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.
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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
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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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Hollingshead, M., Alley, M., Burger, A.M. et al. In vivo antitumor efficacy of 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride), a water-soluble geldanamycin derivative. Cancer Chemother Pharmacol 56, 115–125 (2005). https://doi.org/10.1007/s00280-004-0939-2
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DOI: https://doi.org/10.1007/s00280-004-0939-2