title: 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.
abstract: DX-8951 is a novel water-soluble derivative of camptothecin. We evaluated the effects of DX-8951 on the growth of several pancreatic tumor cell 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 several times more potent than that of SN-38, an active metabolite of CPT-11, and dozens of times more potent than that of SK&F104864 (topotecan). DX-8951 also showed the greatest cytotoxicity against CPT-11-resistant variants, SUIT-2/CPT-11 and KP-1N/CPT-11 cells, and the cross-resistance of these cells to DX-8951 was lower than that to SN-38 and SK&F104864. 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 specific 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 were xenografted subcutaneously and intrasplenically, respectively, into nude mice. The in vivo effects were closely similar to or somewhat superior to those of CPT-11. DX-8951 also showed significant antitumor effects against SUIT-2/CPT-11 solid tumors, against which CPT-11 had no effect. These results suggest that, on the basis of its strong antitumor activity and effectiveness against CPT-11-resistant tumors, DX-8951 may be a useful therapeutic agent in the treatment of human cancer. The potent cytotoxicity of DX-8951 may result from strong inhibition of topoisomerase I, which may then trigger apoptotic cell death.
authors.affiliation: Chemotherapy Division, Kyushu Cancer Center, Fukuoka.
authors.forename: S
authors.initials: S
authors.lastname: Takiguchi
authors.forename: E
authors.initials: E
authors.lastname: Kumazawa
authors.forename: T
authors.initials: T
authors.lastname: Shimazoe
authors.forename: A
authors.initials: A
authors.lastname: Tohgo
authors.forename: A
authors.initials: A
authors.lastname: Kono
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D053938:DNA Fragmentation; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D000077146:Irinotecan; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D013160:Splenic Neoplasms / Q000517:prevention & control / Q000556:secondary; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D011355:Prodrugs; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D019772:Topotecan; C095887:exatecan; D002166:Camptothecin