kw-2170 and Prostatic-Neoplasms

KW-2170 is a novel pyrazoloacridone derivative that intercalates nucleic acids. It has promising in vitro properties against prostate and other cancers and is active in vivo against doxorubicin-resistant cell lines. We wished to investigate its activity and toxicity profile in this Phase II trial in androgen independent prostate cancer.. Overall 44 men were recruited to this multicenter, open label, non-randomized study, with 35 evaluable for prostatic specific antigen (PSA) response.. Five patients had a PSA fall greater than 50% (overall RR 14.3%, 95% CI 4.8-30.3%). Overall median survival was 16 months. In the evaluable group (n = 35), median survival was 18.9 months. The drug was very well tolerated, with the most common toxicities being hematological (anemia, leucopenia, thrombocytopenia), alopecia, fatigue, and nausea. However, most of these were National Cancer Institute Grade 1 or 2; Grade 3 neutropenia occurred in only 11% of patients, and there was no Grade 4 neutropenia. Quality of life as measured by the FACT-P scale was not compromised.. KW-2170 is a very well tolerated chemotherapy agent. It has a relatively low PSA response rate, and did not meet the pre-specified criteria for further studies.

Topics: Acridines; Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Castration; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Pyrazoles; Quality of Life; Survival Rate; Treatment Outcome

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.

Topics: Acridines; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Doxorubicin; Drug Resistance, Multiple; Female; Fibrosarcoma; Gastrointestinal Neoplasms; Humans; Liver Neoplasms; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Molecular Structure; Neoplasms; Prostatic Neoplasms; Pyrazoles; Sarcoma 180; Transplantation, Heterologous; Tumor Cells, Cultured