Docetaxel induces apoptosis in hormone refractory prostate carcinomas during multiple treatment cycles

Abstract

Caspase-cleaved proteins are released from disintegrated apoptotic cells and can be detected in the circulation. We here addressed whether caspase-cleaved cytokeratin 18 (CK18-Asp396) can be used as a serum biomarker for assessment of the clinical efficiency of chemotherapy in hormone-refractory prostate cancer (HRPC). A total of 82 patients with HRPC were evaluated during 751 treatment cycles, either with estramustine (EMP)/vinorelbine or with EMP/docetaxel. The levels of CK18-Asp396 and of total CK18 were measured in patient serum before and during therapy by ELISA. Docetaxel induced significant increases in serum CK18-Asp396 (Po0.0001) and total CK18 (Po0.0002), suggesting induction of apoptosis. Similarly, vinorelbine induced increases in both CK18-Asp396 and CK18 (Po0.001 and 0.011). In contrast, EMP induced increases in total serum CK18 (Po0.0001), but not in CK18-Asp396 (P ¼ 0.13). The amplitudes of docetaxel-induced increases were associated with baseline prostate-specific antigen (PSA) and CK18 serum levels in these patients, consistent with tumoral origin of caspase-cleaved fragments. Docetaxel induced significant increases in CK18-Asp396 during second-, third-and fourth-line therapy and induced increased levels of CK18-Asp396 during treatment cycles 1 -8. In contrast, vinorelbine induced significant increases only during cycles 1 -3. In a subgroup of 32 patients that received EMP/vinorelbine in second line followed by EMP/docetaxel in third line, docetaxel induced stronger increases than vinorelbine (P ¼ 0.008). These results show that the CK18-Asp396 serum marker can be used to assess tumour apoptosis in vivo and suggest that the clinical efficiency of docetaxel in HRPC is due to induction of apoptosis during multiple treatment cycles.

Considerations for the use of plasma cytokeratin 18 as a biomarker in pancreatic cancer

“…The results from the M30 and M65 ELISA assays showed significant variability between patients with regard to the baseline levels of both full-length CK18 (M65) and the proportion of caspase-cleaved CK18 (M30 : M65). Circulating total CK18 concentrations in this study were relatively high compared with prostate (Kramer et al, 2006) and breast (Olofsson et al, 2007) cancer and comparable with those of other gastrointestinal malignancies (Scott et al, 2009) and non-small-cell lung cancer (Hou et al, 2009). In keeping with the other malignant tumour types (Ulukaya et al, 2007;Hou et al, 2009;Koelink et al, 2009), elevated CK18 levels were associated with poorer survival in the overall patient group on univariate analysis, but in this series failed to reach significance on multivariate analysis.…”

“…Early studies suggest that these assays may have important clinical biomarker utility, as increased levels of circulating CK18 may be prognostic and/or predict tumour response to chemotherapy in a number of different solid tumours (Steele et al, 2008;Scott et al, 2009). Studies on specific tumour types include lung (Ulukaya et al, 2007;Hou et al, 2009), breast (Olofsson et al, 2007), prostate (Kramer et al, 2006), head and neck (Ozturk et al, 2009), colorectal (Ausch et al, 2009;Koelink et al, 2009) and testicular (de Haas et al, 2008) tumours. Although a recent study concluded that plasma levels of CK18 are a potential marker of tumour response in patients with advanced gastrointestinal malignancy (Scott et al, 2009) no previous studies have been reported in patients with pancreatic cancer.…”

Serum cytokeratin 18 as a biomarker for gastric cancer

“…Serum CK18 are increased in tumors such as head and neck tumors, endometrial carcinoma, testicular cancer, prostate cancer, breast cancer, lung cancer, colorectal cancer, and pancreatic cancer [18][19][20][21][22][23][24]. Increase in serum M30 levels in cancer were reported for the first time by Uneo et al in breast cancer patients [28].…”

“…Conversely, necrosis of epithelial cells releases full-length CKs into circulation after breakdown of the cell membrane. Monoclonal antibody M6 and M5 detects total soluble CK18 fragments that contain full-length epitope of the protein; thus, M65 can be used to detect CK18 fragments released from necrotic cells in addition to those from apoptotic cells [16,18]. Both assays may provide clinically useful information for the management of patients with epithelial cancers.…”

“…Both assays may provide clinically useful information for the management of patients with epithelial cancers. This assay can be used clinically for patients with several epithelial cancers such as head and neck tumors, endometrial carcinoma, testicular cancer, prostate cancer, breast cancer, lung cancer, colorectal cancer, and pancreatic cancer [18][19][20][21][22][23][24]. In addition, serum levels of M30 and M65 are increased in patients with advanced gastrointestinal adenocarcinoma [2,25].…”