ABSTRACT
BACKGROUND: The study of xeroderma pigmentosum has yielded unforeseen advances regarding how defects in the nucleotide excision repair pathway result in this devastating disease, but development of therapeutic strategies has trailed behind the mechanistic discoveries. OBJECTIVES: This review aims to cover clinical presentation, molecular mechanisms and current management, and highlights more recent insights into targeting the deficiencies secondary to the DNA repair defects to prevent skin cancer and/or neurological degeneration. METHODS: This review article discusses novel therapeutic approaches to xeroderma pigmentosum that focus on metabolic defects downstream of nucleotide excision repair. RESULTS: Current research demonstrates that specific sulfonylureas promote clearance of DNA damage and increase resistance to ultraviolet radiation in a cellular model of xeroderma pigmentosum. Moreover, nicotinamide attenuates the effects of ultraviolet radiation in cells, and caloric restriction decreases DNA damage burden in animal models of xeroderma pigmentosum. CONCLUSIONS: Clinical management of patients with xeroderma pigmentosum still focuses on preventative avoidance of sun exposure as opposed to therapies that would improve the patients' condition; thus, novel approaches to this disease are warranted.
Subject(s)
DNA Damage/drug effects , DNA Repair/drug effects , Sulfonylurea Compounds/therapeutic use , Sunscreening Agents/administration & dosage , Xeroderma Pigmentosum/therapy , Acetohexamide/pharmacology , Acetohexamide/therapeutic use , Administration, Cutaneous , Animals , Caloric Restriction , DNA Damage/radiation effects , Dermatology/methods , Dermatology/trends , Disease Models, Animal , Humans , Niacinamide/pharmacology , Niacinamide/therapeutic use , Protective Clothing , Randomized Controlled Trials as Topic , Sulfonylurea Compounds/pharmacology , Sunlight/adverse effects , Treatment Outcome , Ultraviolet Rays/adverse effects , Xeroderma Pigmentosum/geneticsABSTRACT
The purpose of this histologic and biochemical study was to assess the osteogenic potential of bone inductive proteins complexed with coralline hydroxylapatite as the carrier vehicle after implantation in an extraskeletal site of the rat. Inductive proteins were extracted from bovine demineralized bone. Implants were placed in 16 male, 3-month old Long-Evans rats (200-300 grams), using paired subcutaneous sites overlying the ventral thorax. There were four experimental groups, with eight implants per group. These included hydroxylapatite alone (HA), hydroxylapatite with inductive protein (HA + P), inactive demineralized bone matrix with (IBM + P), and without inductive protein (IBM). All implants were harvested at 21 days. Findings indicate a lack of osteogenic potential in groups HA, HA + P, and IBM. However, when HA and HA + P were compared, there was a 79% increase in standardized field mean nuclear point counts in the HA + P group. Also, compared to the other three implant groups, controls of IBM + P histomorphometrically showed chondroid bone formation and increased alkaline phosphatase activity. In this model system it may be concluded that with a composite system of coralline hydroxylapatite and bovine-derived inductive protein, bone formation was not seen; positive controls consisting of IBM + P demonstrated a statistically significant increase in AP activity with corresponding histologic evidence of bone formation.
