Liposome-mediated therapy of intracranial brain tumors in a rat model

PURPOSE: Malignant brain tumors represent a serious therapeutic challenge, and survival often is low. We investigated the delivery of doxorubicin (DXR) to rat brain tumors in situ via liposomes, to test the hypothesis that intact liposomes undergo deposition in intracranial tumor through a compromised blood-tumor vasculature. Both therapeutic effect and intra-tumor drug carrier distribution were evaluated to identify variables in carrier-mediated delivery having impact on therapy. METHODS: The rat 9L gliosarcoma tumor was implanted orthotopically in Fischer 344 rats in the caudate-putamen region. The tumor-bearing rats were treated with DXR, either free or encapsulated in long-circulating, sterically-stabilized liposomes. Anti-tumor efficacy was assessed by survival time. In parallel, liposomes labeled with a fluorescent phospholipid analog were injected into tumor-bearing rats. At predetermined intervals, the brains were perfused with fixative, sectioned, and imaged with laser scanning confocal microscope (LSCM) to investigate the integrity of the tumor vascular bed and the intratumor deposition of liposomes. RESULTS: Free DXR given in 3 weekly iv injections was ineffective in increasing the life span of tumor-bearing rats at cumulative doses < or = 17 mg/kg, and at the highest dose (17 mg/kg) decreased survival slightly, compared to saline-treated controls. In contrast, DXR encapsulated in long-circulating liposomes mediated significant increases in life span at 17 mg/kg. Rats showed a 29% percent increase in median survival, respectively, compared to saline-control animals. The delay of treatment after tumor implantation was a major determinant of therapeutic effect. Fluorescent liposomes were deposited preferentially in tumor rather than normal brain, and were distributed non-uniformly, in close proximity to tumor blood vessels. CONCLUSIONS: Liposomes can be used to enhance delivery of drugs to brain tumors and increase therapeutic effect. The therapeutic effect may arise from release of drug from liposomes extravasated in discrete regions of the tumor vasculature and the extravascular space.     

Effects of carbon dioxide-induced anesthesia on cholinergic parameters in rat brain

We report that acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) activities in rat brain were virtually identical whether the rat was anesthetized with carbon dioxide (CO2) before decapitation or decapitated without prior sedation. The AChE and ChAT activities were measured in three brain regions: the hippocampus, cerebral cortex, and cerebellum. Enzyme activities varied significantly by brain region, with the highest values in the hippocampus and the lowest values in the cerebellum. Enzyme activities, however, did not vary with the method of euthanasia, either CO2-induced anesthesia prior to decapitation or decapitation without anesthesia. These data suggest that CO2-induced anesthesia prior to decapitation does not alter activities of these cholinergic markers in rat hippocampus, cerebral cortex, and cerebellum. This method of euthanasia eliminates the need to capture a conscious animal, which reduces stress to the animal and the experimenter.     

Differential activation of right superior parietal cortex and intraparietal sulcus by spatial and nonspatial attention

Malignant brain tumors (primary and metastatic) are apparently resistant to most therapeutic efforts. Several randomized trials have provided evidence supporting the efficacy of radiation therapy. Attempts at improving the results of external beam radiotherapy include altered fractionation, radiation sensitizers and concomitant chemotherapy. In low-grade gliomas, all clinical studies with radiotherapy have employed conventional dose fractionation regimens. In high-grade gliomas, hypofractionation schedules represent effective palliative regimens in poor prognosis subsets of patients; short-term survival in these patients has not allowed to evaluate late toxicity. In tumors arising within the central nervous system, hyperfractionated irradiation exploits the differences in repair capacity between tumour and late responding normal tissues. It may allow for higher total dose and may result in increased tumor cell kill. Accelerated radiotherapy may reduce the repopulation of tumor cells between fractions. It may potentially improve tumor control for a given dose level, provided that there is no increase in late normal tissue injury. In supratentorial malignant gliomas, superiority of accelerated hyperfractionated over conventionally fractionated schedules was observed in a randomized trial; however, the gain in survival was less than 6 months. At present no other randomized trial supports the preferential choice for altered fractionation irradiation. Also in pediatric brainstem tumors there are no data to confirm the routine use of hyperfractionated irradiation, and significant late sequelae have been reported in the few long-term survivors. Shorter treatment courses with accelerated hyperfractionated radiotherapy may represent a useful alternative to conventional irradiation for the palliation of brain metastases. Different considerations have been proposed to explain this gap between theory and clinical data. Patients included in dose/effect studies are not stratified by prognostic factors and other treatment-related parameters. This observation precludes any definite conclusion about the relative role of conventional and of altered fractionation. New approaches are currently in progress. More prolonged radiation treatments, up to higher total doses, could delay time to tumor progression and improve survival in good prognosis subsets of patients; altered fractionation may be an effective therapeutic tool to achieve this goal.     

