The interactions of polarographic measurements of oxygen tension and histological grade in human glioma.

PURPOSE: The purpose of this study is to investigate the implications of hypoxia and histological grade for survival in patients with gliomas. MATERIALS AND METHODS: Tissue oxygen tension was measured intraoperatively using an Eppendorf pO2 Histograph. Survival was calculated from the date of the Eppendorf study to the date of last follow-up. Univariate analysis was performed stratifying patients by patient gender, type of anesthesia used, histological grade, extent of surgery, and patient age. Lastly univariate analysis was performed on the cohort after dichotomizing the median pO2 at 2.0 mmHg, 5.1 mmHg, and 10.0 mmHg. RESULTS: From March of 1996 to June of 1999, 25 patients were entered into this prospective trial. Two patients were excluded from analysis because polarographic measurements included normal brain tissue as well as tumor. Thus for analysis we included 13 patients with high grade gliomas (HGG) and 10 with low grade gliomas (LGG). The median tumor oxygen pressure for the entire cohort was 5.1 mmHg. Higher grade (P=0.0012) was prognostic for poorer survival. Patients were then stratified into groups with a median tumor oxygen tensions either above or below 2.0 mmHg, 5.1 mmHg, and 10.0 mmHg; there was no significant difference found in overall survival. CONCLUSIONS: Although histological grade was prognostic for survival, hypoxia, represented as the median tumor oxygen tension, was not a significant independent prognostic indicator of survival in this small and heterogeneous series of patients.

3'-deoxy-3'-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography.

3'-Deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) has been proposed as a new marker for imaging tumor proliferation by positron emission tomography (PET). The uptake of [(18)F]FLT is regulated by cytosolic S-phase-specific thymidine kinase 1 (TK1). In this article, we have investigated the use of [(18)F]FLT to monitor the response of tumors to antiproliferative treatment in vivo. C3H/Hej mice bearing the radiation-induced fibrosarcoma 1 tumor were treated with 5-fluorouracil (5-FU; 165 mg/kg i.p.). Changes in tumor volume and biodistribution of [(18)F]FLT and 2-[(18)F]fluoro-2-deoxy-D-glucose ([(18)F]FDG) were measured in three groups of mice (n = 8-12/group): (a) untreated controls; (b) 24 h after 5-FU; and (c) 48 h after 5-FU. In addition, dynamic [(18)F]FLT-PET imaging was performed on a small animal scanner for 60 min. The metabolism of [(18)F]FLT in tumor, plasma, liver, and urine was determined chromatographically. Proliferation was determined by staining histological sections for proliferating cell nuclear antigen (PCNA). Tumor levels of TK1 protein and cofactor (ATP) were determined by Western blotting and bioluminescence, respectively. Tumor [(18)F]FLT uptake decreased after 5-FU treatment (47.8 +/- 7.0 and 27.1 +/- 3.7% for groups b and c, respectively, compared with group a; P < 0.001). The drug-induced reduction in tumor [(18)F]FLT uptake was significantly more pronounced than that of [(18)F]FDG. The PET image data confirmed lower tumor [(18)F]FLT retention in group c compared with group a, despite a trend toward higher radiotracer delivery for group c. Other than phosphorylation in tumors, [(18)F]FLT was found to be metabolically stable in vivo. The decrease in tumor [(18)F]FLT uptake correlated with the PCNA-labeling index (r = 0.71, P = 0.031) and tumor volume changes after 5-FU treatment (r = 0.58, P = 0.001). In this model system, the decrease in [(18)F]FLT uptake could be explained by changes in catalytic activity but not translation of TK1 protein. Compared with group a, TK1 levels were lower in group b (78.2 +/- 5.2%) but higher in group c (141.3 +/- 9.1%, P < 0.001). In contrast, a stepwise decrease in ATP levels was observed from group a to b to c (P < 0.001). In conclusion, we have demonstrated the ability to measure tumor response to antiproliferative treatment with [(18)F]FLT and PET. In our model system, the radiotracer uptake was correlated with PCNA-labeling index. The decrease in [(18)F]FLT uptake after 5-FU was more pronounced than that of [(18)F]FDG. [(18)F]FLT is, therefore, a promising marker for monitoring antiproliferative drug activity in oncology that warrants additional testing.

Pharmacokinetics of radiolabelled anticancer drugs for positron emission tomography.

Positron emission tomography (PET) provides the oncologist with information on tumour diagnosis, and treatment response monitoring. Mathematical modelling of tissue data, and online plasma radioactive metabolite profiling, enables important tissue kinetic parameters relating to the uptake, distribution and washout as well as arterial input function to be derived. The resultant kinetic data allow for not only diagnosis but also the assessment of therapeutic response endpoints. These endpoints can be used to measure specific therapeutic effects. This novel application of PET can provide information that is often difficult to measure in the intact animal or patient. The pharmacokinetics of radiolabelled N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA), temozolomide and 5-fluorouracil (5-FU) are described.

Pharmacodynamics of radiolabelled anticancer drugs for positron emission tomography.

Positron Emission Tomography (PET) offers an exciting opportunity to monitor key pathways involved in malignant transformation due to the ability to radiolabel and image the behaviour of biological probes. In this review, we will describe how PET can use various radiolabelled compounds to monitor various targets including ligand-receptor interactions using 16alpha-[(18)F]fluoro-17beta-oestradiol (FES) pathways involved in metabolism with [(18)F]fluorodeoxy-glucose ([(18)F]FDG), (11)C-methyl-choline for signal transduction, cell cycle and proliferation with 2-[(11)C]thymidine, cell death using [(124)I]annexin V, [(124)C]colchicine for drug resistance and angiogenesis using [(124)I]anti-VEGF.

Concordant pre- and postsynaptic deficits of dopaminergic neurotransmission in neurologic Wilson disease.

