title: In vivo antitumor efficacy of 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride), a water-soluble geldanamycin derivative.
abstract: OBJECTIVE
  To describe the preclinical basis for further development of 17-dimethyl aminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG, NSC 707545).
  
  
  METHODS
  In vitro proliferation assays, and in vivo model studies in metastatic pancreatic carcinoma and subcutaneous xenograft melanoma and small-cell lung carcinoma models.
  
  
  RESULTS
  17-DMAG emerged from screening studies as a potent geldanamycin analog, with the average concentration inhibiting the growth of the NCI anticancer cell line drug screen by 50% being 0.053 microM. "Head to head" comparison with 17-allylamino-17-demethoxygeldanamycin (17-AAG, NSC 330507) revealed 17-DMAG to possess potent activity against certain cell types, e.g., MDA-MB-231 breast carcinoma and HL60-TB leukemia which were relatively insensitive to 17-AAG. Evidence of oral bioavailability of 17-DMAG in a saline-based formulation prompted more detailed examination of its antitumor efficacy in vivo. 17-DMAG inhibited the growth of the AsPC-1 pancreatic carcinoma xenografts growing as intrahepatic metastases at doses of 6.7-10 mg/kg twice daily for 5 days administered orally under conditions where 17-AAG was without activity. 17-DMAG in an aqueous vehicle at 7.5-15 mg/kg per day for 3 days on days 1-3, 8-10 and 13-17, or 1-5 and 8-12 showed evidence of antitumor activity by the parenteral and oral routes in the MEXF 276 and MEXF 989 melanomas and by the parenteral route in the LXFA 629 and LXFS 650 adenocarcinoma and small-cell carcinoma models. The latter activity was comparable to the historical activity of 17-AAG.
  
  
  CONCLUSIONS
  Taken together, the in vivo activity of 17-DMAG supports the further development of this water-soluble and potentially orally administrable geldanamycin congener.
authors.affiliation: Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Melinda
authors.initials: M
authors.lastname: Hollingshead
authors.forename: Michael
authors.initials: M
authors.lastname: Alley
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Burger
authors.forename: Suzanne
authors.initials: S
authors.lastname: Borgel
authors.forename: Christine
authors.initials: C
authors.lastname: Pacula-Cox
authors.forename: Heinz-Herbert
authors.initials: HH
authors.lastname: Fiebig
authors.forename: Edward A
authors.initials: EA
authors.lastname: Sausville
mesh_terms: D000818:Animals; D016227:Benzoquinones; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D049109:Cell Proliferation; D004354:Drug Screening Assays, Antitumor; D047029:Lactams, Macrocyclic; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary / Q000662:veterinary; D008175:Lung Neoplasms / Q000473:pathology*; D008297:Male; D008545:Melanoma / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D011809:Quinones / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000473:pathology*; D012995:Solubility; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D011809:Quinones; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin