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Investigational New Drugs

, Volume 31, Issue 5, pp 1142–1150 | Cite as

Polycationic calixarene PTX013, a potent cytotoxic agent against tumors and drug resistant cancer

  • Ruud P. M. Dings
  • Joseph I. Levine
  • Susan G. Brown
  • Lucile Astorgues-Xerri
  • John R. MacDonald
  • Thomas R. Hoye
  • Eric Raymond
  • Kevin H. Mayo
PRECLINICAL STUDIES

Summary

Previously, we reported on the anti-tumor activities of two designed calix[4]arene-based topomimetics (PTX008 and PTX009) of the amphipathic, angiostatic peptide Anginex. Here, we chemically modified the hydrophobic and hydrophilic faces of PTX008 and PTX009, and discovered new calixarene compounds that are more potent, cytotoxic anti-tumor agents. One of them, PTX013, is particularly effective at inhibiting the growth of several human cancer cell lines, as well as drug resistant cancer cells. Mechanistically, PTX013 induces cell cycle arrest in sub-G1 and G0/G1 phases of e.g. SQ20B cells, a radio-resistant human head and neck carcinoma model. In the syngeneic B16F10 melanoma tumor mouse model, PTX013 (0.5 mg/Kg) inhibits tumor growth by about 50-fold better than parent PTX008. A preliminary pharmacodynamics study strongly suggests that PTX013 exhibits good in vivo exposure and a relatively long half-life. Overall, this research contributes to the discovery of novel therapeutics as potentially useful agents against cancer in the clinic.

Keywords

Calixarenes Galectin-1 Structure-activity relationships Therapeutics 

Abbreviations

EC

Endothelial cell

HUVEC

Human umbilical vein EC

SAR

Structural activity relationships

PBS

Phosphate buffered saline

Notes

Acknowledgements

This work was supported by research grants from the National institute of Health - National Cancer Institute (CA-096090 and CA-76497) and OncoEthix Inc. to KHM. ER and LA-X were supported by OncoEthix Inc., the Foundation Nelia & Amadeo Barleta (FNAB), and the Association pour la Recherche & l’Enseignement en Cancérologie (AAREC).

Conflict of interest

Co-authors K.H. Mayo and J. R. MacDonald have a financial interest in PepTx, a pharmaceutical company that holds license to commercialize the PTX compounds

Supplementary material

10637_2013_9932_MOESM1_ESM.pdf (860 kb)
ESM 1 (PDF 859 kb)

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Ruud P. M. Dings
    • 1
  • Joseph I. Levine
    • 1
    • 2
  • Susan G. Brown
    • 2
  • Lucile Astorgues-Xerri
    • 3
  • John R. MacDonald
    • 4
  • Thomas R. Hoye
    • 2
  • Eric Raymond
    • 3
  • Kevin H. Mayo
    • 1
  1. 1.Department of Biochemistry, Molecular Biology & BiophysicsUniversity of MinnesotaMinneapolisUSA
  2. 2.Department of ChemistryUniversity of MinnesotaMinneapolisUSA
  3. 3.INSERM U728 and Department of Medical OncologyBeaujon University HospitalParis-ClichyFrance
  4. 4.PepTx, Inc.ExcelsiorUSA

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