Ex vivo chemosensitivity testing and gene expression profiling predict response towards adjuvant gemcitabine treatment in pancreatic cancer

Abstract

Efficacy of chemotherapy for pancreatic cancer may be improved by tailoring it to individual chemosensitivity profiles. Identification of nonresponders before initiation of treatment may help to avoid side effects. In this study, primary pancreatic cancer cells were isolated from 18 patients undergoing pancreaticoduodenectomy for pancreatic cancer. Eight commonly used pancreatic cancer cell lines were used as controls. Ex vivo chemosensitivity for gemcitabine, 5-fluorouracil, mitomycin-C, cisplatinum, oxaliplatinum, paclitaxel and a combination of gemcitabine with oxaliplatinum or mitomycin-C was determined using a cellular ATP-based tumour chemosensitivity assay (ATP-TCA). Quantitative real-time -polymerase chain reaction was performed to determine RNA expression levels of genes implicated in chemoresistance. Chemosensitivity towards cytotoxic agents was highly variable in primary pancreatic cancer cells and pancreatic cancer cell lines. ATP-TCA results for gemcitabine correlated to the tissue expression of human equilibrative nucleoside transporter-1 (hENT1). Time to relapse in patients with gemcitabine-sensitive tumours was significantly higher than in patients with chemoresistant pancreatic cancers (P ¼ 0.01; 71 vs 269 days). Furthermore, time to relapse in gemcitabine-treated patients was related to hENT1 expression (P ¼ 0.0067). Thus, chemosensitivity testing using ATP-TCA in pancreatic cancer is feasible and correlated with time to relapse in gemcitabine-treated patients. This suggests that ATP-TCA testing could be used as a decision-making tool in the adjuvant treatment of pancreatic cancer.

Heterogeneity of chemosensitivity in esophageal cancer using ATP-tumor chemosensitivity assay

“…A number of chemosensitivity assays were developed over the last decades to predict the responsiveness of tumors to chemotherapy [19][20][21] . In recent years, the ATP-TCA method is a novel approach to test chemosensitivity in solid tumors [22][23][24][25][26] .…”

Epigenetic markers for chemosensitivity and chemoresistance in pancreatic cancer—A review

“…Characterization of PC cell lines has proven especially useful in providing new insights into phenotypic changes associated with gemcitabine resistance. 26 Although this approach has identified a number of genes likely to be involved in the development of chemoresistance ( Fig. 1), their clinical impact remains controversial.…”

“…Acquired resistance toward gemcitabine might partially be mediated by upregulation of the apoptosis inhibitors Bcl-2, Bcl-xL, Mcl-1, survivin and the cellular inhibitor of apoptosis protein-1 (cIAP-1). 10,11,[26][27][28] The proapoptotic proteins BNIP3 and Bax related to apoptosis induction in gemcitabine-resistant cell lines with a significant tumor regression. Erkan et al and Akada et al showed that silencing of BNIP3 by small interfering RNA (siRNA) correlated with increased chemoresistance.…”

“…36 Michalski et al could show that hENT1 expression correlated with time to relapse in gemcitabine-treated patients. 26 Nakano et al analyzed that the ratio of hENT1ÂdCK/RRM1ÂRRM2 expression decreased progressively with the development of acquired resistance in gemcitabine-resistant PC cell lines. 37 Nakahira et al reported that transfection of RRM1 siRNA resulted in >90% suppression of RRM1 messenger RNA (mRNA) and protein that was accompanied by a significantly reduced gemcitabine chemoresistance in human PC cell lines.…”

Silencing of GRP94 expression promotes apoptosis in pancreatic cancer cells

“…These are characterized by tumor desmoplasia, early local extension to contiguous structures, metastases to regional lymph nodes and to the liver (2)(3)(4). Moreover, pancreatic cancer cells are usually resistant to the programmed cell death (apoptosis) mediated by conventional chemotherapeutic agents (5,6). It is generally believed that cancer cells have an altered cellular physiology characterized by abundance of growth signals, insensitivity to cycle arrest signals, and evasion of apoptosis (7).…”