Elsevier

European Journal of Cancer

Volume 38, Issue 16, November 2002, Pages 2189-2193
European Journal of Cancer

Challenges of PK/PD measurements in modern drug development

https://doi.org/10.1016/S0959-8049(02)00395-7Get rights and content

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The need for PK and PD endpoints

Modern cancer drug development can be characterised by a number of important principles 1, 2, 3, 4. These include: (1) A focus on the genes and pathways that are driving the molecular pathology and progression of human cancers, providing an intellectual framework and a source of new molecular targets for improving drug efficacy and selectivity; (2) Application of new technologies, such as high throughput screening, combinatorial chemistry and gene expression microarrays, to accelerate the

Development of SR4554 as a hypoxia detection agent

Hypoxia is an extremely important factor in the malignant progression of human cancers 11, 12. Low oxygen levels are a major driving force for tumour angiogenesis and hypoxia is involved directly in resistance to radiation therapy and chemotherapy, as well in the selection for a more aggressive phenotype, including loss of p53. Furthermore, tumour hypoxia has been shown to be an independent prognostic factor in determining metastasis and survival in various types of cancer [13].

The

Development of PD endpoints for the Hsp90 molecular chaperone inhibitor 17AAG

The Hsp90 molecular chaperone is an exciting new molecular target for cancer treatment 20, 21. Of particular relevance is the fact that Hsp90 is responsible for the folding, stability and function of a range of oncogenic ‘client’ proteins, including Raf-1, erbB2, CDK4, oestrogen and androgen receptors and mutant p53. Inhibition of Hsp90 leads to degradation of the oncogenic client proteins by the ubiquitin proteasome pathway. Hence Hsp90 inhibitors may provide a one-step combinatorial attack on

Concluding remarks

PK and PD endpoints are an essential component of the rational development and evaluation of new cancer drugs. They provide enormously helpful information and inform the decision-making process. Particular emphasis should be focused on the development of PD endpoints. Biomarkers that indicate directly whether the molecular target has been modulated are extremely valuable. Endpoints that provide evidence for intervention in a biochemical pathway are also very useful, as are methods to confirm

Acknowledgments

Work carried out in the Cancer Research UK Centre for Cancer Therapeutics (http://www.icr.ac.uk/cctherap/index.html) is funded primarily by Cancer Research UK. Paul Workman is a Cancer Research UK Life Fellow. I thank my Centre colleagues and members of the Cancer Research UK Pharmacokinetic and Pharmacodynamic Advisory Committee for valuable discussions.

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