title: Antitumor activity of KW-2170, a novel pyrazoloacridone derivative.
abstract: 5-(3-Aminopropyl)amino-7,10-dihydroxy-2-(2-hydroxethyl)-aminoethyl -6H-pyrazolo[4,5,1-de]acridin-6-one dihydroxy-chloride (KW-2170), a novel derivative of pyrazoloacridone, was selected and evaluated for its antitumor activity and toxicity in mice. KW-2170 exhibited antitumor activity superior to adriamycin (ADM) against Sarcoma 180, breast carcinoma MM102 and fibrosarcoma Meth A inoculated s.c. in mice. Its therapeutic index (LD10/ED50) was higher than that of ADM on two murine carcinoma models, MM102 and Meth A. KW-2170 showed significant antitumor activity against 17 human tumor xenografts of a total of 24 tumors tested and the total tumor response rate by treatment with KW-2170 was significantly higher than that by ADM (70.8 versus 58.3%). In particular, human lung carcinoma was highly sensitive to KW-2170, and a marked tumor regression was observed on Lu-65 and Lu-99 human lung carcinoma xenograft models. Ovary and pancreas carcinomas were also sensitive to the drug. Additionally, its therapeutic index was also high on these human carcinoma models in comparison with that of ADM. The best antitumor efficacy of KW-2170 was observed by a weekly treatment schedule followed by a single treatment schedule and a successive administration schedule also tended to be toxic to the hosts. KW-2170 exhibited very low cross-resistance against four lines of multidrug resistant tumors expressing high levels of P-glycoprotein, and the drug showed significant antitumor activity against ADM-resistant human ovary carcinoma A2780/ADM and against nasopharynx carcinoma KB-A1 xenografts which were not sensitive to ADM. These results indicate that KW-2170 has a very potent antitumor activity and is feasible as a new antitumor drug against ADM-refractory solid tumors in clinics.
authors.affiliation: Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co. Ltd, Shizuoka-Ken, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ashizawa
authors.forename: M
authors.initials: M
authors.lastname: Shimizu
authors.forename: K
authors.initials: K
authors.lastname: Gomi
authors.forename: M
authors.initials: M
authors.lastname: Okabe
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000166:Acridines / Q000627:therapeutic use* / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity*; D001943:Breast Neoplasms / Q000188:drug therapy; D004317:Doxorubicin / Q000627:therapeutic use / Q000633:toxicity; D018432:Drug Resistance, Multiple; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011720:Pyrazoles / Q000627:therapeutic use* / Q000633:toxicity*; D012510:Sarcoma 180 / Q000188:drug therapy; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D000970:Antineoplastic Agents; D011720:Pyrazoles; D004317:Doxorubicin; C113299:KW 2170