-trations of At III. However, once heparin injections arestopped, a thrombotic tendency may reassert itself, andAt III concentrations may then be too low to neutraliseactivated clotting enzymes. Plasma At III levels returnedto normal two to three days after heparin was stopped.

Denson and Redman offer an alternative explanationfor the presumed hypercoagulability that follows thestopping of heparin therapy. They suggest that, inthromboembolic disease, factor VIII clotting activity(VIII:C) is being continuously destroyed by thrombin.Heparin reduces the amount of circulating thrombinrapidly, allowing factor VIII:C to rise to levels as highas 400-500% of average normal activity. These highlevels of factor VIII:C may predispose to recurrent

thromboembolism if heparin is stopped before the activethrombotic process has resolved. Woods et al.8 reportedinappropriately low levels of At III in their dialysed pa-tients, and suggested that this may also be a conse-quence of intermittent but long-term heparin adminis-tration.What seems clear from these observations is that, in

the interval between cessation of heparin and return tonormal of At III levels, there is a potential risk of recur-rent thromboembolism, probably due to the combinationof low At III levels and high factor VIII:C levels.O’Brien and Etherington,9 agreeing with the findings ofMarciniak and Gockerman,6 suggest that the results

support the practice of starting warfarin a few daysbefore heparin is withdrawn in patients with venous

2. Rosenberg, R. New Engl. J. Med. 1975, 292, 146.3. Yin, E. T., Wessler, S. Biochim. biophys. Acta, 1970, 201, 387.4. Biggs, R., Denson, K. W. E., Akman, N., Borrett, R., Hadden, M. Br. J.

Hæmat. 1970, 19, 283.5. Collen, D., Schetz, J., De Cock, F., Holmer, E., Verstraete, M. Europ. J.

clin. Invest. 1977, 7, 27.6. Marciniak, E., Gockerman, J. P. Lancet, 1977, ii, 581.7. Denson, K. W. E., Redman, C. W. G. ibid. p. 1028.8. Woods, H. F., Dawson, A., Ash, G., Weston, M. J. ibid. 1978, i, 209.9. O’Brien, J. R., Etherington, M. D. ibid. p. 1232.