BACKGROUND AND PURPOSE: Although previous brain imaging studies of Wilson disease (WD) focused on the dopaminergic system, correlational data on the integrity of the pre- and postsynaptic compartments are lacking. The present study was initiated to intra-individually determine the integrity of these compartments in patients with WD. METHODS: A total of 46 patients with WD and 10 matched control subjects underwent [(123)I]2beta-carbomethoxy-3beta-(4[(123)I]iodophenyl)tropane ([(123)I]beta-CIT) and [(123)I]iodobenzamide ([(123)I]IBZM) single photon emission CT (SPECT). For both radiotracers, specific striatal binding ratios (with the cerebellum as the reference region) were calculated after a standardized region-of-interest technique was applied. In addition, the severity of putative neurologic symptoms was evaluated by using a linear scoring system. RESULTS: In patients without neurologic symptoms, striatal binding ratios of both radiotracers did not differ from those of the control group (13.8 +/- 3.1 vs 12.0 +/- 3.4 and 2.00 +/- 0.19 vs 1.90 +/- 0.27; n.s.). In symptomatic patients, however, striatal binding ratios for both [(123)I]beta-CIT and [(123)I]IBZM were significantly reduced (9.1 +/- 2.3 and 1.64 +/- 0.18; P <.001). In all patients with WD, the [(123)I]beta-CIT and [(123)I]IBZM binding ratios were significantly correlated (r = 0.65, P <.001), as were SPECT parameters and the severity of the neurologic symptoms (r = -0.60 and -0.62; P <.001). CONCLUSION: These findings of a concordant bicompartmental dopaminergic deficit in neurologic WD provide in vivo evidence for assigning WD to the group of secondary Parkinsonian syndromes. These results could be relevant in therapeutic decision making in patients with this copper deposition disorder.

Iodine-124 labelled annexin-V as a potential radiotracer to study apoptosis using positron emission tomography.

Annexin-V is a calcium-dependent protein that binds with high affinity to phosphaditylserine exposed during apoptosis. The aim of this study was to radiolabel annexin-V with iodine-124 for use as a potential probe of apoptosis by positron emission tomography. Annexin-V was radioiodinated directly using the cyclotron-produced positron emitter iodine-124 by the chloramine-T (CAT) method and indirectly by the pre-labelled reagent N-succinimidyl 3-[124I]iodobenzoate ([124I]m-SIB). Some reaction parameters of the CAT method such as reaction time and pH were optimised to give radiochemical yields of 22.3 +/- 2.6%(n = 3, gel-filtration). After incubation with [124I]m-SIB, radiolabelled annexin-V was obtained in 14% and 25% yield by FPLC and gel-filtration, respectively. The radiochemical purities from direct and indirect labelling were 97.7 +/- 1.0%(n = 3) and 96.7 +/- 2.1%(n = 3), respectively. The new radiotracers could be stored for up to four days without significant de-iodination. The biological activity of radiolabelled annexin-V was tested in control and camptothecin-treated (i.e. apoptotic) human leukaemic HL60 cells. A significantly higher (21%) binding in treated cells was observed with [125I]m-SIB-annexin-V. The binding of [125I]m-SIB labelled annexin-V to camptothecin treated cells was blocked (68%) by a 100-fold excess of unlabelled annexin-V.

The development of [(124)I]iodinated-VG76e: a novel tracer for imaging vascular endothelial growth factor in vivo using positron emission tomography.

The development of anticancer therapies that target the angiogenic process is an area of major growth in oncology. A method of noninvasively measuring tumor vascular endothelial growth factor (VEGF) in vivo could provide important efficacy information for VEGF-dependent antiangiogenic agents and the role of VEGF in cancer biology. We have developed a novel radiotracer for use with positron emission tomography (PET) that enables noninvasive imaging of VEGF. This radiotracer comprises an IgG1 monoclonal antibody, known as VG76e, that binds to human VEGF, labeled with a positron-emitting radionuclide, iodine-124 ([(124)I]-SHPP-VG76e). Three radiolabeling strategies were evaluated to synthesize the radiotracer with optimal radiochemical yield, purity, and immunoreactivity. To evaluate the pharmacokinetics and VEGF-specific localization of [(124)I]-SHPP-VG76e, two subclones of the HT1080 human fibrosarcoma selected on the basis of differing VEGF production (26.6 and 1/3C, the former producing 2-4-fold more in vitro) were established in culture and grown as solid tumor xenografts in immune-deficient mice. A single i.v. injection of the radiotracer into tumor-bearing mice revealed a time dependent and specific localization of [(125)I]-SHPP-VG76e to the tumor tissue. Three validation studies established the VEGF specificity and potential for use of [(124)I]-SHPP-VG76e in vivo: (a) uptake of [(125)I]-SHPP-VG76e was 1.8-fold higher in HT1080-26.6 compared with HT1080-1/3C tumors (P < 0.05); (b) uptake of [(125)I]-SHPP-VG76e in HT1080-26.6 tumors was specifically blocked by prior administration of excess unlabeled VG76e (P < 0.05); and (c) tumor uptake of the IgG1, [(125)I]-SHPP-CIP5, which has a similar molecular weight as [(125)I]-SHPP-VG76e but does not recognize VEGF, was the same for both HT1080-26.6 and HT1080-1/3C (P > 0.05). Other than tumor localization, [(125)I]-SHPP-VG76e was present in urine and blood and to a lesser extent in heart, lungs, liver, kidney, and spleen. Whole-animal PET imaging studies revealed a high tumor-to-background contrast and also revealed [(124)I]-SHPP-VG76e distributions in the major organs. These studies support further development of [(124)I]-SHPP-VG76e as a radiotracer for measuring tumor levels of VEGF in humans.