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At least 559 records · Page 31Linked to original sources
PubMed1997

Potential of Varicella zoster virus thymidine kinase as a suicide gene in breast cancer cells.

To investigate the potential of the thymidine kinase gene from Varicella zoster virus (VZVtk) to act as a suicide gene, VZVtk was transferred via a dicistronic retroviral construct into MCF7, T-47D and MDA-MB-435 human breast cancer cells. The cytotoxicity of antiviral drugs was then evaluated in vitro on the wild-type and transduced cells. Acyclovir and ganciclovir did not show any selective toxicity for the modified cells. In contrast, (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) was extremely toxic for the VZVtk expressing cells, with IC50 values of 0.6 microM, 0.1 microM and 0.06 microM for MCF7, T-47D and MDA-MB-435 cells, respectively. The selectivity index of BVDU (ie the IC50 value ratio of the wild-type to the VZVtk cells) was 400 for MCF7, 750 for T-47D and 2000 for MDA-MB-435 cells. To test the system in vivo, VZVtk carrying MDA-MB-435 cells were inoculated subcutaneously into nude mice. An intraperitoneal treatment with BVDU administered at the emergence of the tumors, led to a prolonged arrest of the tumor growth and a reduced tumor mass. This effect was BVDU dose-dependent. No bystander effect of BVDU killing could be demonstrated in vitro on mixed populations of VZVtk positive and negative MDA-MB-435 cells. However, an important bystander effect was observed in identical experiments performed on 9L rat gliosarcoma cells infected with the VZVtk-carrying vector. These results demonstrate the efficiency of VZVtk as a suicide gene when BVDU is used as prodrug. The bystander effect measured in vitro, depends however on the tumoral cell type used.

3T3 Cells↗
PubMed1999

Effective cytokine gene therapy against an intracranial glioma using a retrovirally transduced IL-4 plus HSVtk tumor vaccine.

To explore the potential for molecular immunotherapies in the treatment of malignant gliomas, we evaluated the efficacy of subcutaneous tumor cell vaccines in the treatment of intracranial 9L tumors, using 9L gliosarcoma cell lines stably transduced with the murine interleukin-4 cDNA (9L-IL4), the herpes simplex virus-thymidine kinase cDNA (9L-Tk) or both (9L-IL4-Tk). The expression of multiple genes from a single transcript was achieved by incorporating internal ribosomal entry site (IRES) cassettes in the retroviral constructs. Subcutaneous immunization of rats with nonirradiated 9L-IL4 cells or 9L-IL4-Tk cells followed by treatment with ganciclovir (GCV) completely protected the animals from a subsequent intracranial challenge with wild-type 9L cells. In contrast, only 50% of animals immunized with 9L-Tk cells and 0% of 9L-neo immunized animals rejected the same challenge with wild-type 9L. More importantly, treatment of established (day 3) intracranial 9L tumors with genetically engineered tumor cells resulted in long-term survival (> 100 days) for 25-43% of 9L-IL4-Tk immunized animals and for 27% of nonirradiated 9L-IL4 immunized animals. In striking contrast, no 9L-Tk, 9L-neo or irradiated 9L-IL4 immunized animals survived for more than 33 days. As a marker of a cellular immune response, splenocytes from nonirradiated 9L-IL4, 9L-Tk or 9L-IL4-Tk immunized animals produced interferon-gamma (IFN-gamma) in greater amounts than those from 9L-neo immunized or Hank's balanced salts solution (HBSS) treated animals when stimulated with wild-type 9L in vitro. Our findings support the use of tumor cell vaccines expressing the IL-4 and HSVtk genes for the treatment of malignant gliomas.

Animals↗
PubMed2001

Cytokine gene therapy of gliomas: effective induction of therapeutic immunity to intracranial tumors by peripheral immunization with interleukin-4 transduced glioma cells.

To provide a means for comparing strategies for cytokine gene therapy against intracranial (i.c.) tumors, we generated rat gliosarcoma 9L cells transfected with interleukin-4 (9L-IL4), interleukin-12 (9L-IL12), granulocyte-macrophage colony-stimulating factor (9L-GMCSF) or interferon-alpha (9L-IFNalpha). To simulate direct and highly efficient cytokine gene delivery, cytokine transfected 9L tumors were implanted i.c. into syngeneic rats. i.c. injection led to tumor-outgrowth in the brain and killed most animals, whereas these cell lines were rejected following intradermal (i.d.) injection. Cytokine-expressing i.c. 9L tumors, however, had a greater degree of infiltration by immune cells compared with control, mock-transfected 9L-neo, but to a lesser degree than i.d. cytokine-expressing tumors. Tumor angiogenesis was suppressed in cytokine-transfected tumors. In a prophylaxis model, i.d. vaccination with 9L-IL4 resulted in long-term survival of 90% of rats challenged i.c. with parental 9L; whereas 40% of 9L-GM-CSF, 40% of 9L-IFNalpha and 0% of 9L-IL12-immunized rats were protected. In a therapy model (day 3 i.c. 9L tumors), only i.d. immunization with 9L-IL4 had long-term therapeutic benefits as 43% of rats survived >100 days. These data indicate that peripheral immunization with 9L-IL4 had the most potent therapeutic benefit among various cytokines and approaches tested against established, i.c. 9L tumors.

