Permeability of blood vessels in experimental gliomas: uptake of 99mTc-glucoheptonate and alteration in blood-brain barrier as determined by cytochemistry and electron microscopy

Experimental gliomas were induced in rats by prenatal exposure to ethyl nitrosourea. Changes in the blood-brain barrier were determined by the uptake of a water-soluble compound, 99mTc-glucoheptonate. Increased uptake of 99mTc-glucoheptonate was measured in intact tumors and in various sectors of dissected tumors. The extent of 99mTc-glucoheptonate uptake greatly varied among different tumors and among different sectors of the same tumor. Ultrastructural and cytochemical analysis of the capillary endothelial wall revealed major alterations in tight junctions, which became permeable to horseradish peroxidase. In brain tissue around the tumors, uptake of 99mTc-glucoheptonate and ultrastructure of tight junctions were comparable to normal brain capillaries. The results of the present study indicate that altered endothelial tight junctions may provide the main route of transport of 99mTc-glucoheptonate through the endothelial wall.     

Indium-111-Photofrin-II scintillation scan

Photodynamic therapy is under intense investigation as an adjuvant treatment for malignant glial tumors of the central nervous system. Photofrin-II (HpD-II) is currently the most actively investigated photosensitizing agent. A crucial issue regarding the safe and efficacious usage of HpD-II-based photodynamic therapy is the individual in vivo kinetics of tumor uptake and retention, compared with normal brain clearance. The optimal time for photoactivation of sensitized tumor must be known to ensure a high target-to-nontarget ratio, resulting in the maximal tumor destruction while preserving normal brain. Our laboratory developed a radionuclide scan based on 111indium (111In)-labeled HpD-II to evaluate HpD-II localization and clearance noninvasively within a canine model of intracerebral gliosarcoma. Synthesis of the 111In-HpD-II complex in greater than 90% yield is achieved by a simple, rapid labeling method. Radiochemical purity and stability were verified by high-performance liquid chromatography. Using the canine model of intracerebral gliosarcoma, we followed the uptake of 111In-HpD-II in tumors with serial scintillation scanning. Localization of the tumor by 111In-HpD-II has been verified by contrast-enhanced computed tomographic scan followed by gross and histological examination of the enhancing brain region. Total body biodistribution of 111In-HpD-II at various times after injection has been evaluated. The ratio of uptake in tumor compared with surrounding brain peaked at 72 hours after injection. The knowledge of regional distribution and concentration of a photosensitizing agent within a tumor mass and surrounding brain allows for the most efficacious timing and localization of a photoactivating source.     

~(99m)Tc-BDI-1导向诊断膀胱癌的临床研究

目的　评价 99mTc标记抗人膀胱癌单克隆抗体 (BDI 1)用于膀胱癌放射免疫显像 (RII)诊断的临床价值。　方法　采用 2 巯基乙醇直接还原法将 99mTc与BDI 1进行标记 ,制备 99mTc BDI 1。将其灌入 12例非膀胱癌及 32例膀胱癌患者的膀胱内 ,用γ 照相机采集图像 ,根据放射性异常浓聚作出诊断。　结果　 12例非膀胱癌患者均为阴性显像 ,32例膀胱癌患者 30例 (94% )显像。先于膀胱镜检 3个月发现早期复发癌 2例。膀胱癌组织摄取 99mTc BDI 1的程度随肿瘤分级而增加。血样本未检出放射性。　结论　99mTc BDI 1导向膀胱癌的诊断是一种安全可靠的诊断方法。     

The role of Tc-99m MIBI scintigraphy in clinical T1 renal mass assessment: Does it have a real benefit?

