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W R Shapiro

Publications and source records attributed to W R Shapiro.

At least 55 records · Page 3Linked to original sources
PubMed1989

[Capillary permeability factor produced by C 6 glioma cells: role in peritumoral brain edema and possible mechanism of glucocorticoid action].

We studied whether C6 glioma cells produce a diffusible factor that increases capillary permeability of rat brains. Culture supernatant after 4 hours' incubation of C6 glioma cells in serum-free medium was obtained (SUP-N). SUP-N was concentrated 80-fold by dialysis-concentration (MW cut off was 10 kd) (SUP-C). These two supernatant fractions were tested for capillary permeability activity by their infusion into normal rat brains (right caudate-putamen). Control materials (MEM or concentrated MEM) were also infused into the left caudate-putamen as well as supernatants. Capillary permeability was measured by a quantitative autoradiographic method with 14C-aminoisobutyric acid (AIB) and expressed as an unidirectional blood-to-brain transfer constant (K). Effects of infusates were quantitatively estimated by two parameters, i.e., the highest K value (Kmax) (microliter/g/min) and the spatial extent (D1/2) (mm). The protein concentration of SUP-N and SUP-C was 15 and 950 micrograms/ml, respectively. SUP-N showed a slight increase of capillary permeability, particularly, around the needle track (infusion site) in the brain, but it was not significantly different from the control on the value of Kmax. On the other hand, SUP-C markedly increased capillary permeability (Kmax; SUP-C: 10.83 +/- 0.99, control: 2.53 +/- 0.22, p less than .001) and the effect was much more extensive than that of SUP-N (D1/2; SUP-C: 2.23 +/- 0.26, SUP-N: 0.83 +/- 0.07). A factor in SUP-C increased capillary permeability after a lag phase of 1.5 hours reaching the maximum after 6 hours of infusion, and 24 hours later the effect declined to 30% of Kmax at 6 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Pharmacokinetics of tumor cell exposure to [14C]methotrexate after intracarotid administration without and with hyperosmotic opening of the blood-brain and blood-tumor barriers in rat brain tumors: a quantitative autoradiographic study.

Using quantitative autoradiography, we investigated the entry over 90 min of [14C]methotrexate (MTX) into C6 gliomas implanted bilaterally into Wistar rat brains. The [14C]MTX was administered into the right carotid artery, yielding ipsilateral "arterial" brain and tumor concentrations and contralateral "systemic" concentrations. In a separate group of tumor-bearing rats, mannitol 1.6 M was given into the right carotid artery prior to administering the [14C]MTX to disrupt the blood-brain barrier on the ipsilateral side. [14C]MTX tissue concentrations were measured in regions of 50 x 50 x 20 microns in tumor, peritumoral brain tissue (brain adjacent to tumor), and cerebral cortex. In the nonmannitol experiments, tissue concentrations from the rats at each time interval were fitted using a nonlinear curve fitting program, and the pharmacokinetic values of influx and efflux of [14C]MTX into the three compartments were calculated. The influx rate constant K1 for [14C]MTX ranged from 1.3 to 8.2 microliters/g/min in the tumor. Influx rate constants in the cortex were 1.3-1.9 microliters/g/min and in the brain adjacent to tumor were 1.7-2.8 microliters/g/min. The efflux rate constant k2 was approximated for each tissue but was less reliable than the K1 values. The k2 for tumor, brain adjacent to tumor, and cortex was always higher than the corresponding K1. Peak [14C]MTX concentrations in the tumor were highest after arterial infusion with hyperosmolar barrier disruption, lower after arterial administration without barrier modification, and lowest after systemic administration. However, cortical [14C]MTX concentration was also highest after arterial administration with barrier modification and higher than the highest tumor concentration. Furthermore, tissue exposure (concentration x time) was also highest in the cortex after barrier disruption. The [14C]MTX concentration x time (micrograms/min/g x 90 min +/- SEM) ratio between tumor and cortex after systemic administration was 33.4 +/- 4.1:15.7 +/- 1.9; after arterial administration it was 96.3 +/- 11.7:30.3 +/- 3.1; after arterial administration with barrier disruption it was 266.6 +/- 28.8:311.2 +/- 15.9. The greatest tumor:cortex ratio (3.1:1) occurred with arterial drug administration without barrier disruption. Disrupting the barrier enough to permit increased tumor exposure actually increased cortical exposure to a greater degree. The resulting poorer therapeutic ratio would not appear to support this technique in humans, at least for neurotoxic drugs.

