ANTITUMOR EFFECT OF DX-8951, A NOVEL CAMPTOTHECIN ANALOG, ON HUMAN PANCREATIC TUMOR-CELLS AND THEIR CPT-11-RESISTANT VARIANTS CULTURED IN-VITRO AND XENOGRAFTED INTO NUDE-MICE

DX-8951 is a novel water-soluble derivative of camptothecin. We evalua ted the effects of DX-8951 on the growth of several pancreatic tumor c ell lines in vitro and in vivo. In vitro cytotoxic activity of DX-8951 against SUIT-2 and KP-1N cells, as indicated by IC50 value, was sever al times more potent than that of SN-38, an active metabolite of CPT-1 1, and dozens of times more potent than that of SK&F104864 (topotecan) . DX-8951 also showed the greatest cytotoxicity against CPT-ll-resista nt variants, SUIT-2/CPT-11 and KP-1N/CPT-11 cells, and the cross-resis tance of these cells to DX-8951 was lower than that to SN-38 and SK&F1 04864. Topoisomerase I inhibitory activity of DX-8951 was about three- fold stronger than that of SN-38, as measured in crude nuclear extract obtained from SUIT-2 cells. DX-8951 induced DNA fragmentation, a spec ific feature of apoptosis, in SUIT-2 cells more effectively than SN-38 . DX-8951 exhibited potent antitumor effects against SUIT-2 in a solid tumor model and in a liver metastasis model, in which tumor cells wer e xenografted subcutaneously and intrasplenically, respectively, into nude mice. The in vivo effects were closely similar to or somewhat sup erior to those of CPT-11. DX-8951 also showed significant antitumor ef fects against SUIT-2/CPT-11 solid tumors, against which CPT-11 had no effect. These results suggest that, on the basis of its strong antitum or activity and effectiveness against CPT-ll-resistant tumors, DX-8951 may be a useful therapeutic agent in the treatment of human cancer. T he potent cytotoxicity of DX-8951 may result from strong inhibition of topoisomerase I, which may then trigger apoptotic cell death.