IntroductionDespite the increasing accuracy of imaging modalities, the rate of benign renal tumors misclassified as malignant before surgery still non-negligible. Tc-99m sestamibi was demonstrated to be a possible reliable agent in discriminating oncocytoma from renal cell carcinoma (RCC). We aimed to study the efficacy of Tc-99m MIBI tumor scintigraphy in evaluating clinical T1 renal masses.Methods and MaterialsBetween July 2017 and March 2019, patients with clinical T1 renal mass underwent preoperative Tc-99m sestamibi tumor scintigraphy. Tc-99m sestamibi tumor scintigraphy findings were correlated with the postoperative pathology results.ResultsA total of 90 renal masses were included in the study. Male to female ratio was 67/23. The mean age and tumor size were 55.5 ± 11.4 years and 4 ± 1.4 cm, respectively. In pathological evaluation, 20% (18/90) of masses were reported as benign (10 oncocytomas, 4 angiomyolipomas (AML), 2 chronic sclerosis, 1 fibroma and 1 hydatid cyst).While Tc-99m sestamibi uptake was positive in all oncocytomas; 6 patients with chronic sclerosis, fibroma, hydatid cyst and angiomyolipoma pathologies had no uptake. Except for 5 chromophobe cell RCC and 3 oncocytic papillary RCC masses, malignant lesions had no uptake.In predicting benign pathology, Tc-99m sestamibi tumor scintigraphy had positive and negative predictive value of 60% and 91.3%, respectively. The mean Tc-99m 2-methoxy isobutyl isonitrile lesion/normal renal parenchyma ratio of benign and malignant lesions was 0.6 and 0.37, respectively. A relative uptake of 0.49 was an acceptable cutoff point to discriminate oncocytomas from all other pathologies.ConclusionTc-99m sestamibi tumor scintigraphy has a beneficial role in the assessment of clinical T1 renal mass. Masses with negative uptake harbor high probability of being malignant. While evaluating masses with positive uptake, it should be kept in mind that some malignant pathologies may demonstrate similar results.     

Diphtheria toxin effects on brain-tumor xenografts. Implications for protein-based brain-tumor chemotherapy

A model was developed to determine whether protein-based chemotherapeutic agents can cross the blood-brain barrier and successfully treat brain tumors. The human small-cell lung carcinoma N417D was grown as a solid tumor in the nude rat brain, and diphtheria toxin (DT) was administered intravenously as therapy. Because rat cells lack functional DT receptors and are 1000 to 10,000 times less sensitive to DT than human cells, a therapeutic window exists between the implanted human tumor and the nude rat host. The pharmacokinetic and pharmacodynamic characteristics of DT were defined. Within 6 hours, more than 90% of the initial DT concentration was removed from the blood. The blood-to-tumor transfer constant Ki for DT in small N417D tumors was 0.49 microliters/gm-min, one-fourth to one-fifth the reported values for permeability to proteins in other experimental tumor models. Despite the toxin's short plasma half-life and the relatively intact blood-tumor barrier, DT administered intravenously as a single dose significantly extended animal survival. Untreated nude rats developed solid parenchymal tumors and died in 11 to 16 days (median 15 days). When administered at 0.1 micrograms/animal, DT increased the median survival time to 19 days (p less than 0.0016) while 1.0-microgram doses extended median survival times to 26.5 days (p less than 0.0002). A higher dose of DT (3.0 micrograms) had no further beneficial effect on survival (26.1 days). Blood-brain barrier constraints to successful monoclonal antibody-based therapies of brain tumors may have been overestimated since antibody conjugates have plasma half-lives longer than DT, and the permeability of N417D tumors to DT is equal to or less than the permeability of other experimental tumors to large proteins. Recently developed immunotoxins that have the higher potency of DT and a therapeutic window as wide as DT has in this nude rat/human tumor paradigm may be effective in treating brain tumors despite limited blood-tumor permeability.     

Preoperative imaging of abnormal parathyroid glands in patients with hyperparathyroid disease using combination Tc-99m-pertechnetate and Tc-99m-sestamibi radionuclide scans.

