UNASSIGNED: 49 Background: Melanoma has a poor survival rate in advanced stages due to the lack of efficacious approved treatments. However, @entity320 's dermal location enables the application of @entity1 skin models. These models mimic many important characteristics of skin in vivo and obviate the use of invasive procedures. Monitoring gamma-H2AX foci to assess DNA double-strand break (DSB) levels in reconstituted @entity1 3D skin tissue harboring @entity320 cells may provide insights into important questions in @entity5 research. In addition to the differential toxicities of anti- @entity5 agents on the various cell types, we examine how the early drug response of normal tissues might serve as surrogates for predicting treatment efficacy on the @entity5 . METHODS: Commercially available reconstituted 3D human skin tissue consists of dermal fibroblast and epidermal keratinocyte layers with @entity320 A375 cells which have been cultured to form a multilayer, highly differentiated epidermis containing various stages of cutaneous @entity320 . Drugs representative of several different categories were studied, including @entity1732 (a radiomimetic), @entity9800 (a topoisomerase I inhibitor), @entity2903 (a DNA alkylating agent), @entity17528 (a @entity8047 inhibitor), @entity782 (a HDAC inhibitor) and @entity900 (a DNA intercalatingagent). DNA DSB levels were monitored by gamma-H2AX foci formation and apoptosis by TUNEL assay. @entity5 growth was monitored by H_E staining. RESULTS: A wide range of responses in both @entity5 and normal tissue by various drugs were observed, including @entity5 regression and normal tissue @entity137 . The early responses of normal tissues depended on the treatment, providing insights into the use of surrogate tissues as predictors of drug efficacy and later @entity5 regression. CONCLUSIONS: Measuring DNA DSB damage in reconstituted 3D skin tissue is an attractive model for studying the efficacy and @entity137 of genotoxic drugs against @entity320 . If validated, such models would help reduce the use of animals for preclinical studies.

Examining the reliability of surrogate tissue predictability of drug efficacy in reconstituted XXXX 3D skin models containing @entity320 .

@entity1 :: ('9606', 'Species') :: ['human'] @entity137 :: ('MESH:D064420', 'Disease') :: ['toxicity'] @entity8047 :: ('5609', 'Gene') :: ['MEK'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor', 'cancer', 'Tumor', 'tumors'] @entity900 :: ('MESH:D002945', 'Chemical') :: ['cisplatin'] @entity9800 :: ('MESH:D002166', 'Chemical') :: ['camptothecin'] @entity1732 :: ('MESH:D001761', 'Chemical') :: ['bleomycin'] @entity17528 :: ('MESH:C517975', 'Chemical') :: ['AZD6244'] @entity2903 :: ('MESH:C047246', 'Chemical') :: ['temozolomide'] @entity320 :: ('MESH:D008545', 'Disease') :: ['melanoma', 'melanoma tumor', 'melanoma malignancy', 'malignant melanoma'] @entity782 :: ('MESH:C111237', 'Chemical') :: ['Vorinostat']
@entity1 :: (9606,Species) :: ['human']
