Cancer Chemotherapy and Pharmacology

, Volume 56, Issue 2, pp 115–125 | Cite as

In vivo antitumor efficacy of 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride), a water-soluble geldanamycin derivative

  • Melinda Hollingshead
  • Michael Alley
  • Angelika M. Burger
  • Suzanne Borgel
  • Christine Pacula-Cox
  • Heinz-Herbert Fiebig
  • Edward A. Sausville
Original Article

Abstract

Purpose

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 μM. “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.

Keywords

Heat shock protein 90 Ansamycin Xenograft 

Abbreviations

AAALAC

Association for the Assessment and Accreditation of Laboratory Animal Care

17-AAG

17-Allylamino-17-demethoxygeldanamycin

17-DMAG-HCl

17-Dimethylaminoethylamino-17-demethoxygeldanamaycin hydrochloride

GA

Geldanamycin

GI50

Concentration of drug causing 50% growth inhibition

Hsp90

Heat shock protein-90

IP

Intraperitoneal

IV

Intravenous

LC50

Concentration of drug causing 50% cell kill

SC

Subcutaneous

T/C

Treated/control tumor weight

% T/C

growth delay

TGI

Concentration of drug causing total growth inhibition

USPHS

United States Public Health Service

Notes

Acknowledgements

We thank Ms. Kelly Dougherty, Ms. Carrie Bonomi, and Mrs. Cornelia Steidle for their excellent technical assistance. This work was funded by NCI contract NO1-CO 12400 and by a grant (RFP N01-CM-270/N01-CM-97017) from the National Cancer Institute, Bethesda, MD, to H.H.F. and A.M.B.

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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Melinda Hollingshead
    • 1
  • Michael Alley
    • 1
  • Angelika M. Burger
    • 4
  • Suzanne Borgel
    • 3
  • Christine Pacula-Cox
    • 1
  • Heinz-Herbert Fiebig
    • 2
  • Edward A. Sausville
    • 1
    • 5
  1. 1.Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis National Cancer InstituteBethesdaUSA
  2. 2.Institute for Experimental OncologyFreiburgGermany
  3. 3.SAIC-Frederick, Inc.FrederickUSA
  4. 4.Sunnybrook and Women’s College Health Sciences CenterTorontoCanada
  5. 5.Greenebaum Cancer CenterUniversity of MarylandBaltimoreUSA

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