OBJECTIVE: To evaluate the efficacy of combined Tc-99m-pertechnetate and Tc-99m-sestamibi radionuclide scanning for imaging abnormal parathyroid glands in hyperparathyroid disease in a prospective study. SUMMARY BACKGROUND DATA: Established methods to localize abnormal parathyroid glands lack accuracy for routine use. Tc-99m-sestamibi used in conjunction with iodine-123 has excellent potential for preoperative imaging in patients with hyperparathyroid disease. An alternative method for parathyroid imaging was studied using Tc-99m-pertechnetate and Tc-99m-sestamibi. METHODS: Thirty patients with hyperparathyroid disease had Tc-99m-pertechnetate and Tc-99m-sestamibi subtraction radionuclide scanning to visualize abnormal parathyroid glands before surgery. The patients had surgery and pathologic confirmation of all parathyroid glands. RESULTS: In 23 patients with primary hyperparathyroidism, 12 of 13 solitary adenomas were visualized. Six of nine patients with diffuse hyperplasia had bilateral uptake consistent with diffuse hyperplasia. Three of nine patients had negative scans. One patient previously operated on for diffuse hyperplasia had only one gland scanned. Seven patients with renal failure-associated hyperparathyroid disease were scanned: five had bilateral uptake of Tc-99m-sestamibi consistent with hyperplasia, and two who had been previously operated on had localization of remaining abnormal parathyroid glands. CONCLUSIONS: Tc-99m-pertechnetate combined with Tc-99m-sestamibi subtraction radionuclide scanning is less cumbersome to implement than iodine-123 combined with Tc-99m-sestamibi scanning. It has a high sensitivity for imaging solitary parathyroid adenomas or persistent solitary hyperplastic glands. However it does not have the resolution necessary to delineate all parathyroid glands in diffuse hyperplasia.     

Immunohistochemical study of a newly defined oncofetal antigen (HGR-Ag) in tumors of the central nervous system.

The oncofetal antigen (HGR-Ag) in brain tumors was newly defined using the monoclonal antibody derived from tissue extracts of an anaplastic astrocytoma. The HGR-Ag was purified through sequential chromatography using diethylaminoethyl-Sephadex A-50 and Con-A Sepharose affinity columns. The latter method indicated that HGR-Ag is not a glycoprotein, and Western blot analysis indicated a molecular weight of 80-90 kd. Purified antigen was used to produce antibody. This new antibody, designated H1H2, was shown to be an immunoglobulin G1 by immunodiffusion assay. Histological/immunohistochemical studies using the H1H2 antibody on paraffin and frozen tissue sections showed HGR-Ag to be intracellular rather than membrane-associated. The immunoreactivity of H1H2 was highest in malignant astrocytomas, glioblastomas, and normal fetal brain tissue. Neurinomas and certain carcinomas of other organs showed lesser, variable reactivity to H1H2. The strength of the antigen-antibody binding was correlated with the degree of malignancy in human gliomas. H1H2 bound to fetal brain tissue and undifferentiated neural tumors, but not to normal adult brain tissue, so HGR-Ag is probably a fetal oncoantigen.     

Scintigraphic evaluation of primary bone tumors. Comparison of technetium-99m phosphonate and gallium citrate imaging

A prospective investigation of two different radionuclide imaging techniques for the skeleton--technetium-99m phosphonate and gallium-67 citrate--was carried out prior to biopsy in fifty-five patients with primary bone tumors of the extremities and limb girdles. The study showed that the technetium-99m phosphonate scans were not useful in separating benign from malignant lesions or in defining reliably the local extent of malignant tumors. Gallium scans were more accurate in delineating the local extent of malignant tumors and may provide better indentification of benign tumors.     

Cerebral blood flow measured by Xenon enhanced CT in brain tumors

In the management of malignant brain tumors, it is important to know the extent and viability of tumors. However, an ordinary CT scan with iodine enhancement has only a limited ability to distinguish the tumor from surrounding normal tissue. Since the blood flow in tumor tissue was found to be relatively high in a previous experimental report, we have investigated the blood flow in a tumor and the surrounding brain. The Xenon enhanced CT method has several advantages over the conventional isotope method and enables us to evaluate rCBF with the same resolving power as with the CT scan. We evaluated rCBF in 15 brain tumor cases and obtained the following results. Mean rCBF value of the tumor is a little lower than that of gray matter and higher than that of surrounding edema. Our Xe-CT method enables us to distinguish the demarcation between the tumor area and the surrounding edematous area and offers useful information for determining the extent of resection in surgery. Mean lambda value of the tumor which is not obtainable in vivo by radionuclide scanning, was 1.02 +/- 0.06 for gliomas and 0.72 +/- 0.09 for metastatic tumors. rCBF value and lambda value are important elements to know the uptake rate of anticancer drugs into the brain tumors. And to evaluate these value in each brain tumor is useful in the selection of chemotherapeutic agents.     