Animals↗
PubMed1988

A model of radiation myelopathy in the rat. Pathology, regional capillary permeability changes and treatment with dexamethasone.

In order to identify the effects of x-irradiation on spinal cord histology and capillary permeability, we irradiated the upper thoracic spinal cord of adult rats with 3500 cGy to a single lateral field. After 165 +/- 14 (SD) days the rats became paraplegic over 4 to 8 days. Quantitative autoradiography using 14C-amino-isobutyric acid demonstrated a biphasic curve of regional capillary permeability changes (K1). K1 first increased 70 to 85% in all regions of the cord at 30 days, then normalized at 60 days. From 60-151 +/- 8 days in asymptomatic animals there was an apparently exponential increase of K1 in all spinal cord regions progressing at varying rates among regions, most rapidly in the posterior columns and least rapidly in grey matter. K1 continued to rise when the animals became paraplegic. Morphologically, the asymptomatic period was characterized by myelin pallor and vacuolation evident at 30 days, maximal at 60 days, without progression until 151 +/- 8 days when microscopic foci of necrosis appeared in the posterior columns of some clinically normal ('preparetic') animals. The paretic period was characterized by extensive posterior and lateral column necrosis with preservation of grey matter. High dose dexamethasone or indomethacin had no preventative effect when administered just prior to irradiation. Dexamethasone transiently improved motor strength in symptomatic rats and reduced K1 in nonnecrotic portions of the cord. This study suggests that, after a transient peak of 'early delayed' changes in regional capillary permeability, there is progressive damage to the endothelium that may play a primary role in delayed radionecrosis.

Angiography↗
PubMed1988

The prognostic importance of tumor size in malignant gliomas: a computed tomographic scan study by the Brain Tumor Cooperative Group.

The prognostic importance of tumor size was studied in 510 patients with malignant glioma (80% with glioblastoma multiforme) in the Valid Study Group of Study 80-01 of the Brain Tumor Study Group (now the Brain Tumor Cooperative Group [BTCG]). The endpoint was length of survival from randomization, which occurred within 3 weeks of definitive surgery. Following randomization, patients were scheduled to receive radiotherapy (RT) (6,020 cGy) during a 7-week period, along with continuing courses of chemotherapy. Computed tomographic (CT) scan information was available for 124 patients preoperatively, 300 patients postoperatively (preradiation), and 218 patients 9 weeks post-RT (+/- 3 weeks). Tumor size was determined as area (length x width) on the contrast-enhanced scan and survival was compared by log rank statistics. Preoperative tumor area was unrelated to survival (P = .48), but postoperative area was significantly prognostic (P less than .0001); the smaller the residual tumor, the longer the patient lived. Patients with a 75% or greater resection, as determined by measuring the difference between the preoperative and the postoperative scans, tended to have better survival, but the difference was not significant (P = .16). The post-RT area was strongly related to survival (P less than .00001). The percent change in area between the pre- and post-RT scans was also prognostic. Tumor size was of prognostic importance independent of the other known prognostic variables: age, Karnofsky performance score, and whether the tumor was glioblastoma or anaplastic astrocytoma. We conclude that the amount of tumor remaining after surgery is an important baseline variable at the start of RT, and that the tumor size 9 weeks following RT is also prognostic. Surgical resection is most important when it leaves the least amount of residual tumor.

Actuarial Analysis↗
PubMed1988

Brain tumors.

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Antineoplastic Agents↗
PubMed1987

In vitro drug sensitivity testing in human gliomas.

