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Preclinical toxicity of a geldanamycin analog, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), in rats and dogs: potential clinical relevance

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Abstract

Purpose

17-DMAG is a hydrophilic derivative of the molecular chaperone inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG; NSC-330507), which is currently being evaluated for the treatment of cancer in clinical trials. 17-DMAG offers a potential advantage over 17-AAG because its aqueous solubility eliminates the need for complicated formulations that are currently used for administration of 17-AAG. In addition, 17-DMAG undergoes only limited metabolism compared to 17-AAG. The present results are from preclinical toxicity studies evaluating 17-DMAG in rats and dogs.

Methods

Doses of 0, 2.4, 12 and 24 mg/m2 per day were administered to rats, while dogs received doses of 0, 8 or 16 mg/m2 per day. In both species, 17-DMAG was administered i.v. (slow bolus for rats; 1-h infusion for dogs) daily for 5 days. An additional cohort of dogs received 16 mg/m2 per day orally for 5 days. Clinical observations were noted, and standard hematology and clinical chemistry parameters were monitored. Selected tissues were evaluated microscopically for drug-related lesions. Tissue and plasma 17-DMAG concentrations were measured by HPLC/MS at selected time-points on days 1 and 5.

Results

Daily i.v. administration of 17-DMAG at doses of 24 mg/m2 per day in rats or 16 mg/m2 per day in dogs produced lethality on day 6, approximately 24 h following the last dose. Body weight loss was common in rats and dogs. Drug-related gastrointestinal, bone marrow and hepatic toxicities were also common in rats and dogs. Dogs also exhibited signs of renal and gallbladder toxicity. Plasma concentrations of 17-DMAG increased proportionately with dose in rats and disproportionately with dose in dogs. In rat tissues, however, only fourfold to sixfold increases in 17-DMAG concentrations were observed with a tenfold increase in dose. The highest concentrations of 17-DMAG were found in the liver of rats, with progressively lower concentrations in the spleen, lung, kidney and plasma. Regardless of the route of administration, higher drug concentrations were present in plasma (rat and dog) and tissue (rat) samples obtained on day 5 compared to those obtained on day 1. Although plasma concentrations decreased with time, 17-DMAG was still detected in dog plasma for at least 24 h after drug administration.

Conclusions

With the recent approval of 17-DMAG for clinical use, the data generated from these preclinical studies will provide guidance to clinicians as they administer this drug to their patients. The MTD of 17-DMAG was 12 mg/m2 per day in rats and 8 mg/m2 per day in dogs; therefore, the recommended starting dose for phase I trial is 1.3 mg/m2 per day for 5 days. Gastrointestinal and bone marrow toxicity were dose-limiting in rats, and gastrointestinal, renal, gallbladder and bone marrow toxicity were dose-limiting in dogs. All adverse effects were fully reversible in surviving animals after treatment was complete.

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References

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

    CAS  PubMed  Google Scholar 

  2. An WG, Schnur RC, Neckers LM (1997) Depletion of p185erb2, Raf-1 and mutant p53 proteins by geldanamycin derivatives correlates with antiproliferative activity. Cancer Chemother Pharmacol 40:60–64

    CAS  PubMed  Google Scholar 

  3. Bagatell R, Paine-Murrieta GD, Taylor CW, Pulcini EJ, Akinaga S, Benjamin IJ, Whitesell L (2000) Induction of heat shock factor 1-dependent stress response alters the cytotoxic activity of HSP90-binding agents. Clin Cancer Res 6:3312

    CAS  PubMed  Google Scholar 

  4. Banerji U, O’Donnell A, Scurr M, Benson C, Hanwell J, Clark S, Raynaud F, Turner A, Walton M, Workman P, Judson I (2001) Phase I trial of the heat shock protein 90 (HSP90) inhibitor 17-allylamino 17-demethoxygeldanamycin (17AAG). Pharmacokinetic (PK) profile and pharmacodynamic (PD) endpoints. Proc Am Soc Clin Oncol 20:82a

    Google Scholar 

  5. Borgel SD, Carter JP, Sausville EA, Hollingshead MG (2003) The impact of tumor location on the activity of 17-DMAG (NSC-707545), a water soluble geldanamycin analog. Clin Cancer Res 9(16):6215s

    Google Scholar 

  6. DeGeorge JJ, Ahn CH, Andrews PA, Brower ME, Giorgio DW, Goheer MA, Lee-Ham DY, McGuinn WD, Schmidt W, Sun CJ, Tripathi SC (1998) Regulatory considerations for preclinical development of anticancer drugs. Cancer Chemother Pharmacol 41:173

    CAS  PubMed  Google Scholar 

  7. 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

    CAS  PubMed  Google Scholar 

  8. Egorin MJ, Zuhowski EG, Rosen DM, Sentz DL, Covey JM, Eiseman JL (2001) Plasma pharmacokinetics and tissue distribution of 17-(allylamino)-17-demthoxygeldanamycin (NSC 330507) in CD2F1 mice. Cancer Chemother Pharmacol 47:291

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  10. Erlichman C, Toft D, Reid J, Sloan J, Atherton P, Adjei A, Ames M, Croghan G (2001) A phase I trial of 17-allyl-amino-geldanamycin in patients with advanced cancer. Proc Am Assoc Cancer Res 42:833

    Google Scholar 

  11. Grieshaber CK, Marsoni S (1986) Relation of preclinical toxicology to findings in early clinical trials. Cancer Treat Rep 70:65

