Preclinical antitumor activity of benzopyranones

Cancer Research(2005)

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摘要
5891 Agents with selective estrogen receptor modulatory (SERM) activities have been widely used in the treatment and prevention of cancers such as breast cancer and endometrial carcinoma that express estrogen receptors. Furthermore, SERMs (e.g., Tamoxifen) also have been shown to have anticancer activity in cancers that do not express estrogen receptors, suggesting an estrogen receptor-independent antitumor mechanism for the agents. CC-8490 is a novel benzopyranone that has potent SERM activity in bone and breast cancer cell lines that express estrogen receptors. Recently it was discovered that CC-8490 induces apoptosis and inhibits the tumor growth of U87 glioblastoma tumors implanted subcutaneously and prolonged the survival of mice with intracranial glioblastoma. CC-8490 is currently in a Phase I dose escalation study in patients with glioblastoma. In the current preclinical study we evaluated the anticancer activity of CC-8490 and its analogs in various tumor types. CC-8490 and its close analogs were tested in a panel of 15 cancer cell lines representing 9 different tumor types including glioblastoma, leukemia, breast, colon, prostate, pancreatic ovarian, non-small cell and uterine cancers. The compounds inhibited the proliferation of these cancer cells lines and also a multi-drug resistant phenotype (MES-SA-dx5) of a uterine carcinoma cell line (MES-SA) with IC50 values in low micromolar range. CC-8490 and its analogs were also tested in a panel of SCID mouse xenograft models of human cancer cell lines including glioblastoma, non-small cell lung cancer (NSCLC), colon and breast cancers. Once daily intraperitonial administration of CC-8490 and its analog Cpd-A to SCID mice with established U87 glioblastoma tumors at 30 and 50 mg/kg resulted in dose-dependent inhibition of tumor growth with TGD (tumor growth delay) of 2 and 5 days (for CC-8490) and 3 and 7 days (for Cpd-A), respectively. The %T/C ratios on day 38 for CC-8490 were 55 and 35 for 30 and 50 mg/kg, respectively. The %T/C values for Cpd-A on day 39 were 35 and 23 at 30 and 50 mg/kg, respectively. In NCI-H460 (NSCLC) xenograft model, a 30 mg/kg (qd) dose of CC-8490 and its analogs Cpd-A, Cpd-B and Cpd-C inhibited the tumor growth with %T/C ratios of 46, 49, 51 and 53 on day 28, respectively. This inhibition was similar to that of a maximum tolerated dose of 10 mg/kg Docetaxel administered at q4d (i.v.). These compounds were well tolerated as measured by loss of body weights. Tumor growth inhibition with CC-8490 and its analogs in HT-29 (colon cancer) and MDA-MB-231 (breast cancer) xenograft models, their histological and immunohistochemical effects will be presented. In summary, these studies demonstrate that CC-8490 and its close analogs have potent in vitro and in vivo anticancer activity against a variety of human cancer models.
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