Animals↗
PubMed2002

Double suicide gene therapy using a replication defective herpes simplex virus vector reveals reciprocal interference in a malignant glioma model.

Herpes simplex virus thymidine kinase (HSV-TK) and Escherichia coli cytosine deaminase (CD) are non-mammalian enzymes capable of converting innocuous prodrugs into cytotoxic metabolites. Both enzymes have been utilized independently, as well as together in 'suicide' gene therapy protocols to eliminate tumor cells in vitro and in vivo. We have used a set of replication defective HSV vectors expressing either or both enzymes to compare the efficacies of single and double suicide gene therapies in the 9L gliosarcoma model in vitro and in vivo. In cell culture experiments at high and low multiplicities of infection, combined expression of the two genes by vector TOCD/TK along with exposure to the matching prodrugs (ganciclovir and 5-fluorocytosine) showed increased cytotoxicity compared with exposure to either prodrug alone. However, the two gene combination was inferior to single gene treatments, suggesting that HSVtk and CD are mutually counteractive in the prodrug-dependent killing of glioma cells. In animal experiments, survival was not significantly prolonged by administration of both prodrugs to TOCD/TK-treated animals, while each single gene/prodrug pair resulted in increased survival. These results indicate that single suicide gene systems employing HSVtk or CD may be preferable over combinations of the two.

Animals↗
PubMed2004

Intra-arterial delivery of endostatin gene to brain tumors prolongs survival and alters tumor vessel ultrastructure.

Glioblastoma multiforme (GBM) is an incurable malignant brain tumor, usually fatal within 1 year of diagnosis. Using a syngeneic rat 9L gliosarcoma model, we have developed a novel drug delivery method in which naked plasmid DNA is selectively targeted to brain tumors via intra-arterial injection. Using a plasmid encoding the antiangiogenic endostatin, transgene expression can be detected in tumor cells in vivo, and therapeutic efficacy is observed. Administration of this plasmid resulted in an 80% tumor volume reduction 1 week after treatment and enhanced survival time by up to 47%. Treated tumors exhibited a 40% decrease in the number of tumor vessels; ultrastructural analysis of remaining tumor vessels demonstrated a number of changes including markedly narrowed or collapsed lumens. We conclude that intra-arterial injection of plasmids selectively targets therapeutic genes to CNS neoplasms. This method of gene therapy holds promise for the treatment of these highly malignant brain tumors.

Animals↗
PubMed1999

Functional coexpression of HSV-1 thymidine kinase and green fluorescent protein: implications for noninvasive imaging of transgene expression.

Current gene therapy technology is limited by the paucity of methodology for determining the location and magnitude of therapeutic transgene expression in vivo. We describe and validate a paradigm for monitoring therapeutic transgene expression by noninvasive imaging of the herpes simplex virus type 1 thymidine kinase (HSV-1-tk) marker gene expression. To test proportional coexpression of therapeutic and marker genes, a model fusion gene comprising green fluorescent protein (gfp) and HSV-1-tk genes was generated (tkgfp gene) and assessed for the functional coexpression of the gene product, TKGFP fusion protein, in rat 9L gliosarcoma, RG2 glioma, and W256 carcinoma cells. Analysis of the TKGFP protein demonstrated that it can serve as a therapeutic gene by rendering tkgfp transduced cells sensitive to ganciclovir or as a screening marker useful for identifying transduced cells by fluorescence microscopy or fluorescence-activated cell sorting (FACS). TK and GFP activities in the TKGFP fusion protein were similar to corresponding wild-type proteins and accumulation of the HSV-1-tk-specific radiolabeled substrate, 2'-fluoro-2'-deoxy-1beta-D-arabinofuranosyl-5-iodo-uracil (FIAU), in stability transduced clones correlated with gfp-fluorescence intensity over a wide range of expression levels. The tkgfp fusion gene itself may be useful in developing novel cancer gene therapy approaches. Valuable information about the efficiency of gene transfer and expression could be obtained by non-invasive imaging of tkgfp expression with FIAU and clinical imaging devices (gamma camera, positron-emission tomography [PET], single photon emission computed tomography [SPECT]), and/or direct visualization of gfp expression in situ by fluorescence microscopy or endoscopy.

