Assessment of celecoxib pharmacodynamics in pancreatic cancer.

Cyclooxygenase-2 (COX-2) inhibitors are being developed as chemopreventive and anticancer agents. This study aimed to determine the biological effect of the COX-2 inhibitor celecoxib in pancreatic cancer as an early step to the further development of the agent in this disease. Eight patients scheduled for resection of an infiltrating adenocarcinoma of the pancreas were randomized to receive celecoxib at a dose of 400 mg twice daily or placebo for 5 to 15 days before the surgery. In addition, carcinomas from nine additional patients were xenografted in nude mice, expanded, and treated with vehicle or celecoxib for 28 days. Celecoxib markedly decreased the intra-tumor levels of prostaglandin E2 in patient carcinomas and in the heterotransplanted xenografts. However, this effect did not result in inhibition of cell proliferation or microvessel density (as assessed by Ki67 and CD31 staining). In addition, a panel of markers, including bcl-2, COX-1, COX-2, and VEGF, did not change with treatment in a significant manner. Furthermore, there was no evidence of antitumor effects in the xenografted carcinomas. In summary, celecoxib efficiently inhibited the synthesis of prostaglandin E2 both in pancreatic cancer surgical specimens and in xenografted carcinomas but did not exert evident antitumor, antiproliferative, or antiangiogenic effect as a single agent. The direct pancreatic cancer xenograft model proved to be a valuable tool for drug evaluation and biological studies and showed similar results to those observed in resected pancreatic cancer specimens.

Assessment of gefitinib- and CI-1040-mediated changes in epidermal growth factor receptor signaling in HuCCT-1 human cholangiocarcinoma by serial fine needle aspiration.

One specific limitation to the clinical development of targeted cancer therapeutics is the lack of well-validated pharmacodynamic markers. Such tools might conceivably provide a framework within which to better evaluate the selection of specific molecules as therapeutic targets. Nevertheless, the practical application of this hypothesis in clinical development remains elusive. In this study, we present a minimally invasive pharmacodynamic assay for monitoring therapy-mediated changes in the activity of target signaling pathways by using fine needle aspiration (FNA) samples and quantitative ELISA methods. To this end, we used the HuCCT-1 cholangiocarcinoma cell line treated with gefitinib (ZD1839, Iressa), a selective blocker of the epidermal growth factor receptor (EGFR), and CI-1040, a selective inhibitor of the mitogen extracellular regulated kinase [mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase 1/2]. HuCCT-1 cells were resistant to gefitinib and CI-1040 alone but susceptible to the combination of these drugs in vitro and in vivo. This effect was associated with a greater inhibition of ERK1/2 activation, a downstream mediator in the EGFR-mitogen-activated protein/ERK kinase pathway. Using this model, we sought to assess whether FNA-obtained tumor biopsies could be used to measure signaling pathway activation. Cellular extracts prepared from FNA samples yielded adequately cellular, high-quality samples to assess therapy-mediated changes in EGFR and ERK1/2 phosphorylation by Western blotting and quantitative ELISA assays. Treatment with gefitinib alone effectively inhibited EGFR activation but failed to block ERK1/2 phosphorylation and tumor growth. Blocking was achieved by the addition of CI-1040 to the treatment regimen. These results show that the combination of serial FNA sampling with highly sensitive quantitative ELISA assays permits assessment of therapy-mediated changes in signaling pathways, which correlate well with antitumor effects. This assay is simple to implement and broadly applicable to diverse tumor types in clinical studies with cancer patients and may be useful in the development of targeted anticancer agents.

Initially metastatic breast carcinoma has a distinct disease pattern but an equivalent outcome compared with recurrent metastatic breast carcinoma.

BACKGROUND: To date, the clinical features and outcomes of patients with initially metastatic breast carcinoma (IMBC) have not been compared with the corresponding characteristics in patients with recurrent metastatic breast carcinoma (RBC). This issue may be particularly relevant to clinical research, as it may shed light on a potential bias with respect to the selection of patients for clinical trials. METHODS: A retrospective analysis of the medical records of 1350 patients with breast carcinoma was performed. Outcome variables included overall survival, response rate, and progression-free survival. RESULTS: One hundred nineteen of 370 patients with metastatic breast carcinoma had IMBC, whereas the remaining 251 had RBC. The median follow-up duration was 39.4 months, and the median overall survival duration was 24 months. With regard to clinical characteristics, patients with IMBC were older than patients with RBC (61.7 years vs. 58.1 years; P < 0.001) and had a higher incidence of lobular carcinoma (15.9% vs. 7.7%; P = 0.018), a greater proportion of T3-4 tumors (58.8% vs. 27.9%; P < 0.001), a higher incidence of bone as the dominant metastatic site (41.2% vs. 21.5%; P < 0.001), a lower incidence of soft tissue as the dominant metastatic site (10.1% vs. 26.7%; P < 0.001), and a similar incidence of the viscera as the dominant metastatic site (48.7% vs. 51.8%; P = 0.78). Median overall survival duration was similar for patients with IMBC (25.1 months) and patients with RBC (23.3 months; P = 0.81). Statistical analyses also revealed nonsignificant differences between patients with IMBC and patients with RBC in terms of response rate (40.7% vs. 35.2%, respectively; P = 0.35) and median progression-free survival duration (10.2 months vs. 9.0 months, respectively; P = 0.58). CONCLUSIONS: Although patients with IMBC and patients with RBC exhibit distinct histologic and clinical characteristics, similar treatment efficacy results and survival outcomes are observed in these two groups.