title: Evaluation of surrogate tissues as indicators of drug activity in a melanoma skin model.
abstract: The development of novel cancer treatments is a challenging task, partly because results from model systems often fail to predict drug efficacy in humans, and also tumors are often inaccessible for biochemical analysis, preventing effective monitoring of drug activity in vivo. Utilizing a model system, we evaluated the use of drug-induced DNA damage in surrogate tissues as indicators of drug efficacy. Samples of a commercially available melanoma skin model (Mattek MLNM-FT-A375) containing keratinocyte and fibroblast layers with melanoma nodules were subjected to various chemotherapeutic regimens for one, four, or eight days. At these times they were analyzed for DNA double-stranded breaks (γH2AX foci) and apoptosis (TUNEL). A wide range of drug responses in both tumor and normal tissues were observed and cataloged. For the melanoma, the most common drug response was apoptosis. The basal keratinocyte layer, which was the most reliable indicator of drug response in the melanoma skin model, responded with γH2AX foci formation that was abrupt and transient. The relationships between tumor and surrogate tissue drug responses are complex, indicating that while surrogate tissue drug responses may be useful clinical tools, careful control of variables such as the timing of sampling may be important in interpreting the results.
authors.affiliation: Department of Radiation Oncology, Greenbaum Cancer Center, School of Medicine, University of Maryland, Baltimore, Maryland.|Genomic Integrity Group, Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: Palak R
authors.initials: PR
authors.lastname: Parekh
authors.affiliation: Genomic Integrity Group, Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland.|University of Maryland, College Park, Maryland.
authors.forename: Rohini
authors.initials: R
authors.lastname: Choudhuri
authors.affiliation: Genomic Integrity Group, Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: Urbain
authors.initials: U
authors.lastname: Weyemi
authors.affiliation: Genomic Integrity Group, Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland.|Division of Radiation Oncology and Cancer Imaging and Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre and Department of Oncology, University of Melbourne, Melbourne, Australia.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Martin
authors.affiliation: Genomic Integrity Group, Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: William M
authors.initials: WM
authors.lastname: Bonner
authors.affiliation: Genomic Integrity Group, Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: Christophe E
authors.initials: CE
authors.lastname: Redon
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009153:Mutagens / Q000494:pharmacology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009153:Mutagens
keywords: Apoptosis; drug response; melanoma tissue model; surrogate tissue; γH2 AX