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Changes in [18F]-2-fluoro-2-deoxyglucose (FDG) uptake and gadopentetate dimeglumine (Gd-DTPA) enhancement before and after the first course of treatment with a cytostatic agent SU101 (N-[(4-trifluoromethyl)-phenyl]-5-methylisoxazole-4-carboxamide, SUGEN) were assessed using positron emission tomography (PET) and magnetic resonance imaging (MRI) in a pilot study of 8 patients with recurrent supratentorial malignant gliomas. The localization and the volume of Gd-DTPA enhancement and FDG hypermetabolism were analyzed. PET and MRI studies were performed one week before and 7.6+/-3.7 weeks after administration of SU101. The ratios of mean tumor activity to mean contralateral white matter and ipsilateral cerebellar activity were calculated for tumor regions, and SUV values corrected to the subjects' body surface area and glucose level (SUVbsa*glu) were calculated for nontumor regions. Five patients had a substantial increase of tumor volume on both PET and MRI during the first course of SU101. PET and MRI showed roughly equivalent volume changes. Large tumor volume increases were associated with a short time to clinical progression. The metabolic change in the tumor following the first course of SU101 varied from patient to patient, ranging from a 31% reduction to a 43% increase in FDG uptake ratio. Changes in FDG uptake were not predictive of time to progression or survival. In 2 patients with marked clinical deterioration and rapid tumor growth, there were differences in localization of Gd-DTPA enhancement and FDG hypermetabolism suggesting that hypermetabolism beyond the area of contrast enhancement may be of value in predicting rapid progression of high-grade glioma. SU101 did not induce any appreciable changes in SUVbsa*glu for non-tumor brain in 6 of 8 patients.

In the context of brain tumor therapy it is an important issue to assess whether positron emission tomography (PET) investigation of tumor metabolism can predict tumor response to therapy, whether the information obtained with PET is substantially different from that obtained by computed tomography (CT) and magnetic resonance (MR) imaging, and whether this information will be sufficiently useful in the management of patients to warrant the cost of PET studies. Aggressive neurosurgery, radiotherapy and adjuvant chemotherapy have become the standard of care for many patients with primary brain tumors, and the limitations of CT and MR imaging in the post-treatment period have become more apparent. Both techniques are frequently unable to differentiate between therapy-related tissue changes and progressive tumor. Two clinical situations are particularly difficult to resolve: 1) transient radiographic and clinical deterioration following intensive radiotherapy or less commonly following intensive chemotherapy, and 2) clinical deterioration in a patient who has failed initial therapy, but has stable radiographic findings following a second therapy. Available PET tracers in this context fall into the following categories of tumor biochemistry: 1) energy metabolism, 2) amino acid and protein metabolism, and 3) DNA and RNA metabolism. The use of these tracers will be described in detail below. The question is not only whether therapeutic interventions specifically alter one or more of these biochemical processes in tumors, but whether the magnitude of alterations has prognostic value with respect to clinical response and survival. Moreover, an early identification of treatment 'success' or 'failure' could significantly influence patient management by providing more objective criteria for continuing or changing a specific therapeutic strategy.

Herpes simplex virus (HSV) mutants kill dividing tumor cells but spare non-proliferating, healthy brain tissue and may be useful in developing new treatment strategies for malignant brain tumors. Two HSV mutants, a thymidine kinase deficient virus (TK-) and a ribonucleotide reductase mutant (RR-), killed 7/7 human tumor cell lines in tissue culture. The TK-HSV killed Rat RG2 glioma and W256 carcinoma lines but not the rat C6 glioma in culture. TK-HSV replication (12 pfu/cell) was similar to wild-type HSV (10 pfu/cell) in rapidly dividing W256 cells in tissue culture, but was minimal (< 1 pfu/cell) in serum-starved cells, suggesting that the proliferative activity of tumor cells at the site and time of TK-HSV injection may influence efficacy in vivo. Subcutaneous W256 tumors in male Sprague-Dawley rats were injected with TK-HSV or free inoculum. A significant effect of TK-HSV therapy on W256 tumor growth was demonstrated compared to controls (p = 0.002). Complete regression was observed in 4/9 experimental tumors, with no recurrence over 6 months. Tumor growth in the remaining 5/9 animals was attenuated during the first 3 to 5 days after treatment, but not beyond 5 days compared to 9 matched control animals; no tumor regression was observed in any of the control animals. These results suggest that HSV mutants are potentially useful as novel therapeutic agents in the treatment of tumors in immunocompetent subjects.

