title: Chromatin structure, transcriptional activity and DNA repair efficiency affect the outcome of chemotherapy in multiple myeloma.
abstract: BACKGROUND
  Melphalan is one of the most active chemotherapeutic agents in the treatment of multiple myeloma (MM). However, the mechanism underlying differential patient responses to melphalan therapy is unknown.
  
  
  METHODS
  Chromatin structure, transcriptional activity and DNA damage response signals were examined following ex vivo treatment with melphalan of both malignant bone marrow plasma cells (BMPCs) and peripheral blood mononuclear cells (PBMCs) of MM patients, responders (n=57) or non-responders (n=28) to melphalan therapy. PBMCs from healthy controls (n=25) were also included in the study.
  
  
  RESULTS
  In both BMPCs and PBMCs, the local chromatin looseness, transcriptional activity and repair efficiency of the transcribed strand (TS) were significantly higher in non-responders than in responders and lowest in healthy controls (all P<0.05). Moreover, we found that melphalan-induced apoptosis inversely correlated with the repair efficiency of the TS, with the duration of the inhibition of mRNA synthesis, phosphorylation of p53 at serine 15 and apoptosis rates being higher in responders than in non-responders (all P<0.001).
  
  
  CONCLUSIONS
  Our findings provide a mechanistic basis for the link between DNA repair efficiency and response to melphalan therapy. Interestingly, the observation of these phenomena in PBMCs provides a novel approach for the prediction of response to anti-myeloma therapy.
authors: 1] Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA [2] Department of Clinical Therapeutics, University of Athens School of Medicine, 11528 Athens, Greece.
authors: M
authors: M
authors: Gkotzamanidou
authors: First Department of Propedeutic Medicine, University of Athens School of Medicine, 11527 Athens, Greece.
authors: P P
authors: PP
authors: Sfikakis
authors: Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 11635 Athens, Greece.
authors: S A
authors: SA
authors: Kyrtopoulos
authors: Department of Hygiene, Epidemiology and Medical Statistics, University of Athens School of Medicine, 11527 Athens, Greece.
authors: C
authors: C
authors: Bamia
authors: Department of Clinical Therapeutics, University of Athens School of Medicine, 11528 Athens, Greece.
authors: M A
authors: MA
authors: Dimopoulos
authors: Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 11635 Athens, Greece.
authors: V L
authors: VL
authors: Souliotis
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D016022:Case-Control Studies; D002843:Chromatin / Q000235:genetics / Q000473:pathology*; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology; D008297:Male; D008558:Melphalan / Q000494:pharmacology* / Q000627:therapeutic use; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014158:Transcription, Genetic; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002843:Chromatin; D008558:Melphalan