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This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Spanswick, V. J. Articles by Hartley, J. A. Search for Related Content PubMed PubMed Citation Articles by Spanswick, V. J. Articles by Hartley, J. A. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 July 2002, Vol. 100, No. 1, pp. 224-229 NEOPLASIA Repair of DNA interstrand crosslinks as a mechanism of clinical resistance to melphalan in multiple myeloma Victoria J. Spanswick, Charles Craddock, Mallika Sekhar, Prem Mahendra, Paneesha Shankaranarayana, R. George Hughes, Daniel Hochhauser, and John A. Hartley From the Cancer Research UK Drug-DNA Interactions Research Group, Department of Oncology, Royal Free and University College Medical School, London, United Kingdom; the Department of Clinical Haematology and Stem Cell Transplantation, University Hospital, Birmingham, United Kingdom; and the Department of Clinical Haematology, West Middlesex University Hospital, Isleworth, United Kingdom. Melphalan is widely used as a preparative agent in patients with multiple myeloma (MM) undergoing autologous stem cell transplantation (SCT). Although disease relapse is the major cause of death after a melphalan-conditioned autograft, the mechanism remains unclear. Melphalan produces a number of DNA adducts with the DNA interstrand crosslink (ICL) considered to be the critical cytotoxic lesion. By using a modification of the single-cell gel electrophoresis (Comet) assay, we have measured formation and repair of DNA ICL in plasma cells from melphalan- naive and melphalan-treated patients (ie, those who have relapsed after a melphalan-conditioned autologous SCT or oral melphalan therapy). Similar levels of dose-dependent DNA interstand crosslinking were observed in cells from both melphalan-naive and -treated patients. However, marked differences in ICL repair were observed: cells from naive patients showed no repair, whereas those from treated patients exhibited between 42% and 100% repair at 40 hours. In vitro sensitivity to melphalan in plasma cells was found to correlate with ICL repair. These findings suggest that ICL repair may be an important mechanism by which melphalan resistance emerges after autologous SCT or oral therapy. This mechanism may have implications for MM patients undergoing melphalan therapy. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Involvement of the HER2 pathway in repair of DNA damage produced by chemotherapeutic agents Mol. Cancer Ther., November 1, 2009; 8(11): 3015 - 3023. D. Hochhauser, T. Meyer, V. J. Spanswick, J. Wu, P. H. Clingen, P. Loadman, M. Cobb, L. Gumbrell, R. H. Begent, J. A. Hartley, et al. Phase I Study of Sequence-Selective Minor Groove DNA Binding Agent SJG-136 in Patients with Advanced Solid Tumors Clin. Cancer Res., March 15, 2009; 15(6): 2140 - 2147. [Abstract] [Full Text] [PDF] J. H. Wu, J. B. Wilson, A. M. Wolfreys, A. Scott, and N. J. Jones Optimization of the comet assay for the sensitive detection of PUVA-induced DNA interstrand cross-links Mutagenesis, March 1, 2009; 24(2): 173 - 181. [Abstract] [Full Text] [PDF] P. 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