For personal use only. Reproduce with permission from The Lancet Publishing Group. Introduction Skin cancer is the most common cancer in white people in the USA 1 and other countries. Most skin cancers are basal- cell carcinomas. 2 Early steps in the development of skin cancer are the appearance of ultraviolet-light-induced mutations in the P53 and PTCH tumour-suppressor genes. 3 Actinic keratosis is thought to be a precursor to squamous- cell carcinoma. This dysplastic epidermal lesion is generally discrete and variably erythematous, with an irregular, scaly surface. The prevalence ranges from 25% in temperate countries of the northern hemisphere to 40–60% among adults in Australia. 4 Actinic keratosis is widely believed to be premalignant, because each lesion has a chance of progression to invasive squamous-cell carcinoma of about 8%, and many patients with squamous-cell carcinomas have multiple actinic keratoses. 5 The ultraviolet-light-induced mutations in P53 that are found in squamous-cell carcinomas are also found in many actinic keratoses. 6 Patients with xeroderma pigmentosum have an autosomal recessive genetic defect in the pathway that repairs sun-induced damage to DNA. 7 As a result, the rates of malignant disorders of the skin (basal-cell and squamous-cell carcinomas, and the melanocytic disease, melanoma) are 1000 times higher than in the general population, and rates of actinic keratosis are also increased. 8 This defect in DNA repair of damage induced by ultraviolet light has, however, been overcome in cell culture by the intracellular delivery of the bacterial DNA incision repair enzyme T4 endonuclease V. 9 Treatment of an established basal-cell carcinoma generally consists of Mohs micrographic surgery, surgical excision, curettage and electrodesiccation, or cryosurgery, 10 whereas treatment of actinic keratoses consists principally of observation, cryotherapy, or topical fluorouracil. 11 The only topical treatment to date that has shown efficacy in reducing the risk of actinic keratoses 12,13 is sunscreen, but this requires very careful and constant pretreatment. Oral retinoid therapies are largely experimental and have potentially serious and almost always inconvenient side-effects. 14 T4N5 liposome lotion contains the bacterial enzyme T4 endonuclease V encapsulated in a pH-sensitive engineered liposome for delivery into the living cells of the skin. 15 Topical application of these liposomes in a hydrogel lotion to patients with xeroderma pigmentosum accelerated the removal of ultraviolet-light-induced DNA damage (specifically cyclobutane pyrimidine dimers) compared with placebo, when applied after exposure, and the treatment produced no major adverse effects. 16 In this study, we tested the ability of T4N5 liposome lotion to reduce the rate of appearance of new actinic keratoses and basal-cell carcinomas in patients with xeroderma pigmentosum. Covariates included age, sex, and place of study enrolment (USA or elsewhere). EARLY REPORT *Other members given at the end of the paper Applied Genetics Incorporated Dermatics, 205 Buffalo Avenue, Freeport, NY 11520, USA (D Yarosh PhD, J Klein BS, A O’Connor MS); St John’s Institute of Dermatology, King’s College London, St Thomas’ Hospital, London, UK (J Hawk MD); DermResearchCenter of New York, Inc, Stony Brook, NY, and Department of Dermatology, Cornell University Medical College, New York, USA (E Rafal MD); and Department of Dermatology, University of Graz, Graz, Austria (P Wolf MD) Correspondence to: Dr Daniel Yarosh (e-mail:danyarosh@agiderm.com) Summary Background In patients with xeroderma pigmentosum the frequency of all forms of skin cancer is higher than in the general population, owing to a genetic defect in DNA repair. The bacterial DNA repair enzyme, T4 endonuclease V, delivered intracellularly, increases the rate of repair of sunlight-induced DNA damage in human cells. We tested the ability of this enzyme in a liposomal delivery vehicle applied topically (T4N5 liposome lotion) to lower the rate of new skin cancers in patients with xeroderma pigmentosum. Methods 30 patients were enrolled in this prospective, multicentre, double-blind study. Patients were randomly assigned T4N5 liposome lotion or a placebo liposome lotion, to be applied daily for 1 year. At 3-monthly visits, new actinic keratoses and basal-cell carcinomas were identified and removed. Analyses were by intention to treat. Findings 20 patients were assigned T4N5 liposome lotion and ten placebo lotion; one placebo-group patient withdrew before treatment and one withdrew with progressive disease at 9 months. The annualised rate of new actinic keratoses was 8·2 among the patients assigned T4N5 liposome lotion and 25·9 among those assigned placebo (difference 17·7 [95% CI 11·8–26·5]; p=0·004 by Poisson modelling). For basal-cell carcinoma, the annualised rates of new lesions were 3·8 in the treatment group and 5·4 in the placebo group (difference 1·6 [0·38–2·82]). No significant adverse effects were found among any of the patients. Interpretation DNA damage has an important role in the development of skin cancer and precancerous skin lesions. The topical application of DNA repair enzymes to sun- damaged skin of patients with xeroderma pigmentosum lowered the rate of development of two forms of these lesions during a year of treatment. Lancet 2001; 357: 926–29 Effect of topically applied T4 endonuclease V in liposomes on skin cancer in xeroderma pigmentosum: a randomised study Daniel Yarosh, Jonathan Klein, Adrienne O’Connor, John Hawk, Elyse Rafal, Peter Wolf, for the Xeroderma Pigmentosum Study Group* Early report 926 THE LANCET • Vol 357 • March 24, 2001