Summary
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 drugsensitive 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.
Similar content being viewed by others
References
Barranco SC, Drewinko B, Ho D, Humphrey RM, Romsdahl M (1972) Differential sensitivities of human melanoma cells grown in vitro to arabinosylcytosine. Cancer Res 32:2733
Braunschweiger PG, Jones SA, Johnson CS, Furmanski P (1991) Potentiation of mitomycin C and profiromycin antitumor activity in solid tumor models by recombinant human interleukin-1α. Cancer Res 51:5454
Chirgwin JM, Przybyla AE, MacDonald RJ, Rutter WJ (1979) Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 18:5294
Corbett TH, Roberts BJ, Leopold WR, Peckham JC, Wilkoff LJ, Griswold DP Jr, Schabel FM Jr (1984) Induction and chemotherapeutic response of two transplantable ductual adenocarcinomas of the pancreas in C57BL/6 mice. Cancer Res 44:717
Drake S, Burns RL, Nelson JA (1982) Metabolism and mechanisms of action of 9-(tetrahydro-2-furyl)-6-mercaptopurine in Chinese hamster ovary cells. Chem-Biol Interact 41:105
Eifel PJ (1988) Decreased bone growth arrest in weanling rats with multiple radiation fractions per day. Int J Radiat Oncol Biol Phys 15:141
Fidler IJ, Hart IR (1981) Biological and experimental consequences of the zonal composition of solid tumors. Cancer Res 41:3266
Fojo AT, Shen D-W, Mickley LA, Pastan I, Gottesman MM (1978) Intrinsic drug resistance in human kidney cancer is associated with expression of a human multidrug-resistance gene. J Clin Oncol 5:1922
Gerlach JH, Kartner N, Bell DR, Ling V (1986) Multidrug resistance. Cancer Surv 5:25
Heppner GH (1984) Tumor heterogeneity. Cancer Res 44:2259
Heppner GH, Miller BE (1989) Therapeutic implications of tumor heterogeneity. Semin Oncol 18:91
Hokansson L, Trope C (1974) On the presence within tumors of clones that differ in sensitivity to cytostatic drugs. Acta Pathol Microbiol Scand [A] 82:32
Huang P, Siciliano MJ, Plunkett W (1989) Gene deletion, a mechanism of induced mutation by arabinosyl nucleosides. Mutat Res 210:291
Kessel D, Corbett T (1985) Correlations between anthracyline resistance, drug accumulation and membrane glycoprotein patterns in solid tumors of mice. Cancer Lett 28:187
Nelson JA, Hokanson JA, Jenkins VK (1982) Role of the host in the variable chemotherapeutic response of advanced Ridgway osteogenic sarcoma. Cancer Chemother Pharmacol 9:148
Nelson JA, Pan BF, Priebe TS (1991) Mechanisms of resistance to 6-thioguanine in a murine pancreatic tumor. Cancer Chemother Pharmacol (in press)
Skipper H (1986) Puzzling questions regarding a transplantable pancreatic tumor, PANC02 that is very refractory to all classes of anticancer drugs in vivo. Booklet 12. Southern Research Institute, Birmingham, Alabama
Teeter LD, Becker FF, Chisari FV, Li D, Kuo MT (1990) Overexpression of multidrug resistance gene mdr3 in spontaneous and chemically induced mouse hepatocellular carcinomas. Mol Cell Biol 10:5728
Wilkoff LJ, Dulmadge EA (1986) Sensitivity of proliferating cultured murine pancreatic tumor cells to selected antitumor agents. J Natl Cancer Inst 77:1163
Zinn K, DiMaio D, Maniatis T (1983) Identification of two distinct regulatory regions adjacent to the human b-interferon gene. Cell 34:865
Author information
Authors and Affiliations
Additional information
Supported by grant CH-458 from the American Cancer Society, by grant CA-28034 from the National Cancer Institute, and in part by Cancer Center Core Support grant, NIH-NCI-CA-16672. Animals were maintained in facilities approved by the American Association for Accreditation of Laboratory Animal Care and in accordance with current United States Department of Agriculture, Department of Health and Human Services, and National Institutes of Health regulations and standards
Rights and permissions
About this article
Cite this article
Priebe, T.S., Atkinson, E.N., Pan, BF. et al. Intrinsic resistance to anticancer agents in the murine pancreatic adenocarcinoma PANC02. Cancer Chemother. Pharmacol. 29, 485–489 (1992). https://doi.org/10.1007/BF00684853
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00684853