    CAS  PubMed  Google Scholar 

  12. Hostein I, Robertson D, DiStefano F, Workman P, Clarke PA (2001) Inhibition of signal transduction by the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin results in cytostasis and apoptosis. Cancer Res 61:4003–4009

    CAS  PubMed  Google Scholar 

  13. Lowe MC, Davis RD (1984) The current toxicology protocol of the National Cancer Institute. In: Helmann K, Carter SK (eds) Fundamentals of cancer chemotherapy. McGraw-Hill, New York, p 228

    Google Scholar 

  14. Munster PN, Tong L, Schwartz L, Larson S, Kenneson K, De La Cruz A, Rosen N, Scher H (2001) Phase I trial of 17-(allylamino)-17-demethoxygeladanamycin (17AAG) in patients (Pts) with advanced solid malignancies. Proc Am Assoc Clin Oncol 20:83a

    Google Scholar 

  15. Noker PE, Thompson RB, Smith AC, Tomaszewski JE, Page JG (1999) Toxicity and pharmacokinetics of 17-allylaminogeldanamycin (17-AAG, NSC-330507) in dogs. Proc Am Assoc Cancer Res 40:804

    Google Scholar 

  16. Page J, Heath J, Fulton R, Yalkowsky E, Tabibi E, Tomaszewski JE, Smith A, Rodman L (1997) Comparison of geldanamycin (NSC-122750) and 17-allyaminogeldanamycin (NSC-330507) toxicity in rats. Proc Am Assoc Cancer Res 38:2067

    Google Scholar 

  17. Page JG, Noker PE, Tomaszewski JE, Smith AC (1999) Lack of schedule dependent toxicity of 17-allylaminogeldanamycin (17-AAG, NSC-330507) in rats. Proc Am Assoc Cancer Res 40:805

    Google Scholar 

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

    CAS  Google Scholar 

  19. 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

    CAS  PubMed  Google Scholar 

  20. Shah VP, Midha KK, Dighe S, McGilveray IJ, Skelly JP, Yacobi A, Layloff T, Viswanathan CT, Cook CE, McDowall RD (1991) Analytical methods validation: bioavailability, bioequivalence and pharmacokinetic studies. Eur J Drug Metab Pharmacokinet 16(4):249–255

    Google Scholar 

  21. Shah VP, Midha KK, Findlay JWA, Hill HM, Hulse JD, McGilveray IJ, McKay G, Miller KJ, Patnaik RN, Powell ML, Tonelli A, Viswanathan CT, Yacobi A (2000) Bioanalytical method validation—a revisit with a decade of progress. Pharm Res 17(12):1551–1557

    Google Scholar 

  22. Smith DF, Whitesell L, Katsanis E (1998) Molecular chaperones: biology and prospects for pharmacological intervention. Pharmacol Rev 50(4):493

    CAS  PubMed  Google Scholar 

  23. Smith V, Sausville EA, Camalier RF, Fiebig HH, Burger AM (2002) 17-DMAG (NSC-707545), a water-soluble geldanamycin analog, has superior in vitro and in vivo antitumor activity compared to the hsp90 inhibitor 17-AAG. Eur J Cancer 38(S7):60

    Article  Google Scholar 

  24. 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 

  25. Wilson RH, Takimoto CH, Agnew EB, Morrison G, Grollman F, Thomas RR, Saif MW, Hopkins J, Allegra C, Grochow L, Szabo E, Hamilton JM, Monhan BP, Neckers L, Grem JL (2001) Phase I pharmacological study of 17-(allylamino)-17-demethoxygeldanmycin (AAG) in adult patients with advanced solid tumors. Proc Am Soc Clin Oncol 20:82a

    Google Scholar 

  26. Workman P (2002) Challenges of PK/PD measurements in modern drug development. Eur J Cancer 38:2189

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Supported by contracts N01-CM-87100, N01-CM-87102, N01-CM-87103 and N01-CM-07106 and Grant P30CA47904

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Authors and Affiliations

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

    Adaline C. Smith, Joseph M. Covey, Edward A. Sausville & Joseph E. Tomaszewski

  2. Southern Research Institute, P.O. Box 55305, Birmingham, AL, 35255, USA

    Amy L. Lambert & John G. Page

  3. Life Sciences Group, IIT Research Institute, Chicago, IL, 60616, USA

    William D. Johnson & David L. McCormick

  4. Toxicology Research Laboratory, University of Illinois at Chicago, Chicago, IL, 60612, USA

    Alan P. Brown & Barry S. Levine

  5. Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Merrill J. Egorin, Julie L. Eiseman & Julianne L. Holleran

  6. Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Executive Plaza North, Room 8040, Rockville, MD, 20852, USA

    Elizabeth R. Glaze

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  1. Elizabeth R. Glaze
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  2. Amy L. Lambert
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  13. Edward A. Sausville
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  14. Joseph E. Tomaszewski
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Corresponding author

Correspondence to Elizabeth R. Glaze.

Additional information

E.R. Glaze and A.L. Lambert contributed equally to this work.

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Glaze, E.R., Lambert, A.L., Smith, A.C. et al. Preclinical toxicity of a geldanamycin analog, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), in rats and dogs: potential clinical relevance. Cancer Chemother Pharmacol 56, 637–647 (2005). https://doi.org/10.1007/s00280-005-1000-9

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  • DOI: https://doi.org/10.1007/s00280-005-1000-9

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