title: Promising antitumor activity of a novel quinoline derivative, TAS-103, against fresh clinical specimens of eight types of tumors measured by flow cytometric DNA analysis.
abstract: TAS-103, 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno-[2,1-c]quinolin-7-one dihydrochloride, is a dual topoisomerases I and II inhibitor. Antitumor activities of TAS-103 against fresh surgical specimens resected from 525 patients (32 types of tumors) were examined by flow cytometric (FCM) analysis of DNA integrity of tumor cells, and compared with those of five other investigational new drugs and 31 clinically available anticancer agents. Concentrations of clinically available anticancer agents were set at one-tenth of the peak plasma concentration (PPC) of the clinically recommended doses. On the other hand, since PPCs of investigational new drugs in humans were frequently unknown, these were estimated by a method that determines the theoretically achievable concentration in body fluid (TAC method). Correlations between TAC and PPC were examined for 16 clinically available anticancer agents, and it was found that TAC at 7n (the modified Fibonacci's dose-escalation scheme) of 14 drugs corresponded well with each one-tenth of PPC. By defining a 30% or more reduction in the integrated diploid peak as effective and a 60% or more reduction as definitely effective, TAS-103 at 5 microg/ml (7n) showed significantly higher effective rates and definitely effective rates than those of all other investigational new drugs, as well as almost all clinically available anticancer agents, against various malignancies, including non-small cell lung cancer, brain tumor and renal cancer. These results strongly suggest that TAS-103 will be expected to show excellent antitumor activities against a wide range of human tumors.
authors.affiliation: Division of Chemotherapy, Chiba Cancer Center Research Institute, Chuoh-ku, Chiba, Japan. sfujimot@chiba-cc.jp
authors.forename: Shuichi
authors.initials: S
authors.lastname: Fujimoto
mesh_terms: D000634:Aminoquinolines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D004273:DNA, Neoplasm / Q000187:drug effects*; D004171:Diploidy; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007192:Indenes / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D007192:Indenes; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C106647:6-((2-(dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)quinolin-7-one