In vitro drug sensitivity assays have been developed with the goal of predicting the clinical response to chemotherapy. The colony-forming assay, radiolabeled precursor inhibition assay, and microcytotoxicity assay are most commonly used. In retrospective studies, the assays correctly predict clinical response to a chemotherapeutic agent in 50% to 70% of patients and predict clinical resistance in nearly 100% of patients. All of the assays suffer from technical and theoretical problems. In vitro assays depend on cell culture and therefore do not entirely simulate in vivo conditions. Heterogeneity in chemosensitivity is commonly found and can complicate the interpretation of results. Further investigation is needed to determine if these assays will be able to select prospective chemotherapy for patients. The malignant origin of the cells in culture must be verified if meaningful conclusions are to be made.

Antineoplastic Agents↗
PubMed1987

Brain tumors.

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Antineoplastic Agents↗
PubMed1986

Opening the blood-brain and blood-tumor barriers in experimental rat brain tumors: the effect of intracarotid hyperosmolar mannitol on capillary permeability and blood flow.

Using quantitative autoradiography, we investigated the effect of intracarotid infusions of hyperosmolar mannitol solutions on capillary permeability and blood flow. Capillary permeability, expressed in terms of a blood-to-tissue transfer constant (K), was determined in two rat brain tumor models by measuring the entry of 14C-alpha aminoisobutyric acid into brain tumor, into brain tissue adjacent to tumor, and into cortex. Cerebral blood flow was determined by measuring the uptake of 14C-iodoantipyrine in one rat brain tumor model. Blood flow was examined in the same regions as K, as well as in the corpus callosum. Before mannitol administration, K values in both Walker 256 (W256) carcinosarcoma and C6 gliomas were much higher than those in cortex. C6 gliomas were about three times more permeable than were W256 tumors. There was a direct correlation between tumor size and increased capillary permeability. Mannitol at a concentration of 1.37 M did not increase the K values for either tumor or adjacent tissue. At 1.6 M, mannitol increased the K values for both tumors (1.7-fold in C6 glioma and 13-fold in W256) as well as for adjacent tissue. At both concentrations, mannitol markedly increased cortical K values in all groups: by 48- to 72-fold at 1.37 M and by 90- to 105-fold at 1.6 M. The net effect of the mannitol was to reverse the tumor-to-cortex permeability relationship. Cortical blood flow increased modestly after intracarotid mannitol administration on both sides of the brain. These data provide little justification for using intracarotid mannitol during chemotherapy of human brain tumors.

Animals↗
PubMed1986

Apparent glucose utilization in Walker 256 metastatic brain tumors.

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.

Animals↗
PubMed1985

The subpopulations and isolated cell types of freshly resected high grade human gliomas: their influence on the tumor's evolution in vivo and behavior and therapy in vitro.

Human malignant gliomas are karyotypically heterogeneous, composed of many cellular populations and isolated cell types identifiable by cytogenetic techniques. The distributions of cell types vary in high grade tumors. Some tumors are primarily near-diploid (35-57 chromosomes per cell), while others are hyperdiploid with chromosome numbers ranging from 58 to several hundred chromosomes per cell. Regional studies of several tumors suggest that the heterogeneity is not random. Anatomically different regions result from the combination of cellular distribution and their evolution over time. The karyotypic pattern of gliomas also reflects the tumor's evolution from a relatively homogeneous population of near-diploid cells to the hyperdiploid tumor that is removed by the neurosurgeon. The in vitro studies also suggest that there are phenotypic correlates to the karyotypic pattern of the tumor cells. Hyperdiploid cells are unstable in culture, tend to grow rapidly with short doubling times, and are often sensitive to such chemotherapeutic agents as BCNU. In contrast, the near-diploid cells are more normal in appearance, are stable in culture, grow slowly with long doubling times, are more likely to be resistant to the nitrosoureas and ultimately are the 'stem' cells that repopulate the tumor mass.

Carmustine↗
PubMed1985

Apparent glucose utilization in Walker 256 metastatic brain tumors.

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.

Animals↗
PubMed1984

Local blood flow in Walker 256 metastatic brain tumors.

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.

Animals↗