Animals↗
PubMed1998

PTEN mutations in gliomas and glioneuronal tumors.

Cytogenetic and loss of heterozygosity studies have suggested the presence of at least one tumor suppressor gene on chromosome 10 involved in the formation of high grade gliomas. Recently, the PTEN gene, also termed MMAC1 or TEP1, on chromosomal band 10q23 has been identified. Initial studies revealed mutations of PTEN in limited series of glioma cell lines and glioblastomas. In order to systematically evaluate the involvement of PTEN in gliomas, we have analysed the entire PTEN coding sequence by SSCP and direct sequencing in a series of 331 gliomas and glioneuronal tumors. PTEN mutations were detected in 20/142 glioblastomas, 1/7 giant cell glioblastomas, 1/2 gliosarcomas, 1/30 pilocytic astrocytomas and 2/22 oligodendrogliomas. No PTEN mutations were detected in 52 astrocytomas, 37 oligoastrocytomas, three subependymal giant cell astrocytomas, four pleomorphic xanthoastrocytomas, 15 ependymomas, 16 gangliogliomas and one dysembryoplastic neuroepithelial tumor. In addition, all tumors were examined for the presence of homozygous deletions of the PTEN gene; these were detected in 7 glioblastomas that did not have PTEN mutations. Therefore, PTEN mutations occur in approximately 20% of glioblastomas but are rare in lower grade gliomas. These findings confirm that PTEN is one of the chromosome 10 tumor suppressor genes involved in the development of glioblastomas.

Female↗
PubMed1999

Regulation of interleukin-8 expression by reduced oxygen pressure in human glioblastoma.

Oxygen deprivation is an important biological feature of tumor growth. We previously showed that in glioma, anoxia increases expression of IL-8, a chemokine and angiogenic factor. Here, we analysed for the first time the biochemical mechanisms inducing the IL-8 gene upon anoxia in glioma cells, and showed that they differ from those inducing the VEGF gene. Both genes are induced in biologically and genetically heterogenous glioblastoma cell lines (LN-229, LN-Z308, U87MG, T98G), whereas, in gliosarcoma cells (D247MG), only the VEGF gene is induced. The kinetics of IL-8 and VEGF mRNA inductions differ in these cells and reoxygenation experiments showed that the induction is due to the anoxic stress per se. Furthermore, in LN-229 and LN-Z308 cell lines actinomycin D, DRB and nuclear run-on experiments showed that anoxia stimulates increased transcription of both genes. Electromobility shift assays show increased protein binding to the AP-1 site on the IL-8 promoter following anoxia treatment. Finally, in situ hybridization on glioblastoma sections shows that the in vivo expression patterns of IL-8 and VEGF genes overlap, but are not identical. Since intratumoral augmentation of IL-8 and VEGF secretion, following microenvironmental decreases in oxygen pressure, may promote angiogenesis, further definition of these pathways is essential to appropriately target them for antitumoral therapy.

Animals↗
PubMed2002

Dural lesions mimicking meningiomas.

Recently, a number of neoplastic and nonneoplastic entities have been reported that radiographically and clinically mimic meningiomas. Because these lesions occur infrequently and may resemble a meningioma during intraoperative analysis, they may not be considered in the differential diagnosis. This review (and case illustrations) considers some of the newly recognized and notable lesions that can mimic meningiomas, including solitary fibrous tumors, gliosarcomas, leiomyosarcomas, hemangiopericytomas, melanocytomas, Hodgkin's disease, plasmacytomas, inflammatory pseudotumors, neurosarcoidosis, plasma cell granulomas, Rosai-Dorfman disease, Castleman's disease, xanthomas, rheumatoid nodules, and tuberculomas. Awareness that these lesions involve the dura may facilitate intraoperative recognition and, in some cases, preclude unnecessary additional surgery.

Adolescent↗
PubMedDate not supplied

Dexamethasone inhibits glioma-induced formation of capillary like structures in vitro and angiogenesis in vivo.

