Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

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

References

  1. Alley MC, Scudiero DA, Monks A, Hursey ML, Czerwinski MJ, Fine DL, Shoemaker RH, Mayo JG, Boyd MR (1988) Feasibility of drug screening with panels of human tumor lines using a microculture tetrazolium assay. Cancer Res 48:589–601

    CAS  PubMed  Google Scholar 

  2. Alley MC, Pacula-Cox CM, Hollingshead, MG, Camalier RF, Mayo JG, Plowman, J, Malspeis L (1995) Utility of a PVDF filter plate assay to facilitate selection of tumor cell lines for in vivo drug testing. Proc Am Assoc Cancer Res 36:305

    Google Scholar 

  3. Banerji U, Clarke P, Walton M, O‘Donnell A, Raynaud F, Turner A, Judson I, Workman P (2003) Preclinical and clinical activity of the molecular chaperone inhibitor 17-allylamino-17-demethoxygeldanamycin (17AAG) in malignant melanoma (2nd edn) (abstract 2966). Proc Am Assoc Cancer Res 44:587

    Google Scholar 

  4. Beliakoff J, Bagatell R, Paine-Murrieta G, Taylor CW, Lykkesfeldt AE, Whitesell L (2003) Hormone-refractory breast cancer remains sensitive to the antitumor activity of heat shock protein 90 inhibitors. Clin Cancer Res 9:4961–4971

    Google Scholar 

  5. Bonvini P, Gastaldi T, Falini B, Rosolen A (2002) Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), a novel Hsp90-client tyrosine kinase: down-regulation of NPM-ALK expression and tyrosine phosphorylation in ALK(+) CD30(+) lymphoma cells by the Hsp90 antagonist 17-allylamino,17-demethoxygeldanamycin. Cancer Res 62:1559–1566

    Google Scholar 

  6. Burger (2001) Pre-clinical evaluation of a methotrexate-albumin conjugate (MTX-HSA) in human tumor xenografts in vivo. Int J Cancer 92:718–724

    Google Scholar 

  7. Burger AM, Fiebig HH, Stinson SF, Sausville EA (2004) 17-Allyl-amino-17-demethoxygeldanamycin activity in human melanoma models. Anticancer Drugs 15:377–387

    Google Scholar 

  8. DeBoer C, Meulman PA, Wnuk RJ, Peterson DH (1970) Geldanamycin, a new antibiotic. J Antibiot (Tokyo) 23:442–447

    Google Scholar 

  9. Egorin MJ, Rosen DM, Wolff JH, Callery PS, Musser SM, Eiseman JL (1998) Metabolism of 17-(allylamino)-17-demethoxygeldanamycin (NSC 330507) by murine and human hepatic preparations. Cancer Res 58:2385–2396

    CAS  PubMed  Google Scholar 

  10. Egorin MJ, Lagattuta TF, Hamburger DR, Covey JM, White KD, Musser SM, Eiseman JL (2002) Pharmacokinetics, tissue distribution, and metabolism of 17-(dimethylaminoethylamino)-17-demethoxy geldanamycin (NSC 707545) in CD2F1 mice and Fisher 344 rats. Cancer Chemother Pharmacol 49:7–19

    Article  CAS  PubMed  Google Scholar 

  11. Fiebig HH, Burger AM (2001) Human tumor xenografts and explants. In: Teicher BA (ed) Animal models in cancer research. Humana Press, Totowa, pp 113–137

    Google Scholar 

  12. Glaze ER, Lambert AL, Page J, Egorin M, Eiseman J, Holleran J, Tomaszewski JE (2003) Toxicity studies with 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17DMAG; NSC 707545). Clin Cancer Res [Suppl] 9:6215s

    Google Scholar 

  13. Hollingshead MG, Alley MC, Camalier RF, Abbott BJ, Mayo JG, Malspeis L, Grever MR (1995) In vivo cultivation of tumor cells in hollow fibers. Life Sci 57:131–141

    Article  CAS  PubMed  Google Scholar 

  14. Hollingshead M, Plowman J, Alley M, Mayo J, Sausville E (1999) The hollow fiber assay. In: Fiebig HH, Burger AM (eds) Contributions to oncology, vol 54. Relevance of tumor models for anticancer drug development. Karger, Basel, pp 109–120

  15. Jez JM, Chen JC, Rastelli G, Stroud RM, Santi DV (2003) Crystal structure and molecular modeling of 17-DMAG in complex with human Hsp90. Chem Biol 10:361–368

    Article  CAS  PubMed  Google Scholar 

  16. Johnson JI, Decker S, Zaharevitz D, Rubinstein LV, Venditti JM, Schepartz S, Kalyandrug S, Christian M, Arbuck S, Hollingshead M, Sausville EA (2001) Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br J Cancer 84:1424–1431

    Google Scholar 

  17. Kamal A, Thao L, Sensintaffar J, Zhang L, Boehm MF, Fritz LC, Burrows FJ (2003) A high-affinity conformation of Hsp90 confers tumor selectivity on Hsp90 inhibitors. Nature 425:407–410

    Article  CAS  PubMed  Google Scholar 

  18. Monks A, Scudiero D, Skehan P, Shoemaker R, Paull K, Vistica D, Hose C, Langley J, Cronise P, Vaigro-Wolff A, Gray-Goodrich M, Campbell H, Boyd M (1991) Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J Natl Cancer Inst 83:757–766

    Google Scholar 

  19. Paull KD, Shoemaker RH, Hodes L, Monks A, Scudiero DA, Rubinstein L, Plowman J, Boyd MR (1989) Display and analysis of patterns of differential activity of drugs against human tumor cell lines: development of mean graph and COMPARE algorithm. J Natl Cancer Inst 81:1088–1092

