Epidemiology has revealed that physical activity is an important lifestyle factor that reduces the risk of colon cancer. However, the underlying mechanisms of this protective effect have so far not been defined. The aim of this study was to identify molecular targets of physical activity in rat colon mucosa by employing our voluntary exercise model. Twenty male rats underwent a 12-week exercise program, with 9 additional rats serving as a control group. Running distances, body weights and heart weights as measures of physical adaptations were recorded, and changes in mRNA steady-state levels of marker genes involved in vascularization (VEGF, HIF-1 alpha, ODC-1), apoptosis (Bcl-2, PPAR gamma) and prostaglandin synthesis (COX-2) were determined by qRT-PCR. The four housekeeping genes GAPDH, beta-actin, 18S and ALDA served as reference genes. Recorded running distances showed great inter-individual differences resulting in three different groups of low (L-EX, < 2629 m/night; n=5), moderate (M-EX, 3003 - 7458 m/night; n=10) and high (H-EX, > 8314 m/night; n=5) physical activity. The M-EX and H-EX group revealed significant (p<0.05) adaptive changes with an increase in heart mass per kg body weight and a decrease in mean body weight. Amongst the marker genes studied by mRNA expression analysis only ODC-1 appears to be differentially expressed. Its 1.8-fold increased steady-state mRNA level in the H-EX group suggests that synthesis of polyamines may be increased by physical activity. This new finding could provide a link between extensive physical activity and its protective effects on colon cancer development.