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Annals of Oncology Advance Access originally published online on February 27, 2008
Annals of Oncology 2008 19(5):990-995; doi:10.1093/annonc/mdn014
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© The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

phase I and pharmacokinetics

Optimisation of circulating biomarkers of cell death for routine clinical use

A. Greystoke1,2, J. Cummings1, T. Ward1, K. Simpson1, A. Renehan3, F. Butt1, D. Moore1, J. Gietema4, F. Blackhall2,3, M. Ranson2,3, A. Hughes3,5 and C. Dive1,3,*

1 Department of Medical Oncology, Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Manchester, UK
2 Department of Medical Oncology, Christie Hospital Foundation Trust, Manchester, UK
3 School of Cancer and Imaging Sciences, University of Manchester, Manchester, UK
4 Department of Medical Oncology, University Medical Center Groningen, Groningen, The Netherlands
5 Discovery Medicine, AstraZeneca Discovery Medicine, Alderley Park, Macclesfield, UK

* Correspondence to: Prof. C. Dive at The Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Wilmslow Road, Manchester M20 4BX, UK. Tel: +44-161-446-3036; Fax: +44-161-446-3109; E-mail: cdive{at}picr.man.ac.uk

Background: M30TM and M65TM enzyme-linked immunosorbent assays detect circulating cytokeratin 18 fragments released during caspase-dependent or total cell death, respectively, and have potential as biomarkers in epithelial cancers. While these assays have been validated, their robustness for routine clinical use is unknown.

Patients and methods: M30 and M65 were measured in matched serum and plasma samples from 31 lung cancer patients and 18 controls.

Results: Time allowable between sample acquisition and processing is critical for assays in clinical use. A 4-h delay in processing at room temperature increased M30 (P < 0.0001), an effect minimised by incubation on ice. M30 and M65 in serum were resistant to processing variations including delays. Serum and plasma measurements correlated well although M30 but not M65 was lower in serum (P < 0.0005). Less variation between duplicate assays was observed in serum. Prolonged storage (–80°C) led to increased M30 (12%, 6 months; 34%, 1 year). Sample dilution in the supplied assay diluent proved non-linear, whereas dilution in donor serum or porcine plasma restored linearity up to a ratio of 1 : 6.

Conclusion: We present recommendations that improve the reliability of these assays for clinical use and recommend serum as the preferred matrix with data more resistant to variations in collection.

Key words: apoptosis, cell death biomarkers, clinical utility, M30, M65, small-cell lung cancer

Received for publication October 29, 2007. Accepted for publication January 4, 2008.


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