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.
PANC02 is a unique experimental animal tumor that fails to respond significantly to any known clinically active antitumor agent. In this regard, the murine ductal adenocarcinoma resembles its human counterpart. To study the mechanism for its intrinsic resistance to 6-thioguanine (TG), we compared the metabolism of the drug in PANC02 and a reference, TG-sensitive adenocarcinoma, CA-755. In comparison with CA-755, PANC02 cells were approximately 6 times less sensitive to TG and CHO cells were 80 times less sensitive in tissue culture. Nevertheless, the incorporation of TG into the DNA of these three cell lines was approximately equal at the lowest concentrations capable of reducing cloning efficiency by 50%, i.e., 3.0-3.8 pmol (dthioGMP)/nmol (dGMP). In mice bearing bilateral implants of CA-755 and PANC02, only CA-755 responded to TG treatment. At various doses used on various schedules, the incorporation of TG into CA-755 DNA readily achieved that observed to be cytotoxic to the cells in vitro, whereas the incorporation into the DNA of PANC02 tumor cells did not. Although the biochemical basis for the poor incorporation of TG into the DNA of PANC02 in vivo is not known, this factor appears to explain the refractoriness of PANC02 as compared with CA-755 to this antitumor antimetabolite.
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