Mechanisms of resistance to 6-thioguanine in a murine pancreatic tumor.

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.