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-1?, 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.
Original language | English |
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Pages (from-to) | 1340-1348 |
Number of pages | 9 |
Journal | British Journal of Cancer |
Volume | 112 |
Issue number | 8 |
DOIs | |
Publication status | Published - 31 Mar 2015 |