Multidrug resistance gene (MDR1) expression in human brain tumors.

Multidrug resistance for many types of cancer outside the central nervous system (CNS) has been found to be due to the overexpression of the multidrug resistance gene MDR1, of which the gene-product P-glycoprotein acts as a membrane-bound efflux pump for many anticancer drugs. To examine whether brain tumors overexpress the MDR1 gene, 25 brain-tumor specimens were subjected to Northern blot analysis: 10 gliomas, eight meningiomas, three schwannomas, one malignant lymphoma, and three tumors metastatic to the brain. Ten fresh-frozen autopsy specimens of various parts of normal brain were also analyzed. Blots were hybridized with 32P-labeled Chinese hamster complementary deoxyribonucleic acid (cDNA) and 32P-labeled human MDR1 cDNA. The MDR1 gene messenger ribonucleic acid (mRNA) was detected in two tumors using the Chinese hamster probe (one sphenoid wing meningioma and one metastatic prostate tumor) and in one CNS lymphoma using the human probe. Intact mRNA could not be extracted from the fresh-frozen autopsy specimens of normal brain. Seventeen tumors were examined for P-glycoprotein by immunohistochemical staining using murine monoclonal antibody C219: eight gliomas, eight meningiomas, and one craniopharyngioma. The neoplastic cells from two gliomas and three meningiomas and the blood vessels within six gliomas and two meningiomas stained positively for P-glycoprotein. Seven of 10 normal brain specimens stained positively for P-glycoprotein in blood vessels but no specimen demonstrated staining of parenchymal cells. This study demonstrates that the MDR1 gene can be detected in normal brain, and in malignant, benign, and metastatic lesions. P-glycoprotein can be present in tumor blood vessels even when it is not seen in neoplastic cells. Although the role of P-glycoprotein in tumor blood vessels needs to be further examined and more clearly defined, drug resistance in malignant primary brain tumors may result from characteristics not solely of neoplastic cells but also tumor vasculature.     

Chemotherapeutic agent permeability to normal brain and delivery to avian sarcoma virus-induced brain tumors in the rodent: observations on problems of drug delivery

Four chemotherapeutic agents (cyclophosphamide, 5-fluorouracil (5-FU), methotrexate (MTX), and bleomycin) were given intravenously to rats harboring the avian sarcoma virus-induced glioma. Drug content in brain, tumor, and systemic tissue was measured. The uptake of drug and the consistency of drug levels in normal brain and tumor varied widely among these agents. [14C]Cyclophosphamide and its metabolites penetrated normal brain and, to a greater extent, brain tumor. [14C]5-FU and its metabolites also entered normal brain and brain tumor, but to lesser extent than [14C] cyclophosphamide and its metabolites. Immunoreactive MTX entry into tumor was variable, ranging from 30 to 1080 ng/g of tissue, with only minimal concentrations in normal brain. After conventional doses, immunoreactive bleomycin levels in tumor were also variable, ranging from 24 to 164 mu units/g of tissue, and little if any drug entered surrounding brain. In addition, the cerebrovascular permeability of 5-FU and MTX in normal rats was measured. Utilizing the method of Rapoport, the PA (product of permeability and capillary surface area) of 5-FU was found to be 6- to 12-fold greater than that of MTX. The PA of both drugs was increased 4- to 7-fold after osmotic blood-brain barrier opening. The variable "leakiness" of glial tumors, both experimentally and clinically, as well as the varied permeabilities of different water-soluble chemotherapeutic agents, makes the drug delivery problem in brain tumors a very complex issue.     

