Assessing proliferation, cell-cycle arrest and apoptotic end points in human buccal punch biopsies for use as pharmacodynamic biomarkers in drug development

Linking the molecular effects of drug exposure to the mechanisms of either efficacy or toxicity of the drug would improve early oncology drug development. While pharmacodynamic (PD) effects derived directly from diseased/dysfuntional tissue are likely to relate most closely to clinically relevant outcomes (Baselga, 2003), tissue heterogeneity and tissue accessibility may restrict this approach. PD biomarkers in relatively homogenous, more accessible normal tissues may offer an easier approach to establishing proof of drug mechanism and to make an early assessment of exposure–response relationships. Normal tissue-based PD approaches have already been used with success during the clinical development of anticancer drugs acting on biomarkers present within peripheral blood mononuclear cells (Cohen et al, 2003; Peralba et al, 2003), exfoliated buccal squames (van de Vaart et al, 2000; Adjei et al, 2003) and punch biopsies of the skin (Albanell et al, 2002; Malik et al, 2003; Vanhoefer et al, 2004). The choice of normal tissue for a given drug study is likely to depend on a number of different factors, including the level and variability of expression of the biomarker of interest. Literature reports suggest that the buccal mucosa has a high baseline proliferation index (Jordan et al, 1998; Hirota et al, 2002; Kurokawa et al, 2003), making it a potentially attractive tissue for assessing antiproliferative end points. Unfortunately, these indices are often obtained from individuals undergoing follow up for various oral pathologies, therefore field effects skewing these ‘normal' values cannot be ruled out. In addition, there are few published details on the tolerability of repeated buccal biopsies as would be required during time-course PD assessments, or of the baseline variability components of key biomarkers to inform sizing decisions for drug intervention studies designed to impact these markers.