title: Repair of DNA interstrand crosslinks as a mechanism of clinical resistance to melphalan in multiple myeloma.
abstract: 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.
authors.affiliation: Cancer Research UK Drug-DNA Interactions Research Group, Department of Oncology, Royal Free and University College Medical School, London, United Kingdom.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Spanswick
authors.forename: Charles
authors.initials: C
authors.lastname: Craddock
authors.forename: Mallika
authors.initials: M
authors.lastname: Sekhar
authors.forename: Prem
authors.initials: P
authors.lastname: Mahendra
authors.forename: Paneesha
authors.initials: P
authors.lastname: Shankaranarayana
authors.forename: R George
authors.initials: RG
authors.lastname: Hughes
authors.forename: Daniel
authors.initials: D
authors.lastname: Hochhauser
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology*; D020552:Comet Assay; D018736:DNA Adducts / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000494:pharmacology*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D010950:Plasma Cells / Q000187:drug effects / Q000473:pathology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D018736:DNA Adducts; D008558:Melphalan