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PubMed2006

Synergy of gene-mediated immunoprophylaxis and microbeam radiation therapy for advanced intracerebral rat 9L gliosarcomas.

PURPOSE: Microbeam radiation therapy (MRT), a novel experimental radiosurgery that largely spares the developing CNS and other normal tissues, is tolerated well by developing animals and palliates advanced 9LGS tumors. This report, to our knowledge, is the first demonstration that gene-mediated immunotherapy (GMIMPR) enhances the efficacy of MRT for advanced 9LGS tumors. METHODS: Seventy-six male Fischer 344 rats were implanted ic with 10(4)9LGS cells on d0. By d14, the cells had generated approximately approximately 40 mm3 ic 9LGS tumours, experimental models for therapy of moderately aggressive human malignant astrocytomas. Each of the 14 untreated (control) rats died from a large (>100 mg) ic tumor before d29 (median, d21). On d14, the remaining 62 rats were given deliberately suboptimal microbeam radiation therapy (MRT) by a single lateral exposure of the tumor-bearing zone of the head to a 10.1 mm-wide, approximately approximately 11 mm-high array of 20-39 microm-wide, nearly parallel beams of synchrotron wiggler-generated radiation (mainly approximately 50-150 keV X-rays) that delivered 625 Gy peak skin doses at approximately approximately 211 microm ctc intervals in approximately approximately 300 ms either without additional treatments (MRT-only, 25 rats), with post-MRT GMIMPR (MRT+GMIMPR, 23 rats: multiple sc injections of irradiated (clonogenically-disabled) GM-CSF gene-transfected 9LGS cells), or with post-MRT IMPR (MRT+IMPR, 14 rats: multiple sc injections of irradiated (clonogenically-disabled) 9LGS cells. RESULTS: The median post-implantation survivals of rats in the MRT-only, MRT+GMIMPR and MRT+IMPR groups were over twice that of controls; further, approximately approximately 20% of rats in MRT-only and MRT+IMPR groups survived >1 yr with no obvious disabilities. Moreover, over 40% of MRT+GMIMPR rats survived >1 yr with no obvious disabilities, a significant (P<0.04) increase over the MRT-only and MRT+IMPR groups. SIGNIFICANCE: These data suggest that the combination of MRT+GMIMPR might be better than MRT only for unifocal CNS tumors, particularly in infants and young children.

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PubMed1994

Gene therapy of rat 9L gliosarcoma tumors by transduction with selectable genes does not require drug selection.

9L rat glioma cells have been used as a model for brain tumor therapies. It has been reported that in vivo infection of 9L cells with a replication-defective retrovirus expressing the herpes simplex thymidine kinase gene resulted in decreased tumor formation following treatment with the antiviral drug ganciclovir. In the study reported here, rats were injected either intracerebrally or subcutaneously with 9L glioma cells expressing a chimeric hygromycin phosphotransferase-thymidine kinase fusion protein or with unmodified 9L cells. Tumor formation was decreased in the rats receiving modified cells, even in the absence of treatment with ganciclovir. Suppression of tumor growth was also observed with cells modified to express the intracellular selectable marker neomycin phosphotransferase. These results indicate that an intracellular selectable marker, in the absence of pharmacologic selection, can inhibit tumor growth of 9L cells. The demonstration that intracellular marker genes can negatively influence the survival of transplanted cells has important implications for in vivo studies that use genetically modified cells.

Animals↗
PubMed1994

The effect of AGM-1470 in an improved intracranial 9L gliosarcoma rat model.

Angiogenesis is a process fundamental to the growth of many solid tumours. Agents that inhibit angiogenesis may have a role in preventing tumour growth. AGM-1470, a synthetic analogue of fumagillin, has been shown to inhibit tumour growth in several extracranial solid tumour models. Its use has been reported to have minimal side effects. No studies have been reported using AGM-1470 in the treatment of an intracranial tumour. To determine the effect of AGM-1470 on an intracranial glial tumour, we used an improved implantation technique to place 80,000 9L tumour cells into the right caudate nucleus of 25 male Fischer 344 rats. Starting on the first post-implantation day, 12 animals received 30 mg kg-1 AGM-1470 via intraperitoneal injection every other day until death. Thirteen control animals received vehicle only. Evidence of intracranial tumour was apparent in 22/23 animals (96%). All animals treated with AGM-1470 experienced a progressive and significant weight loss when compared to controls. At day 17, treated animals retained 80.0 +/- 2.2% of their initial weight, (mean +/- SD) compared to 100.9 +/- 3.6% for controls (p = 2.25 x 10(-12); student's t-test). AGM-1470 had no effect on survival. Median survival in the treatment group was 24.5 days compared to 25 days in the controls (p = 0.95; Mann-Whitney). AGM-1470, although promising in extracranial tumour models, may not be as effective in controlling the growth of intracranial tumours, and its use is not without significant systemic effects. More studies are needed before this drug is used in human brain tumour trials.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

The efficacy and distribution of suramin in the treatment of the 9L gliosarcoma.

