The evaluation of positron emission tomography to assess pharmacodynamics and pahrmacokinetics of anti cancer drugs

摘要

Positron emission tomography (PET) is a non-invasive imaging technique that is emerging as a useful tool in the field of cancer medicine particularly in drug development. The purpose of this thesis has been to perform clinical studies using two different radiotracers, 5-[^V]fIuorouracil (5-['^F]FU) and 2-[''C]thymidine, to assess pharmacokinetic and pharmacodynamic parameters respectively, which were derived from PET imaging and to establish the contribution that PET can add to drug development, in vivo, in man. udAims: 1) Quantify the pharmacodynamic effects of cytotoxic agents in tumour and normal tissue using 2-["C]thymidine 2) Measure changes in tumour and normal tissue pharmacokinetics of 5-Fluorouracil in response to the modulating agents carbogen and nicotinamide or interferon 3) Assessment of blood flow change in tumour and normal tissue to carbogen and nicotinamide or interferon 4) Interpretation of PET data using novel analysis methods with modified Patlak and spectral analysis udMethods: In the 5-['^]FU study, patients with metastatic gastrointestinal cancer underwent PET scanning at the start of 2 separate chemotherapy cycles. The 2nd scan was performed after the administration of carbogen and nicotinamide or interferon. In the 2-["C]thymidine study patients receiving chemotherapy were scanned before commencing chemotherapy, and 1 week after the 3''' cycle of chemotherapy. Patients also had conventional imaging before the start of and after 3 cycles of treatment. udFindings: After carbogen and nicotinamide administration, 5-['^]FU uptake was increased in tumour, but not in normal tissue. Regional perfusion was elevated in tumours but decreased in kidneys after carbogen and nicotinamide. After interferon administration, there was an increase in 5-['^]FU retention in tumours, but no increase in uptake. Regional perfusion in tumour and normal tissue was unaltered by interferon. Retention of 2-["C]thymidine decreased in tumour in keeping with the results of conventional radiology, suggesting a pathological response, assessed in vivo, to chemotherapy.