Vascularization, oxygenation, and metabolism of colorectal cancer. Implications for cytotoxic treatment.

Vascularization, oxygenation, and metabolism are important parameters of a tumor, determining its development and treatment response. The overall goals of this thesis were to: 1) describe these parameters in colorectal cancer, both in animal models and in humans; 2) explore the possibility to manipulate vascularization, oxygenation and metabolism for the improvement of cytotoxic treatment; 3) monitor uptake and metabolism of fluorinated cytotoxic drugs in colorectal cancer in an early stage of the treatment. The specific questions were addressed whether vascularization as measured by dynamic contrast enhanced MRI (DCE-MRI) and uptake and metabolism of 5-fluorouracil (FU) as measured by fluorine-19 magnetic resonance spectroscopy (19F MRS) could predict response to cytotoxic treatment. This research shows that nicotinamide and carbogen can decrease tumor hypoxia in murine colon carcinoma, both in subcutaneously implanted tumors and in an orthotopic liver metastases model. Moreover, carbogen increases blood volume, decreases extracellular pH and increases in FU uptake in murine colon carcinoma. Since extensive hypoxia is present in human liver metastases, as is demonstrated in this research, the improvement of tumor oxygenation by nicotinamide and/or carbogen may be translated into the clinical situation. This research demonstrates that DCE-MRI is a reproducible method to assess tumor vascularization of colorectal liver metastases. Combined with the measurement of hypoxia and FDG uptake it can elucidate the complex relationship between vascularization, oxygenation and metabolism in tumor tissue. Kinetic parameters of DCE-MRI before start of first-line cytotoxic treatment did not predict tumor response after two months, suggesting that the supply of chemotherapy by tumor vasculature is not a major determining factor in the response to first-line treatment. Finally, this research shows that 19F MRS can be used to monitor both FU and capecitabine uptake and metabolism in the livers and liver metastases of patients with colorectal cancer. No evident correlations between 19F MRS parameters and tumor response were found which may imply that in liver metastases FU uptake and catabolism are not limiting factors for response