Suramin inhibits the stimulation of brain tumor deoxyribonucleic acid synthesis in vitro at concentrations of 200 to 400 mg/ml. This report evaluates suramin in the rodent 9L tumor model. Survival was analyzed by treating 10 tumor-bearing animals with suramin (7 mg/kg/d intraperitoneally) for 7 days, beginning 1 week after implantation, and compared with 20 untreated animals. Tissue distribution was analyzed with reverse-phase high-pressure liquid chromatography in homogenized organs of normal animals. Tumor concentration was measured over time in animals treated with a range of suramin doses, beginning 2 weeks after implantation. Suramin imparted no benefit as tumor-bearing control animals and treated animals survived 24.7 +/- 3.4 days and 24.5 +/- 1.5 days, respectively. In the animals receiving 7 mg/kg/d, renal concentrations of suramin were highest--339.8 +/- 30.9 mg/g as late as 25 days after treatment. Concentration in the brain peaked at only 3.3 +/- 1.3 mg/g after 10 days. Concentration in the tumor peaked at 74.4 +/- 16.5 mg/g the day of the last injection, significantly less than estimated by in vitro studies of efficacy. After injections of 35 mg/kg/d, tumor levels reached 230.9 +/- 139.2 mg/g with no evidence of inhibition of tumor progression. The response to a 7 mg/kg direct brain inoculation of suramin was assessed and compared with saline as a control. Animals treated with suramin died after 1 to 3 hours. Intracerebral hematoma volume at the injection site was 13.9 +/- 10.7 mm3 and 1.9 +/- 3.32 mm3 in the suramin-treated and control animals, respectively (P = 0.02), confirming the reported anticoagulant activity of suramin. Suramin is without efficacy in the 9L model because of poor systemic delivery. Alternative direct inoculation results in lethal local hemorrhage. Further consideration is necessary before the broad clinical application of this drug.

Animals↗
PubMed1996

Sensitivity of 9L gliosarcomas to photodynamic therapy.

Photodynamic therapy (PDT) has been used clinically for the treatment of malignant brain gliomas. However, the efficacy of this treatment to date has remained equivocal. This study focused on determining the sensitivity of 9L glio sarcoma in Fischer 344 rats to PDT with increasing doses of 632 nm light and making a comparison of the responses of normal and tumor tissue in the brain at these doses. This sensitivity was then correlated with the concentrations of Photoforin present in these tissues at the time of treatment. Our study indicates that the level of Photofrin in the tumor was 13 times that present in normal brain 48 h after injection. However, this selective localization of the photosensitizer was not reflected in a selective tissue response to PDT. There was minimal tumor response to a dose of 35 J cm-2, which has been reported previously to cause necrosis to the normal brain. Increasing energy dose levels resulted in an increased tumor response to PDT; however, normal tissue remained more sensitive than tumor tissue at all energy dose levels examined. These data indicate that, although Photofrin is retained to a significantly higher degree in the tumor than in the normal brain tissue, the normal brain is more sensitive than the tumor to PDT under the conditions outlined in this study.

Animals↗
PubMed1991

31P magnetic resonance spectroscopy is sensitive to tumor hypoxia: perfusion and oxygenation of rat 9L gliosarcoma after treatment with BCNU.

The mechanism behind the relative increase in high-energy phosphates observed by MRS in many tumors following chemotherapy is poorly understood. To test the hypothesis that this metabolic activation is associated with a decrease in tumor hypoxia, tumor blood flow and oxygenation were measured in tumors that were also analyzed by MRS. 31P MR spectra were acquired with a GE 2T CSI spectrometer from subcutaneous 9L tumors in rats 4 days following treatment with BCNU (10 mg/kg) and from age-matched sham-treated control tumors. BCNU-treated tumors (n = 13) underwent a significant improvement in bioenergetic state compared to control tumors (n = 14), showing a relative increase in high-energy phosphate (Pi/phosphocreatine) (p less than 0.01), and a relative decrease in Pi (Pi/alpha nucleoside biphosphate) (p less than 0.01). Gamma camera imaging of 133Xe washout, following injection of 133Xe in saline into control and treated 9L tumors 4 days after treatment, was used to measure tumor perfusion. Sham-treated control tumors (n = 21) were perfused at a rate of 35.4 (+/- 6.4 SE) mL/100 g/min, while BCNU-treated tumors (n = 20) were perfused at a rate of 55.1 (+/- 7.5 SE) mL/100 g/min (T = 1.96; p less than 0.05). The partial pressure of oxygen (pO2), measured with a polarographic electrode was found to be significantly higher in treated 9L than in sham-treated controls.(ABSTRACT TRUNCATED AT 250 WORDS)

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