DNA damage response as a biomarker in treatment of leukemias.
Early assessment of cancer response to the treatment is of great importance in clinical oncology. Most antitumor drugs, among them DNA topoisomerase (topo) inhibitors, target nuclear DNA. The aim of the present study was to explore feasibility of the assessment of DNA damage response (DDR) as potential biomarker, eventually related to the clinical response, during treatment of human leukemias. We have measured DDR as reported by activation of ATM through its phosphorylation on Ser 1981 (ATM-S1981(P)) concurrent with histone H2AX phosphorylation on Ser139 (gammaH2AX) in leukemic blast cells from the blood of twenty patients, 16 children/adolescents and 4 adults, diagnosed with acute leukemias and treated with topo2 inhibitors doxorubicin, daunomycin, mitoxantrone or idarubicin. Phosphorylation of H2AX and ATM was detected using phospho-specific Abs and measured in individual cells by flow cytometry. The increase in the level of ATM-S1981(P) and gammaH2AX, varying in extent between the patients, was observed in blasts from the blood collected one hour after completion of the drug infusion with respect to the pre-treatment level. A modest degree of correlation was observed between the induction of ATM activation and H2AX phosphorylation in blasts of individual patients. The number of the studied patients (20) and the number of the clinically non-responding ones (2) was too low to draw a conclusion whether the assessment of DDR can be clinically prognostic. The present findings, however, demonstrate the feasibility of assessment of DDR during the treatment of leukemias with drugs targeting DNA.
Brander Cancer Research Institute, Department of Pathology, New York Medical College, Valhalla, NY 10595, USA.
H Dorota
HD
Halicka
M Fevzi
MF
Ozkaynak
Oya
O
Levendoglu-Tugal
Claudio
C
Sandoval
Karen
K
Seiter
Malgorzata
M
Kajstura
Frank
F
Traganos
Somasunadaram
S
Jayabose
Zbigniew
Z
Darzynkiewicz
D000293:Adolescent; D000328:Adult; D000368:Aged; D064007:Ataxia Telangiectasia Mutated Proteins; D015415:Biomarkers; D018797:Cell Cycle Proteins / Q000097:blood* / Q000378:metabolism; D002648:Child; D004249:DNA Damage; D026942:DNA Topoisomerases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000097:blood* / Q000378:metabolism; D003630:Daunorubicin / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006657:Histones / Q000097:blood* / Q000378:metabolism; D006801:Humans; D015255:Idarubicin / Q000627:therapeutic use; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008942:Mitoxantrone / Q000627:therapeutic use; D010766:Phosphorylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D017346:Protein Serine-Threonine Kinases / Q000097:blood* / Q000378:metabolism; D059003:Topoisomerase Inhibitors; D025521:Tumor Suppressor Proteins / Q000097:blood* / Q000378:metabolism
D015415:Biomarkers; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C468783:H2AX protein, human; D006657:Histones; D059003:Topoisomerase Inhibitors; D025521:Tumor Suppressor Proteins; D008942:Mitoxantrone; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D026942:DNA Topoisomerases; D015255:Idarubicin; D003630:Daunorubicin