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Inhibition of intracellular Ca2+ signalling, cytotoxicity and antitumor activity of the herbicide oryzalin and its analogues
Authors:Garth Powis  Alfred Gallegos  Robert T Abraham  Curtis L Ashendel  Loen H Zalkow  Robert Dorr  Katerina Dvorakova  Sydney Salmon  Steadman Harrison  John Worzalla
Institution:(1) Arizona Cancer Center, University of Arizona, 1515 N. Campbell Avenue, Tucson, AZ 85724-5024, USA Tel. (520) 626-6408; Fax (520) 626-4848, US;(2) Mayo Clinic, Rochester, MN 55905, USA, US;(3) Purdue University, West Lafayette, IN 47907, USA, US;(4) Georgia Institute of Technology, Atlanta, GA 30332, USA, GE;(5) Lilly Research Laboratories, Indianapolis, IN 46285, USA, IN
Abstract:Purpose: Studies were conducted on oryzalin (3,5-dinitro-N,N-di(n-propyl)sulfanilamide), a widely used dinitroaniline sulfonamide herbicide, which was identified from plant extracts as an inhibitor of mitogen- and growth factor-mediated intracellular free Ca2+ (Ca2+]i) signalling in mammalian cells. Methods and Results: Oryzalin inhibited vasopressin, bradykinin and platelet-derived growth factor Ca2+]i signalling in Swiss 3T3 fibroblasts with IC50 values of 14, 16 and 18 μM, respectively. 45Ca2+ uptake into nonmitochondrial stores of saponin-permeabilized Swiss 3T3 cells was inhibited by oryzalin with an IC50 of 34 μM. Oryzalin inhibited colony formation of HT-29 colon carcinoma cells with an IC50 of 8 μM and inhibited the growth of a number of other cancer cell lines and primary human tumors in vitro with IC50 values in the range 3 to 22 μM. A number of oryzalin analogues were studied and an association was found between the ability to inhibit Ca2+]i signalling and inhibition of the growth of HT-29 human colon cancer cells (P=0.001) and of CCRF-CEM human leukemia cells (P=0.016). Oryzalin at doses up to 600 mg/kg administered orally or subcutaneously daily to mice for 3 to 10 days beginning a day after tumor inoculation inhibited the growth of murine B16 melanoma by 63% but showed no appreciable activity when administered subcutaneously or intraperitoneally to mice beginning a number of days after tumor inoculation against a variety of human tumor xenografts. The peak plasma concentration of oryzalin following repeated subcutaneous administration of oryzalin at 600 mg/kg per day to mice was 37 μM and of its major metabolite N-depropyl oryzalin was 53 μM. Conclusion: It is unlikely that the absence of significant antitumor activity of oryzalin is a result of the inability to achieve adequate plasma concentrations. Received: 24 December 1996 / Accepted: 20 March 1997
Keywords:Intracellular Ca2+  Cell proliferation Oryzalin
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