Primary central nervous system lymphoma

A retrospective analysis of 21 cases of primary central nervous system (CNS) lymphoma is reported. All patients presented with a solitary mass in the supratentorial region. None had previously received immunosuppressive therapy. Neuroradiological studies included technetium-99m-pertechnetate brain scanning in eight cases, cerebral arteriography in all 21 cases, and computerized tomography (CT) in 14 cases. The characteristic features were increased uptake in brain scans, mass effect in arteriograms, and marked contrast enhancement on CT scans. Abnormal tumor vessels were occasionally seen on arteriography, and subtraction films were usually required to appreciate tumor stain. All patients underwent craniotomy, and histological studies of the tumors showed a diffuse type of lymphoma in all cases. Immunoglobulin testing was performed in 19 cases and a monoclonal spike was verified in 10, suggesting a B cell origin. All patients were followed until their death except one who was still alive 12 months from onset of symptoms. Therapy included subtotal resection in all 21 cases, whole-brain irradiation in six cases, chemotherapy in two cases, and a combination of whole-brain irradiation and chemotherapy in nine cases. Three different forms of chemotherapy were used. The results suggest that chemotherapy is an important addition to subtotal resection and whole-brain irradiation in the treatment of primary CNS lymphoma.     

Increased delivery of tumor-specific monoclonal antibodies to brain after osmotic blood-brain barrier modification in patients with melanoma metastatic to the central nervous system

We evaluated the delivery of melanoma-specific radiolabeled monoclonal antibody (MAb) Fab fragments in a pilot study of three patients with melanoma metastatic to the central nervous system. Tumor samples demonstrated excellent immunohistochemical reactivity with Fab 96.5, specific for a 97,000-molecular-weight melanoma antigen (p97), or Fab 48.7, specific for a melanoma-associated proteoglycan antigen. All three patients received 131I-labeled tumor-specific Fab (5 to 7 mg, 1 mCi/mg) intravenously. On a separate occasion, two patients received 131I-labeled nonspecific Fab (5 to 7 mg, 1 mCi/mg). There was no uptake of either antibody into the region of the tumor (as documented by gamma camera brain images). However, there was increased uptake in the blood-brain barrier (BBB)-modified areas in all three patients when radiolabeled tumor-specific MAb was administered intravenously in conjunction with osmotic BBB opening. In one patient, the estimated cerebrovascular permeability X capillary surface area (PA) for the tumor-bearing hemisphere 3 hours after disruption was 1.16 X 10(-6) sec-1 compared to the PA of 0.395 X 10(-6) sec-1 in the nondisrupted hemisphere. Serial brain scans showed that greater than 90% of the radiolabeled antibody cleared from the brain by 72 hours. The highest radiation doses (rads) calculated per 7 mCi injection were: left brain (barrier-modified hemisphere), 5.46; right brain (non-barrier modified hemisphere), 1.68; thyroid, 98; stomach, 9.1; kidney, 39.9; and total body, 1.33. There seemed to be increased uptake of antibody in the tumor region after barrier modification in one patient, but antibody clearance from that region occurred at the same rate as from surrounding and apparently tumor-free brain. In one patient who had carcinomatous meningitis, we demonstrated antibody bound to only a fraction of the antigen binding sites on tumor cells in the cerebrospinal fluid after BBB modification. We have not shown distinct, persistent localization of antibody in brain tumor; studies investigating MAb dose and other parameters as the basis for this problem are under way.     

