Pyrimidine nucleotide metabolism in human colon carcinomas: Comparison of normal tissues, primary tumors and xenografts

Abstract

The activities of 5 enzymes involved in the pyrimidine metabolism were measured in xenografts of 8 human colon adenocarcinomas and in the corresponding primary tumors and normal tissues. The enzymes studied were thymidine kinase, thymidine phosphorylase, uridine kinase, uridine phosphorylase and thymidylate synthase. With the exception of the phosphorylases in one tumor, all enzyme activities were higher in primary tumors than in the corresponding normal tissues. The average activities of thymidine kinase and thymidylate synthase were of the same order of magnitude in xenografts and in primary tumors. The uridine metabolizing enzymes tend to have a higher activity in xenografts than in primary tumors. The most consistent and significant change was a sharp decrease in thymidine phosphorylase activity in xenografts as compared to primary tumors. Whether or not the difference in thymidine phosphorylase activity between xenografts and primary tumors is related to the contribution of non-cancerous cells in primary tumors remains to be determined. However, these results raise questions concerning the representativeness of xenografts with reference to primary tumors and suggest that care should be taken in the application of this model.

In vivoactivity of novel capecitabine regimens alone and with bevacizumab and oxaliplatin in colorectal cancer xenograft models

“…When the human colon cancer cell line, WiDr, was incubated with paclitaxel, docetaxel, or mitomycin C, or tumor necrosis factor-related apoptosis-inducing ligand, each agent greatly induced TP (27). However, a decrease in TP activity in xenografts compared with primary tumors means that care is needed when extrapolating findings to the clinical setting (28).…”

Thymidine Phosphorylase and 2-Deoxyribose Stimulate Human Endothelial Cell Migration by Specific Activation of the Integrins α5β1 and αVβ3

“…Significantly less is known about the corresponding actions of TP, despite evidence that it is overexpressed in a large percentage and wide range of human solid tumors (22)(23)(24)(25)(26). Recent studies suggest that there are similarities in the transcriptional regulation of TP and VEGF, and there is a tendency for VEGF and TP to be co-expressed in some human cancers (34)(35)(36).…”

“…TP is chemotactic for endothelial cells and has angiogenic activity in several in vivo assays, although it did not directly stimulate endothelial cell proliferation (16 -20). Studies have established a role for TP in experimental and clinical tumor angiogenesis, including transfection studies in which the TP gene increased the vascularization and growth of tumors growing in nude mice (20,21), and immunohistochemical studies of primary human solid tumors, in which TP was often found to be elevated in the tumors when compared with the corresponding nonneoplastic regions of the same organs (22)(23)(24)(25)(26). The mechanism by which TP mediates angiogenesis is unknown; we have used endothelial cell migration as an in vitro model to address this question.…”

Platelet-derived endothelial cell growth factor thymidine phosphorylase in tumour growth and response to therapy

“…It is not clear whether this is due to its release from the tumour itself or production and release by host cells and tissues in response to tumour growth/proliferation. Activity of another pyrimidine phosphorylase, UrdPase, has also been reported to be elevated in primary human tumours, including colon (Luccioni et al, 1994) and melanoma (Leyva et al, 1983). One study in human colon carcinoma has suggested PNP activity is also enhanced and suggests a positive relationship with enzyme activity and tumour invasiveness (Sanflippo et al, 1994).…”