A phase II evaluation of pentoxifylline combined with radiation in the treatment of brain metastases

Pentoxifylline (PTX) has pharmacological properties that suggest potential utility as a radiation sensitizer, and preclinical animal studies have been promising. In a non-randomized phase II trial, we used PTX plus standard-dose external-beam whole-brain radiation treatment (WBRT) in patients with brain metastases. Seventeen patients were entered; 14 received both WBRT and PTX and were considered evaluable. Nine of the 14 completed treatment. Analyzing data on all 14 evaluable patients according to intent to treat, median survival time was 33 days, comparable to published data from historical controls. PTX toxicity was not a common cause of patient dropout, supporting higher PTX doses in future trials.     

Therapeutic efficiency and safety of a second-generation replication-conditional HSV1 vector for brain tumor gene therapy

A second-generation replication-conditional herpes simplex virus type 1 (HSV) vector defective for both ribonucleotide reductase (RR) and the neurovirulence factor gamma34.5 was generated and tested for therapeutic safety and efficiency in two different experimental brain tumor models. In culture, cytotoxic activity of this double mutant HSV vector, MGH-1, for 9L gliosarcoma cells was similar to that of the HSV mutant, R3616, which is defective only for gamma34.5, but was significantly weaker than that of the HSV mutant hrR3, which is defective only for RR. The diminished tumoricidal effect of the gamma34.5 mutants could be accounted for by their reduced ability to replicate in 9L cells. The MGH-1 vector did not achieve significant prolongation of survival in vivo in the syngeneic 9L rat gliosarcoma model for either single brain tumor focus or multiple intracerebral and leptomeningeal tumors, when the vector was applied intratumorally or intrathecally, respectively, and with or without subsequent ganciclovir (GCV) treatment. In identical 9L brain tumor models with single and multiple foci, application of hrR3 with or without GCV was previously shown to result in marked long-term survival. Contrary to the findings with intrathecal injection of hrR3, no vector-related mortality was observed in any animals treated with MGH-1. Thus, in these rat brain tumor models, the double mutant, replication-conditional HSV vector MGH-1 showed a higher therapeutic safety than the RR-minus vector, hrR3, but had clearly decreased therapeutic efficiency compared to hrR3. The development of new HSV vectors for brain tumor gene therapy will require a balance between maximizing therapeutic efficacy and minimizing toxicity to the brain. Standardized application in brain tumor models as presented here will help to screen new HSV vectors for these requirements.     

Interstitial delivery of carboplatin via biodegradable polymers is effective against experimental glioma in the rat

