title: Antiproliferative effect in vitro and antitumor activity in vivo of brefeldin A.
abstract: OBJECTIVE
  An empiric in vitro screen of human tumor cell lines found brefeldin A inhibited the growth of immortalized human cell lines, with particular sensitivity to brefeldin in a series of immortalized melanoma cell lines and nonimmortalized prostate carcinoma explants. Brefeldin A alters the morphology and function of the Golgi apparatus, endosomal, and trans-Golgi compartments in different cell types. The studies presented here sought to obtain evidence of in vivo antitumor activity by brefeldin A.
  
  
  METHODS
  Antiproliferative activity was studied in prostate carcinoma cells in vitro using cell counts, protein, and viable stains. Activity was also studied in vivo against subcutaneous and subrenal capsule melanoma models.
  
  
  RESULTS
  Protracted exposures in vitro (between 24 and 72 hours) are necessary to cause persistent growth inhibition of immortalized PC3 prostate carcinoma cells. In human melanoma athymic mouse xenografts, brefeldin A showed antitumor activity in vivo when given 16 to 64 mg/kg/injection intraperitoneally q 7 h x 2, daily for 5 days. Activity was also observed in the intraperitoneal LOX IMVI (65%-100% increase in life span, with 17%-50% day 60 survivors); early-stage subcutaneous LOX IMVI and SK-MEL-5 (86%-100% growth inhibition), and subrenal capsule SK-MEL-5 and M19-MEL models.
  
  
  CONCLUSIONS
  Brefeldin A possesses noteworthy antitumor activity in vivo and antiproliferative effects in vitro in certain cell types. Strategies to allow protracted exposure of tumor cells to brefeldin A while preserving a therapeutic index are needed to assess the clinical potential of brefeldin A.
authors.affiliation: Laboratory of Biological Chemistry, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20892-7458, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Sausville
authors.forename: K L
authors.initials: KL
authors.lastname: Duncan
authors.forename: A
authors.initials: A
authors.lastname: Senderowicz
authors.forename: J
authors.initials: J
authors.lastname: Plowman
authors.forename: P A
authors.initials: PA
authors.lastname: Randazzo
authors.forename: R
authors.initials: R
authors.lastname: Kahn
authors.forename: L
authors.initials: L
authors.lastname: Malspeis
authors.forename: M R
authors.initials: MR
authors.lastname: Grever
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D020126:Brefeldin A / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011500:Protein Synthesis Inhibitors / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D011500:Protein Synthesis Inhibitors; D020126:Brefeldin A