    Google Scholar 

  20. Nimmanapalli R, O’Bryan E, Bhalla K (2001) Geldanamycin and its analogue 17-allylamino-1-demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of Bcr-Abl-positive human leukemic blasts. Cancer Res 61:1799–1804

    CAS  PubMed  Google Scholar 

  21. Omura S, Iwai Y, Takahashi Y, Sadakane N, Nakagawa A, Oiwa H, Hasegawa Y, Ikai T (1979) Herbimycin, a new antibiotic produced by a strain of Streptomyces. J Antibiot (Tokyo) 32:255–261

    Google Scholar 

  22. Sausville EA, Tomaszewski JE, Ivy P (2003) Clinical development of 17-allylamino,17-demethoxygeldanamycin. Curr Cancer Drug Targets 3:377–383

    Google Scholar 

  23. Schulte TW, Neckers LM (1998) The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares important biologic activities with geldanamycin. Cancer Chemother Pharmacol 42:273–279

    Article  CAS  PubMed  Google Scholar 

  24. Smith V, Sausville EA, Camalier RF, Fiebig HH, Burger AM (2003) 17-DMA-geldanamycin is a novel water soluble orally bioavailable Hsp-90 inhibitor with potent in vitro and in vivo anti-cancer activity (2nd edn). Proc Am Assoc Cancer Res 44:153

    Google Scholar 

  25. Solit DB, Zheng FF, Drobnjak M, Munster PN, Higgins B, Verbel D, Heller G, Tong W, Cordon-Cardo C, Agus DB, Scher HI, Rosen N (2002) 17-Allylamino-17-demethoxygeldanamycin induces the degradation of androgen receptor and HER-2/neu and inhibits the growth of prostate cancer xenografts. Clin Cancer Res 8:986–993

    CAS  Google Scholar 

  26. Stancato LF, Silverstein AM, Owens-Grillo JK, Chow YH, Jove R, Pratt WB (1997) The hsp90-binding antibiotic geldanamycin decreases Raf levels and epidermal growth factor signaling without disrupting formation of signaling complexes or reducing the specific enzymatic activity of Raf kinase. J Biol Chem 272:4013–4020

    Google Scholar 

  27. Stebbins CE, Russo AA, Schneider C, Rosen N, Hartl FU, Pavletich NP (1997) Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Cell 89:239–250

    Article  CAS  PubMed  Google Scholar 

  28. Supko JG, Hickman RL, Grever MR, Malspeis L (1995) Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother Pharmacol 36:305–315

    Article  CAS  PubMed  Google Scholar 

  29. Uehara Y, Hori M, Takeuchi T, Umezawa H (1985) Screening of agents which convert ‘transformed morphology’ of Rous sarcoma virus-infected rat kidney cells to ‘normal morphology’: identification of an active agent as herbimycin and its inhibition of intracellular src kinase. Jpn J Cancer Res 76:672–675

    Google Scholar 

  30. Uehara Y, Hori M, Takeuchi T, Umezawa H (1986) Phenotypic change from transformed to normal induced by benzoquinonoid ansamycins accompanies inactivation of p60src in rat kidney cells infected with Rous sarcoma virus. Mol Cell Biol 6:2198–2206

    CAS  PubMed  Google Scholar 

  31. Webb CP, Hose CD, Koochekpour S, Jeffers M, Oskarsson M, Sausville E, Monks A, Vande Woude GF (2000) The geldanamycins are potent inhibitors of the hepatocyte growth factor/scatter factor-met-urokinase plasminogen activator-plasmin proteolytic network. Cancer Res 60:342–349

    Google Scholar 

  32. Whitesell L, Mimnaugh EG, De Costa B, Myers CE, Neckers LM (1994) Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci U S A 91:8324–8328

    CAS  PubMed  Google Scholar 

  33. Xu L, Eiseman JL, Egorin MJ, D’Argenio DZ (2003) Physiologically-based pharmacokinetics and molecular pharmacodynamics of 17-(allylamino)-17-demethoxygeldanamycin and its active metabolite in tumor-bearing mice. J Pharmacokinet Pharmacodyn 30:185–219

    Article  CAS  PubMed  Google Scholar 

  34. Xu W, Yuan X, Jung YJ, Yang Y, Basso A, Rosen N, Chung EJ, Trepel J, Neckers L (2003) The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells. Cancer Res 63(22):7777–7784

    Google Scholar 

Download references

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.

Author information

Author notes

  1. Angelika M. Burger

    Present address: Sunnybrook and Women’s College Health Sciences Center, Toronto, ON, M4N 3M5, Canada

Authors and Affiliations

  1. Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, 20892, USA

    Melinda Hollingshead, Michael Alley, Christine Pacula-Cox & Edward A. Sausville

  2. Institute for Experimental Oncology, Am Flughafen 12-14, Freiburg, 79108, Germany

    Heinz-Herbert Fiebig

  3. SAIC-Frederick, Inc., P.O. Box B, Frederick, MD, 21702, USA

    Suzanne Borgel

  4. Greenebaum Cancer Center, University of Maryland, 22 S. Greene St., Baltimore, 21201-1595, MD, USA

    Edward A. Sausville

Authors
  1. Melinda Hollingshead
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Alley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Angelika M. Burger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Suzanne Borgel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christine Pacula-Cox
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Heinz-Herbert Fiebig
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Edward A. Sausville
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edward A. Sausville.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-004-0939-2

Keywords

Search

Navigation