ANTITUMOR-ACTIVITY OF KW-2170, A NOVEL PYRAZOLOACRIDONE DERIVATIVE

thyl)aminoethyl-6H-pyrazolo[4,5,1-de]acridin-6-one dihydroxychloride ( KW-2170), a novel derivative of pyrazoloacridone, was selected and eva luated for its antitumor activity and toxicity in mice. KW-2170 exhibi ted antitumor activity superior to adriamycin (ADM) against Sarcoma 18 0, breast carcinoma MM102 and fibrosarcoma Meth A inoculated s.c. in m ice. Its therapeutic index (LD10/ED50) was higher than that of ADM on two murine carcinoma models, MM102 and Meth A. KW-2170 showed signific ant 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 lu ng carcinoma xenograft models. Ovary and pancreas carcinomas were also sensitive to the drug. Additionally, its therapeutic index was also h igh on these human carcinoma models in comparison with that of ADM. Th e best antitumor efficacy of KW-2170 was observed by a weekly treatmen t schedule followed by a single treatment schedule and a successive ad ministration schedule also tended to be toxic to the hosts. KW-2170 ex hibited very low cross-resistance against four lines of multidrug resi stant tumors expressing high levels of P-glycoprotein, and the drug sh owed 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 antitumo r drug against ADM-refractory solid tumors in clinics. [(C) 1998 Rapid Science Ltd.].