Melphalan-induced DNA damage in vitro as a predictor for clinical outcome in multiple myeloma.

2.50
Hdl Handle:
http://hdl.handle.net/10146/33813
Title:
Melphalan-induced DNA damage in vitro as a predictor for clinical outcome in multiple myeloma.
Authors:
Dimopoulos, Meletios A.; Souliotis, Vassilis L.; Anagnostopoulos, Athanasios; Bamia, Christina; Pouli, Anastasia; Baltadakis, Ioannis; Terpos, Evangelos; Kyrtopoulos, Soterios A.; Sfikakis, Petros P.
Abstract:
BACKGROUND AND OBJECTIVES: As new therapeutic options for multiple myeloma (MM) emerge, identification of biological markers which could predict clinical response to standard treatment with high-dose melphalan (HDM) supported by autologous stem cell transplantation (ASCT) becomes more important. DESIGN AND METHODS: Melphalan-induced damage formation and repair of monoadducts and interstrand cross-links in the p53 gene were studied in peripheral blood mononuclear cells obtained from 32 patients prior to therapy. The same studies were performed in the peripheral blood cells of these patients immediately after subsequent HDM administration. Clinical response and time to progression were correlated with molecular endpoints obtained in vitro. RESULTS: Values for all molecular end-points examined in vitro were highly correlated with the respective in vivo results within individual patients. All in vitro end-points indicative of increased DNA damage and slower repair capacity were predictive of a favorable response to HDM; the area under the curve of total adducts (AUC-TA) had the highest predictive ability. Using the cut-off value of 736 adducts/10(6) nucleotides x h for the AUC-TA, the positive predictive value for clinical response to HDM was 100%. Moreover, patients with an AUC-TA equal to or higher than this cut-off value had significantly longer times to progression than had patients with an AUC-TA lower than the cut-off value (hazard ratio 0.19; 95% confidence intervals 0.06 to 0.60). INTERPRETATION AND CONCLUSIONS: An in vitro assay to quantify melphalan-induced p53-specific damage formation/repair can be used to select those patients with MM who are more likely to benefit from HDM supported by ASCT.
Citation:
Haematologica 2007, 92 (11):1505-1512
Journal:
Haematologica
Issue Date:
Nov-2007
URI:
http://hdl.handle.net/10146/33813
DOI:
10.3324/haematol.11435
PubMed ID:
18024399
Additional Links:
http://www.haematologica.org/cgi/content/full/92/11/1505
Type:
Article
Language:
en
ISSN:
1592-8721
Sponsors:
Funding: this work was supported by grant No. 157 from the University of Athens, School of Medicine (to PPS). VLS and SAK are partners of ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a network of excellence operating within the European Union 6th Framework Program, Priority 5: "Food Quality and Safety" (Contract No 513943).
Appears in Collections:
Articles

Full metadata record

DC FieldValue Language
dc.contributor.authorDimopoulos, Meletios A.-
dc.contributor.authorSouliotis, Vassilis L.-
dc.contributor.authorAnagnostopoulos, Athanasios-
dc.contributor.authorBamia, Christina-
dc.contributor.authorPouli, Anastasia-
dc.contributor.authorBaltadakis, Ioannis-
dc.contributor.authorTerpos, Evangelos-
dc.contributor.authorKyrtopoulos, Soterios A.-
dc.contributor.authorSfikakis, Petros P.-
dc.date.accessioned2008-08-01T09:40:28Z-
dc.date.available2008-08-01T09:40:28Z-
dc.date.issued2007-11-
dc.identifier.citationHaematologica 2007, 92 (11):1505-1512en
dc.identifier.issn1592-8721-
dc.identifier.pmid18024399-
dc.identifier.doi10.3324/haematol.11435-
dc.identifier.urihttp://hdl.handle.net/10146/33813-
dc.description.abstractBACKGROUND AND OBJECTIVES: As new therapeutic options for multiple myeloma (MM) emerge, identification of biological markers which could predict clinical response to standard treatment with high-dose melphalan (HDM) supported by autologous stem cell transplantation (ASCT) becomes more important. DESIGN AND METHODS: Melphalan-induced damage formation and repair of monoadducts and interstrand cross-links in the p53 gene were studied in peripheral blood mononuclear cells obtained from 32 patients prior to therapy. The same studies were performed in the peripheral blood cells of these patients immediately after subsequent HDM administration. Clinical response and time to progression were correlated with molecular endpoints obtained in vitro. RESULTS: Values for all molecular end-points examined in vitro were highly correlated with the respective in vivo results within individual patients. All in vitro end-points indicative of increased DNA damage and slower repair capacity were predictive of a favorable response to HDM; the area under the curve of total adducts (AUC-TA) had the highest predictive ability. Using the cut-off value of 736 adducts/10(6) nucleotides x h for the AUC-TA, the positive predictive value for clinical response to HDM was 100%. Moreover, patients with an AUC-TA equal to or higher than this cut-off value had significantly longer times to progression than had patients with an AUC-TA lower than the cut-off value (hazard ratio 0.19; 95% confidence intervals 0.06 to 0.60). INTERPRETATION AND CONCLUSIONS: An in vitro assay to quantify melphalan-induced p53-specific damage formation/repair can be used to select those patients with MM who are more likely to benefit from HDM supported by ASCT.en
dc.description.sponsorshipFunding: this work was supported by grant No. 157 from the University of Athens, School of Medicine (to PPS). VLS and SAK are partners of ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a network of excellence operating within the European Union 6th Framework Program, Priority 5: "Food Quality and Safety" (Contract No 513943).en
dc.language.isoenen
dc.relation.urlhttp://www.haematologica.org/cgi/content/full/92/11/1505en
dc.subjectmelphalanen
dc.subjectmultiple meylomaen
dc.subjectprediction of clinical outcomeen
dc.subjectin vitro-induced adductsen
dc.subjectp53-specific damage formation/repairen
dc.subject.meshAdult-
dc.subject.meshAged-
dc.subject.meshDNA Damage-
dc.subject.meshFemale-
dc.subject.meshHematopoietic Stem Cell Transplantation-
dc.subject.meshHumans-
dc.subject.meshMale-
dc.subject.meshMelphalan-
dc.subject.meshMiddle Aged-
dc.subject.meshMultiple Myeloma-
dc.subject.meshPatient Selection-
dc.subject.meshPredictive Value of Tests-
dc.subject.meshTreatment Outcome-
dc.titleMelphalan-induced DNA damage in vitro as a predictor for clinical outcome in multiple myeloma.en
dc.typeArticleen
dc.identifier.journalHaematologicaen
All Items in ECNIS-NIOM are protected by copyright, with all rights reserved, unless otherwise indicated.