Thallium-201 tumor/cardiac ratio estimation of residual astrocytoma

Treatment of high-grade astrocytoma includes surgery, chemotherapy, and various methods of irradiation. Radiation therapy usually results in necrosis and edema around the primary tumor site. Contrast-enhanced computerized tomography (CT) and standard radionuclide imaging techniques are unable to reliably distinguish recurrent tumor from necrosis or edema since these images depict localization of contrast material or tracer, which primarily depends on blood-brain barrier breakdown. Thallium-201 (201Tl) appears to incorporate into viable tumor cells more rapidly than into normal brain cells. This report describes a new method to quantify the uptake of 201T1 in the tumor: the tumor-to-cardiac uptake ratio (T/C). Twenty-three 201T1 brain scans were performed on eight patients to differentiate recurrent viable high-grade astrocytoma from posttherapy changes. Planar images of the head and heart were obtained in order to calculate the ratio of tumor counts to cardiac counts. This ratio represents a numerical estimation of 201T1 uptake in the brain tumor relative to cardiac counts and is expressed as the T/C index. The T/C index correlated well with the clinical course in all eight patients. In general, however, CT suggested more extensive regrowth of tumor than the actual clinical status suggested. In one patient's course of radiological monitoring, tumor recurrence was detected by means of 201T1 imaging four months prior to its appearance on CT. In conclusion, when performed serially, the T/C index can provide an accurate estimate of residual tumor burden or recurrence, and detect and quantify viable tumor during therapy.     

Penetration of 99mTcO4- into cerebrospinal fluid from blood on brain scintigraphy (author's transl)]

It is well known that the permeability of the blood brain barrier and blood cerebrospinal fluid barrier changes more or less in various diseases of the central nervous system. At present, thee is no clinically available index which reflects the alteration of the permeability of the blood brain barrier and blood cerebrospinal fluid barrier. The brain scintiraphy is an examination which detects a breakdown in the blood brain barrier, its clinical usefullness is limited only in a localized and extremely pathological proces of the brain. In this report, a cerebrospinala fluid isotope measurement comined with the brain scintigraphy was presented as a clinical examination for blood brain barrier function. Thirty minutes prior to brain scintigraphy, potassium perchlorate (4 mg/kg) was given orally to reduce the accumulation of 99mTc04-in the choroid plexus and to minimize iradiation for tr other organs. Spinal tap was performed two hours after injection of 99mTc04- according to Haines's method...     

Osmotic blood-brain barrier modification: monoclonal antibody, albumin, and methotrexate delivery to cerebrospinal fluid and brain

In the dog, osmotic opening of the blood-brain barrier (BBB) in the posterior circulation via the vertebral artery and in the anterior circulation via the internal carotid artery was utilized to increase the delivery of three substances of varying molecular weight to the central nervous system. The cerebrospinal fluid (CSF) concentration of all three agents dramatically increased after BBB opening. In contrast to methotrexate, Evans blue-albumin and monoclonal antibody (MAb) concentrations in CSF were 6-fold greater when given after posterior rather than anterior circulation BBB opening. Conversely, MAb delivery to brain parenchyma was optimized after osmotic BBB modification via the carotid artery. This suggests that, with higher molecular weight substances, osmotic barrier opening has a differential effect on the blood-brain vs. blood-CSF barriers.     

Characterization of the neoplastic potential of solitary solid thyroid lesions with Tc-99m-Pertechnetate and Tc-99m-sestamibi scanning

Background: Radionuclide scans that use Tc-99m-pertechnetate or I-123 currently lack the specificity to assess the malignant potential of solitary solid lesions of the thyroid gland. Tc-99m-sestamibi scanning was used to determine the neoplastic potential of thyroid lesions. Methods: Patients with lesions of the thyroid underwent Tc-99m-sestamibi imaging to assess the neoplastic potential of their thyroid lesions, identified as solitary and cold by radionuclide imaging with Tc-99m-pertechnetate. Tc-99m-sestamibi uptake was correlated with fine-needle aspiration cytology or surgical pathology. Results: Twenty-seven patients were evaluated using Tc-99m-pertechnetate and Tc-99m-sestamibi scans: 14 had right thyroid lesions, and 13 had left thyroid lesions. Of 27 patients, 10 had a positive Tc-99m-sestamibi scan: one Hürthle cell adenoma, one papillary carcinoma, six follicular adenomas, and two nodular goiters. Of 27 patients, 17 had a negative Tc-99m-sestamibi scan: one follicular carcinoma, one papillary carcinoma, two follicular adenomas, one Hürthle cell adenoma, one metastatic adenocarcinoma, one medullary carcinoma, four nodular goiters, and six colloid nodules. Positive Tc-99m-sestamibi scan identified neoplasms with a sensitivity of 53%, a specificity of 83%, and a positive predictive value of 80%. Conclusions: Tc-99m-sestamibi scanning lacks sufficient sensitivity for diagnosis of solitary thyroid nodules. Future work may define a role for its use in recurrent or metastatic thyroid neoplasms. Presented at the 47th Annual Cancer Symposium of The Society of Surgical Oncology, March 17–20, 1994, Houston, TX.     

