Xeroderma

Currently, 13-cis-retinoic acid is the most studied chemopreventive agent that decreases the incidence of second primary tumors in patients with head-and-neck cancer, reverses premalignant lesions, and reduces appearance of nonmelanoma skin cancer in patients with xeroderma pigmentosum. Unfortunately, this vitamin A derivative has a significant clinical toxicity, which limits its utility in a practice setting. 

Xeroderma pigmentosum (XP) is an autosomal recessive genetic disease. The clinical syndrome includes... 

P., Hubert, M., Decroix, Y. and Sarasin, A. (1986). Deficiency in the catalase activity of Xeroderma pigmentosum cells and simian virus 40 transformed human cell extracts. Cancer Res. 46, 538-544. 

Defects have been found in these mechanisms that cause various human diseases. For example, patients with the genetic disease xeroderma pigmentosum are especially sensitive to ultraviolet light and develop skin cancer. Skin fibroblasts cultured from these patients have been shown to be defective in DNA repair. 

Cleaver, J.E., DNA repair with purines and pyrimidines in radiation- and carcinogen-damaged normal and Xeroderma pigmentosum human cells, Cancer Res., 33, 362,1972. 

Stich, H.F. and San, R.H.C., Reduced DNA repair synthesis in Xeroderma pigmentosum cells exposed to the oncogenic 4-nitroquinoline 1-oxide and 4-hydroxayminoquinoline 1-oxide, Mutat. Res., 13,279,1971. 

Theron T, Fousteri MI, Volker M, Harries LW, Botta E, Stefanini M, Fujimoto M, Andressoo JO, Mitchell J, Jaspers NG, McDaniel LD, Mullenders LH, Lehmann AR (2005) Transcription-associated breaks in xeroderma pigmentosum group D cells from patients with combined features of xeroderma pigmentosum and Cockayne syndrome. Mol Cell Biol 25(18) 8368-8378 Thiriet C, Hayes JJ (2005) Chromatin in need of a fix phosphorylation of H2AX connects chromatin to DNA repair. Mol Cell 18(6) 617-622... 

Thymine dimers (Gj) UV radiation Excision endonuclease (deficient in Xeroderma pigmentosum) DNA polymerase DNA ligase... 

Xeroderma pigmentosum is an autosomal recessive disorder, characterized by extreme sensitivity to sunlight, skin freckling and ulcerations, and skin cancer. The most common defidency occurs in the excinudease enzyme. 

The deficiency of an excision endonuclease may produce an exquisite sensitivity to ultraviolet radiation in Xeroderma pigmentosum. Which of the following functions would be absent in a patient deficient in this endonuclease ... 

Environmental influences (e.g., the autosomal recessive disease xeroderma pigmento-siun will be expressed more severely in individuals who are exposed more frequently to ultraviolet radiation)... 

Carboplatin Oxaliplatin Xeroderma pigmentosum 751 Lys>Gln Carriers have poorer response to B O p... 

Investigations by Yarosh over almost two decades have proven that liposomal carriers allow uptake of a DNA repair enzyme into the skin [57], This uptake significantly reduces the number of new actinic keratoses and new lesions of basal cell carcinoma in patients with xeroderma pigmentosum who were treated for 12 months [58], Moreover, in a mice model, transdermal vaccination by antigen incorporation into liposomes has also been demonstrated [59,60],... 

Yarosh, D., et al.. Effect of topically apphed T4 endonuclease V in liposomes on skin cancer in xeroderma pigmentosum a randomised smdy. Lancet, 357, 926-29, 2001. 

Basal cell nevus syndrome or xeroderma pigmentosum The efficacy and safety of imiquimod cream have not been established for patients with basal cell nevus syndrome or xeroderma pigmentosum. 

Natarajan, A.T., Verdegaal-lmmerzeel, E.A.M., Ashwood-Smifh, M.J. and Poulton, G.A. (1981) Chromosomal damage induced hy furocoumarins and UVA in hamster and human cells including cells from patients with ataxia telangiectasia and xeroderma pigmentosum. Mutation Research, 84, 113-124. 

Xeroderma pigmentosum is caused by a defect in excision repair of thymine dimers, most freguently due to the absence of a UV-specific excinuclease, an enzyme that helps remove thymine dimers. 

Patients with xeroderma pigmentosum are prone to develop skin cancer later in life. 

The answer is B. The patient has many of the features characteristic of xeroderma pigmentosum. The lesion, hyperpigmentation (freckles), and erythema are located over sun-exposed areas. His corneas have also suffered damage from exposure to ultraviolet irradiation from the sun. His photosensitivity is also manifested in easy sun-burning and aversion to sun exposure. This condition often leads to skin cancer. 

The answer is C. Thymine dimers are repaired by the process of nucleotide excision repair, which involves many enzyme activities that recognize the mutated structure, cut the DNA strand on both sides of the mutation, remove (excise) the affected fragment, and then refill the gap. One of the major genes leading to xeroderma pigmentosoum encodes a specific excinuclease. 

Park DJ, Stoehlmacher J, Zhang W et al. A Xeroderma pigmentosum group D gene polymorphism predicts clinical outcome to platinum-based chemotherapy in patients with advanced colorectal cancer. Cancer Res 2001 61 8654-8658. 

The specific interaction of chemicals or radiation with DNA activate cdlular DNA repair processes which appear to play an important role in carcinogenesis. Eukaryotic cells show enhanced repair capacity for repair of viral nucleic add if the host cells are first damaged by chemicals or irradiation. The ihanced susceptibility to cancer of patients with defective repair systems, such as those with xeroderma pigmentosum, suggests that intact repair mechanisms are protective... 

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