Intrinsic resistance to anticancer agents in the murine pancreatic adenocarcinoma PANC02

Abstract

PANC02 is a ductal adenocarcinoma of the pancreas that is resistant to every known class of clinically active antitumor agent. To study the mechanism(s) underlying the intrinsic drug resistance of this tumor, a mammary adenocarcinoma (CA-755) that also grows in C57/BL mice and is known to be drug sensitive was used for comparison. PANC02 resistance and CA-755 sensitivity to several antitumor agents and to X-ray therapy was confirmed in mice, and PANC02 also demonstrated relative resistance in tissue culture. Relative to Chinese hamster ovary (CHO) and CA-755 cells, PANC02 did not appear to show a higher rate of mutation to drug resistance in culture as based on the 6-thioguanine resistance marker. Although P-glycoprotein characteristic of the multidrug resistance (MDR) phenomenon could be demonstrated at the mRNA level using a sensitive RNAse protection assay, the level of expression found was several orders of magnitude lower than that observed in phenotypic MDR cell lines. Furthermore, quinidine failed to increase the sensitivity of PANC02 cells to Adriamycin under conditions that clearly potentiated the toxicity of the drug to a CHO cell line exhibiting classic MDR traits. The heterogeneity in the distribution of drugs was inferred as being significantly greater in PANC02 versus CA-755 cells in vivo as based on measurements of within-animal, within-tumor variance in the distribution of the marker compounds inulin and antipyrine. Although it may not be the only mechanism involved, this greater intratumor heterogeneity in drug distribution could theoretically play a major role in the intrinsic drug resistance of PANC02 in vivo.

In vitro Effect of 5-Fluorouracil, Verapamil and Hyperthermia on the Human Pancreatic Adenocarcinoma Cell Line ASPC-1

“…While several agents have shown a significant inhibition to gether, none of them could induce the regres sion of the tumor when used singly [28]. Our data confirm the suggestion that human pan creatic adenocarcinoma is resistant to most of the effective chemotherapy agents [26,27], Hyperthermia seems to be one of the most im portant agents to enhance the antineoplastic capacity of chemotherapeutic drugs. The pos sibility of enhancing the effect of cytotoxic drugs on tumor cells by means of hyperther mia has been clearly shown by many in vitro and in vivo experiments [29,30].…”

“…It is well-known that pancreatic cancer is one of the neoplasms with resistance to every known class of clinically active antitumor agent [26,27], In vitro studies showed 5-FU to have a sufficient antitumor effect in human pancreatic adenocarcinoma cell lines, even at clinically attainable concentrations and expo sure times [13]. With in vivo studies, none of the fluoropyrimidines inhibited human pan creatic cancer cell growth [28].…”

TGFβ Inhibition Prior to Hypofractionated Radiation Enhances Efficacy in Preclinical Models

“…Pancreatic adenocarcinomas are highly angiogenic and fibrotic tumors, and TGFb overexpression in pancreatic cancer correlates with decreased survival (43,44). The Panc02 murine pancreatic adenocarcinoma cell line is highly resistant to chemotherapy and radiotherapy when injected into syngeneic mice (32). While in vitro Panc02 cells are similarly radiosensitive as CT26 cells, in vivo CT26 tumors are markedly more radiosensitive (Supplementary Fig.…”

Enhancement of antitumor immunity of dendritic cells pulsed with heat-treated tumor lysate in murine pancreatic cancer

“…Here, we used an immunocompetent C57BL/6 murine model to evaluate antitumor immunity against the pancreatic cancer cell line, PANC02. PANC02 is a chemically induced ductal pancreatic cancer cell line and is resistant to various antitumor agents [20,21]. For that reason, PANC02 cells highly resemble the human counterpart.…”