PURPOSE: Carboplatin has shown promise experimentally as an antineoplastic agent against both primary central nervous system (CNS) tumors and several solid tumors that frequently metastasize to the brain. Unfortunately, carboplatin is limited in its clinical use for tumors in the CNS by systemic toxicity and poor penetration through the blood brain barrier. Recent advances in polymer technology have made feasible the intracranial implantation of a biodegradable polymer capable of local sustained delivery of chemotherapy for brain neoplasms. This study assessed the toxicity and efficacy of carboplatin delivered from intracranial sustained release polymers in the treatment of experimental gliomas in rodents. METHODS: Two biodegradable anhydride polymer systems were tested: a copolymer of 1,3-bis-(p-carboxyphenoxy propane) and sebacic acid, and a copolymer of fatty acid dimer and sebacic acid. The polymers were loaded with carboplatin and dose escalation studies evaluating toxicity were performed by implanting carboplatin-loaded polymers into the brains of rats. Next, efficacy was tested. F-98 glioma cells were injected intracranially into rats, and 5 days later polymers containing the highest tolerated doses were implanted at the site of tumor growth. The survival of animals receiving carboplatin-loaded polymer was compared with that of animals receiving intraperitoneal doses of the same agent. RESULTS: Carboplatin-polymer was well tolerated at doses up to 5% loading in both polymer systems. Locally delivered carboplatin effectively prolonged survival of rats with F98 gliomas. Maximal treatment effect was seen with 5% loading of either polymer, with median survival increased threefold over control (P < 0.004). Systemic carboplatin also significantly prolonged survival, but the best intracranial polymer dose was significantly more effective than the best systemic dose tested. CONCLUSIONS: Carboplatin can be safely delivered intracranially by biodegradable sustained- release polymers. This treatment improves survival in rodents with experimental gliomas, with locally delivered carboplatin being more effective than systemic carboplatin.     

The role of the striatum in the evolution of the mammalian forebrain

AIM: To test if anesthetic procedures change the hemodynamic pattern in animals with experimental septic shock. METHODS: The effect of two anesthetics on systemic hemodynamic and skeletal muscle microcirculatory responses in high cardiac output live E. coli bacteremia was studied in rats and compared to the effect of two other anesthetic procedures in previously published studies. RESULTS: Baseline blood pressures and cardiac outputs were similar in rats with decerebrate, ketamine/xylazine, pentobarbital or urethane/chloralose anesthesia. There was a relative baseline tachycardia in decerebrate rats. Ketamine/xylazine anesthetized rats had reduced blood pressure, cardiac output, and heart rate. In decerebrate, pentobarbital, and urethane/chloralose anesthesia, cardiac output increased initially during bacteremia but did not remain elevated in pentobarbital anesthesia. Blood pressure and heart rate remained constant in pentobarbital, decerebrate, and urethane/chloralose anesth esia. During bacteremia, cardiac output, blood pressure, and vascular resistance did not change with ketamine/xylazine, but the heart rate increased. Baseline diameters of cremaster muscle large (A1) arterioles were higher in decerebrate anesthesia. A1 arterioles constricted during high cardiac output bacteremia in decerebrate rats, and pentobarbital or urethane/chloralose-anesthetized rats. A4 arterioles in bacteremia dilated in decerebrate and pentobarbital anesthesia, but did not change under urethane/chloralose and ketamine/xylazine anesthesia. CONCLUSION: Anesthetics influence baseline systemic variables and the response of systemic hemodynamics of rats to E. coli bacteremia. During bacteremia, anesthetics primarily affect the reactivity of skeletal muscle small arterioles. Ketamine/xylazine anesthesia has the most pronounced effect on systemic and microcirculatory variables and seems to be an inappropriate choice in sepsis experiments in rats.     

Tissue distribution of methotrexate following administration as a solution and as a magnetic microsphere conjugate in rats bearing brain tumors

A novel magnetic microsphere-methotrexate (MM-MTX) drug delivery system was synthesized and evaluated in rats bearing rat glioma-2 (RG-2) tumors. Methotrexate was linked to the surface of the magnetic particle via an aminohexanol linker that would release free drug following hydrolysis. Male Fischer 344 rats bearing RG-2 tumors were administered 3 mg/kg of methotrexate (MTX) either as MM-MTX or as a solution (MTX-S) over 5 min. A 6000 gauss magnetic field was applied for 15 min from the end of MM-MTX administrations. Serial sacrifices were conducted at 15 min, 30 min and 45 min after drug administrations, organs collected, and analyzed for total MTX by a radioassay. At all times, MTX right brain (ipsilateral), brain tumor, and left brain concentrations were approximately 3.5 to 5-fold greater in the MM-MTX group compared to the MTX-S group. MTX concentrations in all other organs were less following administration of MM-MTX than MTX-S except in lung at 30 and 45 min. The targeting efficacy, an index for site-specificity, for both MM-MTX and MTX-S were similar and indicated some enhancement in MTX localization in brain tumor. Confocal and conventional light microscopic analyses demonstrated a diffuse distribution of MM-MTX in tumor consistent with extravascular uptake, whereas a predominant capillary distribution of MM-MTX was observed in normal brain. Following 45 min, the animals treated with MM-MTX died possibly due to redistribution of particles to the lung. This toxicity was dose-dependent. High brain MTX concentrations coupled with extravascular uptake of MM-MTX provide a basis for further investigations with this novel drug delivery system.     

