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Cancer Chemotherapy and Pharmacology

, Volume 61, Issue 6, pp 911–921 | Cite as

Identification, characterization and potent antitumor activity of ECO-4601, a novel peripheral benzodiazepine receptor ligand

  • Henriette GourdeauEmail author
  • James B. McAlpine
  • Maxime Ranger
  • Bryan Simard
  • Francois Berger
  • Francis Beaudry
  • Pierre Falardeau
Original Article

Abstract

Purpose

ECO-4601 is a structurally novel farnesylated dibenzodiazepinone discovered through DECIPHER® technology, Thallion’s proprietary drug discovery platform. The compound was shown to have a broad cytotoxic activity in the low micromolar range when tested in the NCI 60 cell line panel. In the work presented here, ECO-4601 was further evaluated against brain tumor cell lines. Preliminary mechanistic studies as well as in vivo antitumor evaluation were performed.

Methods

Since ECO-4601 has a benzodiazepinone moiety, we first investigated if it binds the central and/or peripheral benzodiazepine receptors. ECO-4601 was tested in radioligand binding assays on benzodiazepine receptors obtained from rat hearts. The ability of ECO-4601 to inhibit the growth of CNS cancers was evaluated on a panel of mouse, rat and human glioma cell lines using a standard MTT assay. Antitumor efficacy studies were performed on gliomas (rat and human), human breast and human prostate mouse tumor xenografts. Antitumor activity and pharmacokinetic analysis of ECO-4601 was evaluated following intravenous (IV), subcutaneous (SC), and intraperitoneal (IP) bolus administrations.

Results

ECO-4601 was shown to bind the peripheral but not the central benzodiazepine receptor and inhibited the growth of CNS tumor cell lines. Bolus SC and IP administration gave rise to low but sustained drug exposure, and resulted in moderate to significant antitumor activity at doses that were well tolerated. In a rat glioma (C6) xenograft model, ECO-4601 produced up to 70% tumor growth inhibition (TGI) while in a human glioma (U-87MG) xenograft, TGI was 34%. Antitumor activity was highly significant in both human hormone-independent breast (MDA-MB-231) and prostate (PC-3) xenografts, resulting in TGI of 72 and 100%, respectively. On the other hand, IV dosing was followed by rapid elimination of the drug and was ineffective.

Conclusions

Antitumor efficacy of ECO-4601 appears to be associated with the exposure parameter AUC and/or sustained drug levels rather than C max. These in vivo data constitute a rationale for clinical studies testing prolonged continuous administration of ECO-4601.

Keywords

Dibenzodiazepine Peripheral benzodiazepine receptor (PBR) Cancer Glioma Xenografts 

Abbreviations

AAALAC

International Association for Assessment and Accreditation of Laboratory Animal Care

AUC

Area under the curve

CCAC

Canadian Council on Animal Care

CBR; GABAA

Central benzodiazepine receptor

D5W

5% dextrose

q3d × 7

Every 3 days for 7 cycles

IV

Intravenous

IP

Intraperitoneal

MPTP

Mitochondrial permeability transition pore

q1d × 5

Once daily for 5 consecutive days

qod

Once every other day

PBR

Peripheral benzodiazepine receptor

SC

Subcutaneous

Notes

Acknowledgments

The authors would like to thank Anna Avrutskaya, Robert Mullin and Jennifer Streicker (From Piedmont Reserch Center) and Simon Taylor and Kresimir Pucaj (Nucro-Technics) for performing animal studies. We also thank Mario Chevrette for helpful discussions and revisions.

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Henriette Gourdeau
    • 1
    Email author
  • James B. McAlpine
    • 1
  • Maxime Ranger
    • 1
  • Bryan Simard
    • 2
  • Francois Berger
    • 2
  • Francis Beaudry
    • 3
  • Pierre Falardeau
    • 1
  1. 1.Thallion Pharmaceuticals Inc.St LaurentCanada
  2. 2.INSERM U318GrenobleFrance
  3. 3.Department of Veterinary Biomedicine, Faculty of Veterinary MedicineUniversity of MontrealSt HyacintheCanada

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