ABSTRACT
BACKGROUND: Familial cylindromatosis is a rare genetic disorder, giving rise to neoplasms of the skin appendages. We have recently shown that loss of the cylindromatosis tumour suppressor gene leads to activation of NF-kappaB, a transcription factor having antiapoptotic activity. This provides a possible explanation for the deregulated growth of cylindromas. In cell-based assays, salicylate can prevent NF-kappaB activation caused by loss of the cylindromatosis gene, suggesting that salicylic acid application might be a potential treatment for cylindromatosis. OBJECTIVES: To assess the effectiveness of topical application of salicylic acid on familial cylindromas. METHODS: Cylindromas in five patients from four different cylindromatosis families were treated with twice daily and then once daily topical salicylic acid. Clinical response was determined by serial tumour measurements. RESULTS: In total 17 cylindromas in five patients were studied: 12 target lesions and five control lesions. The median size of the cylindromas was 1.0 cm (range, 0.6-2.8 cm). Two of the 12 cylindromas showed a complete remission. Another eight lesions showed some response, but not sufficient to qualify as partial remission. The control lesions remained stable or increased in size. CONCLUSIONS: Salicylic acid is a well-tolerated and potential new treatment for cylindromatosis.
Subject(s)
Carcinoma, Adenoid Cystic/drug therapy , Carcinoma, Skin Appendage/drug therapy , Keratolytic Agents/administration & dosage , Neoplastic Syndromes, Hereditary/drug therapy , Salicylic Acid/administration & dosage , Administration, Topical , Carcinoma, Adenoid Cystic/genetics , Carcinoma, Adenoid Cystic/metabolism , Carcinoma, Skin Appendage/genetics , Carcinoma, Skin Appendage/metabolism , Female , Follow-Up Studies , Genes, Tumor Suppressor , Humans , I-kappa B Kinase/metabolism , Keratolytic Agents/therapeutic use , NF-kappa B/metabolism , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/metabolism , Pilot Projects , Remission Induction , Salicylic Acid/therapeutic useABSTRACT
E2F transcription factors regulate genes involved in cell-cycle progression. In mammalian cells, physiological E2F exists as an E2F/DP heterodimer. Currently, eight E2F and two DP subunits have been characterized. We report here the characterization of a new member of the DP family, DP-4. While DP-4 exhibits certain similarities with members of the DP family, it also possesses a number of significant differences. Thus, DP-4 forms a heterodimer with E2F subunits, binds to the E2F site and associates with pocket proteins including pRb. In contrast to DP-1, however, DP-4/E2F-1 complexes exhibit reduced DNA binding activity. Furthermore, DP-4 interferes with E2F-1-dependent transcription and delays cell-cycle progression. These results highlight an emerging complexity in the DP family of E2F subunits, and suggest that DP-4 may endow E2F heterodimers with distinct transcription properties.