Radiosurgery alone or in combination with whole-brain radiotherapy for brain metastases

PURPOSE: Evaluation of the treatment outcome after radiosurgery (RS) alone or in combination with whole-brain radiotherapy (WBRT) with special attention to prescribed dose and its influence on local control and survival. PATIENTS AND METHODS: Between September 1984 and January 1997, 236 patients with 311 brain metastases treated with radiosurgery met the following inclusion criteria: one to three brain metastases per patient; no previous WBRT; and Kamofsky performance status (KPS) > or = 50%. One hundred fifty-eight patients treated only with RS received a median dose of 20 Gy prescribed to the 80% isodose line; 78 patients received RS with a median dose of 15 Gy/80% and an additional course of WBRT. RESULTS: For the entire series, overall median survival was 5.5 months, with control of CNS disease achieved in 92% of the treated brain metastases; the results were not significantly different between patients treated by RS with or without WBRT. However, in patients without evidence of extracranial disease, median survival was increased for patients who received WBRT (15.4 vs 8.3 months; P=.08). Additionally, there was a suggestion that increased doses for patients treated with RS only resulted in improved outcome. Four lesions were suspicious for radiation necrosis by magnetic resonance imaging (MRI); in one of the four lesions, radiation necrosis was confirmed histologically. The incidence of transient low-grade toxicity was 18%; symptoms could be treated by the temporary administration of steroids. CONCLUSION: RS is an effective, noninvasive means of controlling brain metastases when used alone or in combination with WBRT. There is a trend for superior local control and especially in patients without extracranial disease for superior survival when RS is used in conjunction with WBRT. Randomized trials would seem to be warranted, comparing the benefit of RS with or without additional WBRT.     

Dose-rate dependence of heat radiosensitization

The dose rate dependence of heat radiosensitization was studied using rat astrocytoma cells in culture and a clinically relevant protocol of heat dose and heat radiation sequence. Cells were treated with a minimally toxic heat dose of 43 degrees C for 30 minutes, after which they were irradiated with varying doses of radiation at dose rates ranging from 0.567 to 300 cGy/min. This heat dose substantially reduced the extrapolation number (n), but had little effect on Do of the radiation survival curve at dose rates of 50 cGy/min or greater. At dose rates less than 10 cGy/min, 43 degrees C for 30 min had little effect on n and only for the lowest dose rate studied (0.567 cGy/min) was there a significant reduction in Do (60%). The thermal enhancement ratio did not vary inversely with radiation dose rate over the dose rate range studied but, instead, was maximal at the two dose rate extremes (0.567 and 300 cGy/min). These data demonstrate that a clinically relevant heat dose enhances very low dose rate, as well as high dose rate, ionizing radiation, but suggest that little benefit is to be gained from using dose rates intermediate between conventional radiotherapeutic high dose rates or dose rates representative of interstitial implants.     

