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Pharmacodynamics

PET power

Nature Reviews Drug Discovery volume 3, page 476 (2004)Cite this article

Without understanding the potency and kinetics of target inhibition by drugs in patients, it is difficult to determine mechanisms of sensitivity and resistance, and to establish optimal dosing and scheduling parameters. Notwithstanding advances in our understanding of the molecular basis of carcinogenesis, little is known about the pharmacodynamics of therapeutic agents, including successful drugs such as imatinib (Glivec; Novartis) and retinoic acid. Furthermore, the effects of an inhibitor on a tumour target can only be determined if an assay has been developed and if tumour tissue can be collected before and after therapy, which is difficult in patients with solid tumours.

Smith-Jones and colleagues have developed a new technique to image the pharmacodynamics of 17-AAG, a potent anti-breast-cancer agent that exerts its effect by indirectly inducing the degradation of the cell-surface protein kinase HER2. Members of the HER kinase family, such as epidermal growth factor receptor and HER2, are overexpressed, amplified or mutated in a variety of tumour types. 17-AAG, a geldanamycin derivative, binds to heat-shock protein 90 (Hsp90), which is required for the conformational maturation and stability of key signalling molecules, including HER2.

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References

ORIGINAL RESEARCH PAPER

  1. Smith-Jones, P. M. et al. Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors. Nature Biotechnol. 9 May 2004 (doi:10.1038/nbt968)

FURTHER READING

  1. Gambhir, S. S. Molecular imaging of cancer with positron emission tomography. Nature Rev. Cancer 2, 683–693 (2002)

    Article  CAS  Google Scholar 

  2. Dancey, J. & Sausville, E. A. Issues and progress with protein kinase inhibitors for cancer treatment. Nature Rev. Drug Discov. 2, 296–313 (2003)

    Article  CAS  Google Scholar 

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Authors
  1. Melanie Brazil
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Brazil, M. PET power. Nat Rev Drug Discov 3, 476 (2004). https://doi.org/10.1038/nrd1425

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  • DOI: https://doi.org/10.1038/nrd1425

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