The purpose of the proposed study is to determine the feasibility of monitoring the pharmacokinetics of a 13C-labeled drug [3-13C]temozolomide (TMZ) by NMR spectroscopy in a large animal model at clinical dose levels. Studies will be performed on transplantable gliomas in adult beagles and in dogs with spontaneous brain tumors. Preliminary studies have already demonstrated the feasibility of monitoring [3-13C]TMZ by selective 13C polarization transfer spectroscopy in mice with subcutaneous RIF-1 tumors at 9.4 after administration of doses that were 25 times the clinical dose of 200 mg/m2 (5.91 mg/kg). The proposed study will determine the feasibility of undertaking clinical trials of this method in human subjects. Temozolomide is currently in Phase II clinical trials and has shown promising activity against human brain tumors and melanomas. The proposed study employs temozolomide as a prototype to test the general concept of using 13C-labeling of antineoplastic agents as a method for monitoring their pharmacokinetics by NMR spectroscopy. This method would facilitate tailor-fitting of chemotherapy schedules to the needs of individual patients and reliably identifying nonresponsive patients at an early stage of chemotherapy, thereby sparing them unnecessary toxicity and expense. The first objective of this project is to determine the optimum method for detecting [3-13CJTMZ. Four methods will be evaluated on phantoms and on dogs with transplantable gliomas on a 4.7T/50 cm animal spectrometer: 1) selective polarization transfer from 1H to 13C with detection of 13C, 6 2) inverse polarization transfer from 13C to 1H with detection of 1H, 42 3) gradient echo heteronuclear multiple quantum coherence transfer from 13C to 1H with detection of 1H, 4 4) proton observe carbon decouple spectroscpy.5 These methods will be compared with respect to sensitivity, power deposition and motion sensitivity. The method chosen on the basis of these studies will be implemented on clinical 1.5 T and 4T scanners and used to monitor the pharmacokinetics of [3-13C]TMZ in dogs with transplantable gliomas and spontaneous brain tumors. The labeled drug will be synthesized by the applicants, who have developed a more efficient and economical method of synthesis of [3-13C]TMZ than had been reported in the literatue.33
| Mancuso, Anthony; Zhu, Aizhi; Beardsley, Nancy J et al. (2005) Artificial tumor model suitable for monitoring 31P and 13C NMR spectroscopic changes during chemotherapy-induced apoptosis in human glioma cells. Magn Reson Med 54:67-78 |