A physician''s analysis of the business of refractive surgery

BACKGROUND AND PURPOSE: A well-demarcated infarct was observed after 4 hours of rat middle cerebral artery (MCA) occlusion with xylazine/ketamine but not pentobarbital or isoflurane anesthesia. This study examined whether this reflected vascular changes and, because xylazine induces hyperglycemia, whether glucose could cause similar vascular effects in cerebral ischemia. METHODS: To examine the effects of anesthetics, rats were anesthetized for thread occlusion of the MCA with either xylazine/ketamine, pentobarbital, or isoflurane. To evaluate the effects of glycemia, acute hyperglycemia was induced by glucose injection. In both experiments, cerebral plasma volume (CPV) was determined using 3H-inulin after 4 hours of permanent occlusion, and cerebral blood flow was measured using [14C]iodoantipyrine following 2 hours of reperfusion after 2 or 4 hours of occlusion. The presence of cerebral hemorrhage after reperfusion was checked macroscopically and infarct volume with 2,3,5-triphenyltetrazolium staining. RESULTS: The ischemic CPV was about 50% of the contralateral values with xylazine/ketamine but not with the other anesthetics. On reperfusion, ischemic cerebral blood flow with xylazine/ketamine anesthesia was approximately half that with pentobarbital. Use of xylazine/ketamine also resulted in more frequent hemorrhagic infarcts and a larger infarct volume. Induced hyperglycemia resulted in a CPV decrease in the ischemic compared with nonischemic tissue (4.0 +/- 0.5 versus 7.4 +/- 0.2 microL/g; P < .001). Hyperglycemia also caused poor reperfusion and increased the occurrence of hemorrhagic infarction (hyperglycemia, 15 of 20; normoglycemia, 1 of 11; P < .01). CONCLUSIONS: Hyperglycemia induces marked cerebrovascular changes, both during ischemia and during reperfusion, that may exacerbate tissue damage. Change in CPV during ischemia may be a useful clinical indicator in predicting poor hemodynamic recovery and occurrence of hemorrhagic infarction after reperfusion therapy.     

Ketamine increases the striatal N-[11C]methylspiperone binding in vivo: positron emission tomography study using conscious rhesus monkey

A system for positron emission tomography study of conscious monkeys was newly developed. By use of this system in combination with a microdialysis technique, the effect of ketamine on the binding and release of dopamine was investigated. The administration of ketamine (5 mg/kg) caused sedation accompanied by psychotic symptoms such as nystagmus and stereotyped movements of extremities. During this psychotomimetic period produced by ketamine, a significant increase in the accumulation of the dopamine D2 receptor ligand N-[11C]methylspiperone was observed in the striatum compared with the level in the conscious state, while no significant change was observed in the frontal cortex and cerebellum. In contrast to the use of ketamine as the anesthetic, pentobarbital (25 mg/kg), which produced deeper anesthesia but no psychotic symptoms, caused a decrease in the accumulation of N-[11C]methylspiperone in the striatum. Kinetic analysis, conducted by a graphical method, revealed that the value of the association constant (K3) for N-[11C]methylspiperone binding in the striatum was increased to approximately 130% by ketamine and decreased to approximately 70% by pentobarbital compared with the control values. Furthermore, the release of dopamine from the striatum measured by microdialysis was not affected by ketamine anesthesia. These results indicate that ketamine facilitates striatal dopaminergic neurotransmission through increasing the binding activity of dopamine D2 receptors in the striatum, and suggest that these changes may be related to the psychotomimetic behavioral symptoms of this drug.     

Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain

Programmed cell death (apoptosis) occurs during normal development of the central nervous system. However, the mechanisms that determine which neurons will succumb to apoptosis are poorly understood. Blockade of N-methyl-D-aspartate (NMDA) glutamate receptors for only a few hours during late fetal or early neonatal life triggered widespread apoptotic neurodegeneration in the developing rat brain, suggesting that the excitatory neurotransmitter glutamate, acting at NMDA receptors, controls neuronal survival. These findings may have relevance to human neurodevelopmental disorders involving prenatal (drug-abusing mothers) or postnatal (pediatric anesthesia) exposure to drugs that block NMDA receptors.     

Treatment of a habitual smoker using nicotine gum: a case report

39 untreated patients with local cancer of the bladder without distal metastases were included in the trial to assess efficacy of combined drug plus radiation treatment, its toxicity and chances to preserve the bladder. The examination comprised tumor biopsy, ultrasonography, computed tomography, excretory urography and routine laboratory tests. The patients received one or two courses of intraarterial chemotherapy, radiation (50 Gy) and two doses of cysplatinum in a dose 70 mg/m2 before and after radiation. A complete response was achieved in 66.6%, partial in 12.8%, stabilization in 10.3% and progression in 10.3% of patients. One-year survival was reported in 89.7%, recurrence-free survival with functioning bladder being 66.7%. Side effects were mild and did not demand the treatment discontinuation.     