Local blood flow (F) in metastatic Walker 256 (WL-256) brain tumors produced by the intracarotid artery injection of WL-256 tumor cells in rats was measured using 14C-iodoantipyrine and quantitative autoradiography. Blood flow was variable in the tumors; the overall range was 2 to 222 ml hg-1 min-1 and the maximum range in an individual tumor extended over 150 ml hg-1 min-1. Small tumors had mean blood flows similar to surrounding brain. Medium to large tumors had significantly lower flows; the lowest values were usually measured in necrotic or cystic regions, although low values (less than 20 ml hg-1) were also measured in some viable-appearing tumor regions. Blood flow was significantly reduced in brain adjacent to medium and large but not small tumors. A global depression of brain and tumor blood flow was measured in two animals with hydrocephalus and the largest tumor burden. The blood flow patterns of the WL-256 metastatic tumor model are not uniquely different from other brain tumor models although some individual differences exist.

Local blood-to-tissue transfer constants (K) in metastatic Walker 256 (WL-256) brain tumors produced by the intracarotid artery injection of WL-256 tumor cells in rats were measured using 14C-alpha-aminoisobutyric acid and quantitative autoradiography. Small compact and diffuse infiltrative intraparenchymal tumors had values of K similar to that of contralateral nontumorous brain tissue. Medium and large tumors, meningeal metastases and intraventricular tumors had higher K values (5 to 30 fold) than contralateral nontumorous brain tissue indicating that intraparenchymal tumor size and location in meningeal and choroidal tissue influence the permeability of tumor capillaries. The local intratumor values of K varied considerably in these tumors and this variability of K correlated to only a few specific histopathologic features of the tumors. The value of K abruptly decreased at the tumor-brain interface when this interface was sharply defined, indicating that the metastatic tumors have only a small effect on the permeability of adjacent brain capillaries. Low blood-to-tumor transport of water soluble drugs will significantly affect drug concentrations in the tumor and the tumor-drug exposure.

Regional rates of apparent glucose utilization (GU) in metastatic Walker 256 (WL-256) brain tumors produced by the intracarotid injection of WL-256 tumor cells in rats were measured using 14C-deoxyglucose and quantitative autoradiography. Apparent glucose utilization was uniform within individual small and medium size tumors without necrosis, varied considerably among different tumors within this group, and did not correlate with tumor size or location. High values of GU in medium and large-size tumors correlated with viable-appearing tissue in contrast to necrotic tissue and were always 1.3 to 3 times higher than that of adjacent and contralateral nontumorous brain. The apparent net extraction of glucose (En) in viable tumor regions was estimated to be several fold higher than that in remote brain tissue; analysis of this data for medium and large tumors indicates that the calculated values of GU and En overestimate the actual rates of utilization and net extraction of glucose. Local cerebral glucose utilization (LCGU) was higher than normal adjacent to small tumors and lower than normal adjacent to large tumors. The LCGU in many gray-matter structures remote from the intracerebral tumors was reduced and roughly proportional to the metastatic tumor burden. The comparatively high uptake of 2-deoxyglucose by viable tumor cells has diagnostic and localization value and suggests that appropriate glucose analogues could be developed to produce a tumor-selective inhibition of glycolysis and tumoricidal effect.

Regional rates of apparent glucose utilization (GU) in metastatic Walker 256 (WL-256) brain tumors produced by the intracarotid injection of WL-256 tumor cells in rats were measured using 14C-deoxyglucose and quantitative autoradiography. Apparent glucose utilization was uniform within individual small and medium size tumors without necrosis, varied considerably among different tumors within this group, and did not correlate with tumor size or location. High values of GU in medium and large-size tumors correlated with viable-appearing tissue in contrast to necrotic tissue and were always 1.3 to 3 times higher than that of adjacent and contralateral nontumorous brain. The apparent net extraction of glucose (En*) in viable tumor regions was estimated to be several fold higher than that in remote brain tissue; analysis of this data for medium and large tumors indicates that the calculated values of GU and En* overestimate the actual rates of utilization and net extraction of glucose. Local cerebral glucose utilization (LCGU) was higher than normal adjacent to small tumors and lower than normal adjacent to larger tumors. The LCGU in many gray-matter structures remote from the intracerebral tumors was reduced and roughly proportional to the metastatic tumor burden. The comparatively high uptake of 2-deoxyglucose by viable tumor cells has diagnostic value and suggests that appropriate glucose analogues could be developed to produce a tumor-selective inhibition of glycolysis and tumoricidal effect.