1. Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer.
- Author
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Mahon KL, Lin HM, Castillo L, Lee BY, Lee-Ng M, Chatfield MD, Chiam K, Breit SN, Brown DA, Molloy MP, Marx GM, Pavlakis N, Boyer MJ, Stockler MR, Daly RJ, Henshall SM, and Horvath LG
- Subjects
- Aged, Aged, 80 and over, Antineoplastic Agents pharmacology, Cell Line, Tumor, Coculture Techniques, Docetaxel, Humans, Male, Middle Aged, Prostatic Neoplasms, Castration-Resistant drug therapy, Taxoids pharmacology, Cytokines blood, Drug Resistance, Neoplasm, Kallikreins blood, Macrophages metabolism, Prostate-Specific Antigen blood, Prostatic Neoplasms, Castration-Resistant metabolism
- 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.
- Published
- 2015
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