Predicting the chemosensitivity of pancreatic cancer cells by quantifying the expression levels of genes associated with the metabolism of gemcitabine and 5-fluorouracil

Abstract

Abstract. Gemcitabine (GEM) is the standard treatment for advanced/metastatic pancreatic cancer. However, there is a substantial subset of patients in whom the efficacy of GEM, when used as a single agent, is inadequate. Recently, the 5-fluorouracil (5-FU) prodrugs capecitabine and S-1 have been used as an alternative, either alone or in combination with GEM. The aim of the present study was to investigate the expression pattern of genes that render pancreatic cancer cells sensitive to GEM and 5-FU, and to identify markers for individualized chemotherapy, even in patients who have developed resistance. We investigated the correlation between the expression of genes associated with the metabolism of GEM and 5-FU, and sensitivity to these drugs in 15 human pancreatic cancer cell lines. We also established GEM-and 5-FU-resistant pancreatic cancer cell lines to investigate changes in the expression levels of these genes and the effects of one drug on cells resistant to the other. We found no correlation between pancreatic cancer cell sensitivity to either GEM-or 5-FU. GEM-resistant cells did not become resistant to 5-FU and vice versa. High expression of RRM1 (P=0.048) and TS x DPD (P= 0.035) correlated significantly with sensitivity to GEM and 5-FU, respectively. 5-FU-resistant cells expressed significantly higher levels of TP than parental cells (P<0.05). In conclusion, pancreatic cancer cells showed no crossresistance to GEM and 5-FU. Quantitative analyses of RRM1, TP, DPD and TS mRNA levels in pancreatic cancer cells may be useful for predicting their sensitivity to GEM and 5-FU.

Novel Pancreatic Cancer Cell Lines Derived from Genetically Engineered Mouse Models of Spontaneous Pancreatic Adenocarcinoma: Applications in Diagnosis and Therapy

“…The expression levels of E-cadherin in UN-KC-6141, UN-KPC-960, and UN-KPC-961 cells correlated with decreased drug resistance. It is important to note that even though the KC and KPC-derived PDAC cell lines were not as resistant to Gemcitabine as the Panc02 cells, these cytotoxicity levels are in the range of those found in human PDAC cell lines [21] , [22] .…”

“…The IC-50 values of the KC and KPC cell lines ranged from 0.5 µM to 5 µM. Although Panc02 cells were more resistant to Gemcitabine, these IC-50 values are in the comparable range of human PC cells [21] , [22] . Interestingly, at higher Gemcitabine concentrations (30–100 µM) ( Fig.…”

Ribonucleotide Reductase Large Subunit M1 Predicts Poor Survival Due to Modulation of Proliferative and Invasive Ability of Gastric Cancer

“…Currently, chemotherapy for GCs is based on a 5-fluorouracil protocol. RRM1 overexpression has been correlated with 5-fluorouracil resistance in pancreatic cancer [45]. In table 2, highly expression of RRM1 impact the poor outcome of GC patients with 5-fluorouracil based chemotherapy, but not significantly.…”

Precision Medicine and Pancreatic Cancer

“…RRM1, a multimeric enzyme that converts ribonucleotides to deoxyribonucleosides has been reported as a predictive marker of gemcitabine treatment response in pancreatic cancer in several preclinical studies..(37, 38). Several very small clinical studies in pancreatic cancer have demonstrated an association between low RRM1 expression (as determined by quantitative reverse transcription PCR,(37, 39) or immunohistochemistry.…”