Production and characterisation of a C595 antibody-99mTc conjugate for immunoscintigraphy of bladder cancer

Current radiological techniques for staging bladder cancer are inaccurate, especially in the identification of pelvic lymph node metastases. Immunoscintigraphy has the potential to offer improved staging for bladder cancer. The aim of this study was to label the anti-MUC1 monoclonal antibody C595 with ^99mtechnetium (Tc), the most widely used diagnostic radionuclide, and assess the potential of the resultant conjugate for intravenous immunoscintigraphy of bladder cancer. A direct, reduction-mediated technique was used to label the antibody. The resultant conjugate was shown to be highly immunoreactive, stable and bound specifically to MUC1. The ability of the conjugate to bind to bladder tumours was demonstrated in an ex vivo model where the mean tumour:normal urothelial uptake was 5.7:1 and by intravesical administration in patients with bladder cancer where the mean tumour:normal urothelial uptake was 20.4:1. The ability of the conjugate to localise MUC1-expressing tumours was demonstrated in a nude mouse xenograft model. A conjugate of ^99mTc-C595 has been produced and characterised, and it may be suitable for intravenous immunoscintigraphy, a potential novel staging tool for bladder cancer. Received: 10 May 2000 / Accepted: 11 September 2000     

Liposomes as carriers of cisplatin into the central nervous system--experiments with 9L gliomas in rats.

The anticancer agent cis-diamminedichloroplatinum (cisplatin) has several disadvantages, including extreme nephrotoxicity, rapid binding to plasma proteins, and poor penetration of the central nervous system. In this study liposomes, which can cross the blood-brain barrier, were investigated for their potential in delivering therapeutic agents to brain tumors. Liposomes prepared from egg phosphatidylcholine and cholesterol in a 3:1 molar ratio were divided into 1-ml aliquots and either labeled with 14C or treated with horseradish peroxidase (HRP). The preparations were administered via the carotid artery to rats bearing 9L glioma. Radioactive uptake by brain tumor and normal tissues was measured with a liquid scintillation counter. The presence of HRP-containing liposomes in capillary endothelium and brain tumor cells was demonstrated by light and electron microscopic histochemical techniques. Thirty minutes after injection of 14C-labeled liposomes, radioactive uptake was higher in the spleen than in normal brain, brain tumor, liver, and kidney. Also uptake was greater in brain tumor and lower in kidney than that of cisplatin given alone. Light microscopy showed HRP-containing liposomes in brain tumor tissue 30 minutes after injection. On electron microscopy, liposomes were found to be regularly distributed in surface invaginations and vesicles of capillary endothelial cells. They were also observed within tumor cells. These results indicate that liposomes can penetrate the blood-brain barrier and hold promise as drug carriers in the treatment of brain tumors with cisplatin.     

The effect of 5-lipoxygenase inhibition on blood-brain barrier permeability in experimental brain tumors.

To determine if leukotrienes are important mediators of vascular permeability in brain tumors, the effect of 5-lipoxygenase inhibitors on blood-tumor barrier permeability in rats harboring HK Walker 256 brain tumors was examined using quantitative autoradiography with alpha-14C-aminoisobutyric acid. The 5-lipoxygenase enzyme converts arachidonic acid to leukotrienes. Three 5-lipoxygenase inhibitors were utilized: BW755C, nordihydroguaiaretic acid, and AA-861. All three 5-lipoxygenase inhibitors significantly decreased vascular permeability both within the tumors and in brain adjacent to tumor. This suggests that capillary permeability in and adjacent to tumors is influenced by endogenous leukotrienes and that leukotrienes play an important role in brain tumor edema.