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Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer

McMahon, K. L., Lin, H. M., Castillo, L., Lee, B. Y., Lee_Ng, M., Chatfield, Mark D., Chiam, K., Breit, S. N., Brown, D. A., Molloy, M.P., Marx, G.M., Pavlakis, N., Boyer, M. J., Stockler, M. R., Daly, R. J., Henshall, S.M. and Horvath, L. G. (2015). Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer. British Journal of Cancer,112(8):1340-1348.

Document type: Journal Article
Citation counts: Altmetric Score Altmetric Score is 7
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IRMA ID 75039815xPUB799
Title Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer
Author McMahon, K. L.
Lin, H. M.
Castillo, L.
Lee, B. Y.
Lee_Ng, M.
Chatfield, Mark D.
Chiam, K.
Breit, S. N.
Brown, D. A.
Molloy, M.P.
Marx, G.M.
Pavlakis, N.
Boyer, M. J.
Stockler, M. R.
Daly, R. J.
Henshall, S.M.
Horvath, L. G.
Journal Name British Journal of Cancer
Publication Date 2015
Volume Number 112
Issue Number 8
ISSN 0007-0920   (check CDU catalogue  open catalogue search in new window)
Scopus ID 2-s2.0-84928215113
Start Page 1340
End Page 1348
Total Pages 9
Place of Publication United Kingdom
Publisher Nature Publishing Group
HERDC Category C1 - Journal Article (DIISR)
Abstract Background:
Docetaxel improves symptoms and survival in metastatic castration-resistant prostate cancer (CRPC). However, ~50% of patients are chemoresistant. This study examined whether changes in cytokine levels predict for docetaxel resistance in vitro and in a clinical cohort.

Methods: PC3 cells or their docetaxel-resistant subline (PC3Rx) were co-cultured with U937 monocytes, with and without docetaxel treatment, and cytokine levels were measured. The circulating levels of 28 cytokines were measured pre-/post cycle 1 of docetaxel from 55 men with CRPC, and compared with prostate-specific antigen (PSA) response.

Results: PC3Rx-U937 co-culture expressed more cytokines, chiefly markers of alternative macrophage differentiation, compared with PC3-U937 co-culture. Docetaxel treatment enhanced cytokine production by PC3Rx-U937 co-culture, while reducing cytokine levels in PC3-U937. In patients, changes in the levels of seven circulating cytokines (macrophage inhibitory cytokine 1 (MIC1), interleukin (IL)-1ra, IL-1β, IL-4, IL-6, IL-12 and IFNγ) after cycle 1 of docetaxel were associated with progressive disease (all P<0.05). The combination of changes in MIC1, IL-4 and IL-6 most strongly predicted PSA response (P=0.002).

Conclusions:
In vitro studies suggest docetaxel resistance is mediated, at least in part, by cytokines induced by the interaction between the docetaxel-resistant tumour cells and macrophages. Early changes in circulating cytokine levels were associated with docetaxel resistance in CRPC patients. When considered together, these data suggest a significant role for the inflammatory response and macrophages in the development of docetaxel resistance in CRPC.
Keywords Castration-resitant prostate cancer
Docetaxel chemotherapy
Cytokines
Therapeutic response
Macrophage
DOI http://dx.doi.org/10.1038/bjc.2015.74   (check subscription with CDU E-Gateway service for CDU Staff and Students  check subscription with CDU E-Gateway in new window)
 
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