Altered response to histamine in brain tumor vessels: the selective increase of regional cerebral blood flow in transplanted rat brain tumor

The authors studied the effect of intracarotid administration of histamine on the regional cerebral blood flow (rCBF) in transplanted rat C6 glioma by the hydrogen clearance method. Histamine infusion at doses of 1 and 10 micrograms/kg/min produced an increase of rCBF in the tumor (24.6% +/- 16.4%, p < 0.002, and 37.6% +/- 18.2%, p < 0.0001, respectively) and also in brain surrounding the tumor (26.8% +/- 16.2%, p < 0.002, and 34.9% +/- 9.2%, p < 0.0001, respectively) without any significant changes in the ipsilateral hemisphere. Intravenous administration of pyrilamine (H1 antagonist) and cimetidine (H2 antagonist) reduced blood flow responses to histamine; cimetidine was a more effective blocking agent than pyrilamine. Intracarotid infusion of histamine (1 and 10 micrograms/kg/min) with intravenous injection of Evans blue dye disclosed the selective extravasation of dye in the tumor and the brain surrounding the tumor. These results indicated that brain tumor vessels could respond to histamine differently than normal brain capillaries. The mechanism of selective response to histamine could be explained either by increased permeability or by altered characteristics of histamine receptors in the tumor vessels.     

Effect of ketamine on heterogeneity of cerebral microregional venous O2 saturation in the rat

Heterogeneity of microregional O2 supply and consumption balance exists in the brain. Previous studies have shown that anesthetics such as pentobarbital and isoflurane, decrease the heterogeneity of O2 saturation in the small veins of the brain. This study was performed to determine whether ketamine, an anesthetic, would alter this heterogeneity. Rats were anesthetized with isoflurane for the cannulation of the femoral artery and vein. Ninety minutes after discontinuation of isoflurane, they either received injections with ketamine 100 mg/kg intraperitoneally (IP) (n = 7) or were used as conscious controls (n = 7). In each rat, regional cerebral blood flow (rCBF) was determined by 14C-iodoantipyrine autoradiography, and microregional arterial and venous (diameter 20-100 microns) O2 saturation was measured by microspectrophotometry in the anterior cortex, posterior cortex, and pons. The average rCBF and O2 consumption were similar between the two groups in each brain region except in the anterior cortex, where the O2 consumption of the ketamine group was slightly higher than that of the conscious animals. The average regional O2 supply-to-consumption ratios were similar in the three brain regions in both of the groups. However, there was heterogeneity of the O2 saturation in small veins in all the brain regions that we studied. The coefficient of variation [CV = (SD/mean X 100] of venous O2 saturation of the ketamine group in the anterior cortex (19.8 +/- 7.2), in the posterior cortex (18.8 +/- 9.4), and in the pons (16.7 +/- 6.5) was not significantly different from that in the conscious animals (22.8 +/- 6.4, 23.1 +/- 5.3, and 15.7 +/- 6.4, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Overexpressed phytochrome C has similar photosensory specificity to phytochrome B but a distinctive capacity to enhance primary leaf expansion

PURPOSE: Only few quantitative data are available on late effects in the healthy brain after radiosurgery. An animal model can contribute to systematically investigate such late effects. Therefore, a model applying radiosurgery at the rat brain was established. A long-term (19 months) follow up study with 66 animals after radiosurgery was carried out. METHODS AND MATERIALS: In 60 animals, an area in the frontal lobe of the brain was irradiated stereotactically with a 15 MV linac. Different doses of 20, 30, 40, 50, and 100 Gy with two field sizes (3.9 and 5.9 mm collimator) were selected, using the integrated logistic formula with input parameters from human brain. The induced alteration of the blood-brain barrier permeability was investigated by means of contrast enhanced magnetic resonance imaging. RESULTS: A first intracranial signal enhancement was observed in one animal 160 days after irradiation with 100 Gy. Beginning at 5 months all animals in the two 100 Gy groups homogeneously showed contrast enhancement, but none of the other groups. This remained until 13 months after irradiation. The volume of contrast enhancement as well as the increase of signal intensity were different between the two 100 Gy groups. After 19 months, the animals irradiated with lower doses also showed contrast enhancements, although not uniformly throughout one group. A maximum likelihood fit of the logistic formula P(D) = 1/[1 + (D50/D)k] to the incidence of late effects for the 5.9 mm collimator at 19 months after irradiation results in the parameters D50 = 37.4(-5.2,+6.1) Gy and k = 4.7 +/- 2.4. CONCLUSIONS: An animal model was established to study late normal brain tissue response. The observed late effects appeared very similar to the estimation of the integrated logistic formula for human brain. Based on these radiosurgery techniques, future experiments will focus on modifications in the irradiation modalities, i.e., irregular volumes, radiation quality or fractionation.     

