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¹ School of Pharmaceutical Sciences, Zhejiang University, Hangzhou; ² Y-Chem Ltd.; and ³ Institute of Medicinal Chemistry, Department of Chemistry, East China Normal University, Shanghai, China

Requests for reprints: Bo Yang or Yiyu Cheng, Institute of Pharmacology and Toxicology, School of Pharmaceutical Science, Zhejiang University, 353 Yanan Road, 310031 Hangzhou, China. Phone: 86-571-8712-7021; Fax: 86-571-8712-7021. E-mail: yang924{at}zju.edu.cn or chengyy{at}zju.edu.cn

The present data showed that 10-methoxy-9-nitrocamptothecin (MONCPT), a family of camptothecin analogues, possessed high antitumor activity in vitro and in vivo. Cytotoxicity assays showed that MONCPT was a potential and highly efficient antitumor compound with IC₅₀ values of 0.1 to 500 nmol/L in nine tumor cell lines. The high cytotoxic potency of MONCPT was paralleled with its ability to increase the cellular accumulation of DNA damage. DNA relaxation assay also showed that MONCPT exerted high potency as a topoisomerase I inhibitor. Moreover, administration of MONCPT (5–20 mg/kg) for 15 to 17 days significantly inhibited tumor growth in human androgen–independent prostate tumor (PC3) and human non–small cell lung tumor (A549) xenografts; the inhibition rates ranged from 29.6% to 98%. The cytotoxic effect of 1,000 nmol/L of MONCPT in PC3 cells was associated with causing an arrest in G₀-G₁ phase, whereas that of 10 and 100 nmol/L MONCPT was relative to a persistent block in G₂-M phase. Furthermore, down-regulation of CDK2, CDK4, and cyclin D1 was observed in PC3 cells treated with 1,000 nmol/L of MONCPT, whereas overexpression of CDK7, CDK1, and cyclin B1 was seen in PC3 cells treated with 10 and 100 nmol/L of MONCPT. These results suggested that cell cycle regulation might contribute to the anticancer properties of MONCPT and strongly support the further anticancer development of MONCPT. [Mol Cancer Ther 2006;5(4):962–8]

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Received 9/26/05; revised 11/29/05; accepted 1/25/06.