Formation and repair kinetics of Pt-(GpG) DNA adducts in extracted circulating tumour cells and response to platinum treatment.
BACKGROUND
Pt-(GpG) intrastrand crosslinks are the major DNA adducts induced by platinum-based anticancer drugs. In the cell lines and mouse models, the persistence of these lesions correlates significantly with cell damage. Here we studied Pt-(GpG) DNA adducts in circulating tumour cells (CTC) treated with cisplatin in medium upfront to systemic therapy from patients with advanced non-small-cell lung cancer (NSCLC).


METHODS
Blood was drawn before systemic treatment and the CD45/CD15-depleted fraction of mononuclear cells was exposed to cisplatin, verified for the presence of CTC by pan-cytokeratin (pCK) staining and immunoanalysed for the level of Pt-(GpG) in DNA.


RESULTS
Immunostaining for pCK, CD45 and subsequently for Pt-(GpG) adducts in the cisplatin-exposed cells (ex vivo) at different time points depicted distinct differences for adduct persistence in CTC between responders vs non-responders.


CONCLUSIONS
Pt-(GpG) adducts can be detected in CTC from NSCLC patients and assessing their kinetics may constitute a clinically feasible biomarker for response prediction and dose individualisation of platinum-based chemotherapy. This functional pre-therapeutic test might represent a more biological approach than measuring protein factors or other molecular markers.
Molecular Oncology Risk-Profile Evaluation, Department of Medical Oncology, West German Cancer Center, University Duisburg-Essen, Essen 45122, Germany.
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I
Nel
T C
TC
Gauler
W E
WE
Eberhardt
A-C
AC
Nickel
M
M
Schuler
J
J
Thomale
A-C
AC
Hoffmann
D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D018736:DNA Adducts / Q000096:biosynthesis* / Q000235:genetics; D015226:Dinucleoside Phosphates / Q000737:chemistry*; D006801:Humans; D017493:Leukocyte Common Antigens / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D016256:Lewis X Antigen / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy*; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating; D010984:Platinum / Q000737:chemistry*; D014407:Tumor Cells, Cultured
D018736:DNA Adducts; D015226:Dinucleoside Phosphates; D016256:Lewis X Antigen; C018309:guanylyl-(3'-5')-guanosine; D010984:Platinum; D017493:Leukocyte Common Antigens; D002945:Cisplatin