Radiation therapy enhances the therapeutic effect of immunotherapy on pulmonary metastases in a murine renal adenocarcinoma model

In order to improve the efficacy of immunotherapy, we have evaluated the effects of radiation therapy combined with interleukin 2 (IL-2) treatment in a murine metastatic renal adenocarcinoma model (Renca). Pulmonary metastases were induced in Balb/c mice by intravenous injection of Renca and five days later a sublethal dose of radiation (300 rads) was administered either to the whole body or to the left lung only. One day following radiation, immunotherapy was given for 5 consecutive days of IL-2 at 5,000 Cetus units intraperitoneally, twice daily. The animals were either sacrificed on day 23 or 33 to assess tumor burden, or were followed for long term survival. We found that pretreatment with irradiation greatly enhanced the therapeutic efficacy of immunotherapy and was manifested by a significant reduction in pulmonary metastases and an increase in survival. When combined with immunotherapy, local tumor irradiation was not only as effective as whole body irradiation, but irradiation of one lung reduced the number of metastases similarly in both lungs. This suggests that local tumor irradiation may act through a systemic mechanism to increase the anti-tumor response mediated by IL-2 therapy.     

Stereotactic radiosurgery for patients with nonsmall cell lung carcinoma metastatic to the brain

BACKGROUND: A retrospective study of patients undergoing stereotactic radiosurgery for one to four brain metastases from nonsmall lung cell carcinoma (NSCLC) was performed to document outcomes and risks. METHODS: Seventy-seven patients underwent radiosurgery during a 7-year interval; 71 also underwent whole brain radiation therapy. Univariate and multivariate analyses were used to determine significant prognostic factors affecting survival. RESULTS: The overall median survival was 10 months after radiosurgery, and 15 months from the diagnosis of brain metastases. Five factors significantly affected survival: extent of systemic disease, presence of a neurologic deficit, size of the intracranial tumor, initial imaging appearance of intratumoral necrosis, and initial resection of the primary tumor of the chest. Median survival time was 26 months in a subgroup of patients with no extracranial metastases, no neurologic deficits, and a small tumor without necrosis. The authors evaluated 91 tumors with imaging. Local tumor control was achieved in 77 lesions (85%) and tumoral radiation necrosis developed in 4 lesions (4.4%). Nineteen new metastatic tumors developed during the observation interval. CONCLUSIONS: Stereotactic radiosurgery for NSCLC brain metastases is effective and is associated with few complications. The early detection of brain metastases and treatment with radiosurgery combined with radiation therapy provide the opportunity for extended high quality survival.     

Astrocytes protect against X-ray-induced neuronal toxicity in vitro

The role of neuronal damage in the radiation-induced CNS injury resulting from brain tumor therapy remains poorly understood. To begin to define the radioresponse of neurons, the survival of rat cortical neuron cultures was investigated. Neuronal survival was reduced by approximately 40% 24-48 h after irradiation with 3.5 Gy. The addition of the free radical scavenger NAC after irradiation increased neuronal survival. Neurons were also significantly less sensitive to radiation in co-cultures with astrocytes or in the presence of astrocyte-conditioned medium. Medium conditioned on astrocytes was found to acquire significant free radical scavenging capability. However, this antioxidant property does not appear to be responsible for neuronal radioprotection. The ability of astrocytes to reduce radiation-induced neuronal toxicity appears to be mediated by a soluble protein(s) of mol. wt > 10 kDa.