Dexamethasone is used frequently in brain tumor therapy of patients. In animal models it is known to inhibit the angiogenesis of solid tumors. We addressed the question, if this is also true in brain tumors. C6 malignant glioma and 9L gliosarcoma cells were implanted into rat-brains. Dexamethasone 3 mg/kg/d intraperitoneal increased the survival compared to saline treated controls. The tumors size and the vascular density were smaller in the dexamethasone groups in both models. In vitro dexamethasone inhibited the growth of the C6 cells but not of 9L cells. Thus the growth inhibition of brain tumors in vivo appeared to be mediated partly by direct growth inhibition of tumor cells in C6 cells but additionally by antiangiogenesis in both tumor models. Several in vitro models were used to address the mechanisms of antiangiogenesis. There was no effect of dexamethasone on the proliferation of central nervous endothelial cells and no effect on the formation of capillary like structures on matrigel. Dexamethasone inhibited, however, the formation of capillary like structures in a coculture model with glioma cells in vitro. Surprisingly, progesterone had the same effect in this model. The in vitro effect was mediated via glucocorticoid receptors since receptor antagonists could inhibit it. The primary target appeared to be the tumor cell because only this cell had the complete set of receptors. These data show, that antiangiogenic therapeutic effects are possible by influencing primarily the tumor cell. This way of targeting might be of value for future developments of new strategies.

Animals↗
PubMed2007

Combination angiostatic therapy completely inhibits ocular and tumor angiogenesis.

Angiostatic therapies designed to inhibit neovascularization associated with multiple pathological conditions have only been partially successful; complete inhibition has not been achieved. We demonstrate synergistic effects of combining angiostatic molecules that target distinct aspects of the angiogenic process, resulting in the complete inhibition of neovascular growth associated with development, ischemic retinopathy, and tumor growth, with little or no effect on normal, mature tissue vasculature. Tumor vascular obliteration using combination angiostatic therapy was associated with reduced tumor mass and increased survival in a rat 9L gliosarcoma model, whereas individual monotherapies were ineffective. Significant compensatory up-regulation of several proangiogenic factors was observed after treatment with a single angiostatic agent. In contrast, treatment with combination angiostatic therapy significantly reduced compensatory up-regulation. Therapies that combine angiostatic molecules targeting multiple, distinct aspects of the angiogenic process may represent a previously uncharacterized paradigm for the treatment of many devastating diseases with associated pathological neovascularization.

Angiogenesis Inhibitors↗
PubMed2002

An anti-transferrin receptor-avidin fusion protein exhibits both strong proapoptotic activity and the ability to deliver various molecules into cancer cells.

We have developed an antibody fusion protein (anti-rat TfR IgG3-Av) with the ability to deliver different molecules into cancer cells. It consists of avidin genetically fused to the C(H)3 region of a human IgG3 specific for the rat transferrin receptor. It forms strong, noncovalent interactions with biotinylated molecules such as glucose oxidase and beta-galactosidase, and delivers them into the rat myeloma cell line Y3-Ag1.2.3 through receptor-mediated endocytosis. Importantly, the beta-galactosidase retains activity after internalization. Furthermore, we have unexpectedly discovered that anti-rat TfR IgG3-Av, but not a recombinant anti-rat TfR IgG3 or a nonspecific IgG3-Av, possesses proapoptotic activities against Y3-Ag1.2.3 and the rat T cell lymphoma cell line C58 (NT) D.1.G.OVAR.1. These activities were not observed in two rat cell lines of nonhematopoietic lineage (bladder carcinoma BC47 and gliosarcoma 9L). Anti-human TfR IgG3-Av also demonstrated proapoptotic activity against the human erythroleukemia cell line K562. Studies showed that anti-rat TfR IgG3-Av exists as a dimer, suggesting that cross-linking of the surface transferrin receptor may be responsible for the cytotoxic activity. These findings demonstrate that it is possible to transform an antibody specific for a growth factor receptor that does not exhibit inhibitory activity into a drug with significant intrinsic cytotoxic activity against selected cells by fusing it with avidin. The antitumor activity may be enhanced by delivering biotinylated therapeutics into cancer cells. Further development of this technology may lead to effective therapeutics for in vivo eradication of hematological malignancies, and ex vivo purging of cancer cells in autologous transplantation.

Animals↗
PubMed2000

Brain-enriched hyaluronan binding (BEHAB)/brevican cleavage in a glioma cell line is mediated by a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family member.

Brain-enriched hyaluronan binding (BEHAB)/brevican is a brain-specific extracellular matrix protein containing a cleavage site between Glu(395)-Ser(396), which bears remarkable homology to the "aggrecanase" site in the cartilage proteoglycan aggrecan. Expression of BEHAB/brevican is dramatically increased in human gliomas, notoriously invasive tumors. Recently, we showed that the rat 9L gliosarcoma cell line, which does not express BEHAB/brevican and forms non-invasive tumors when grown as intracranial grafts, can form invasive tumors when transfected with a 5' cDNA fragment of BEHAB/brevican, but not when transfected with the full-length cDNA. In marked contrast, the highly invasive CNS-1 glioma cell line expresses and cleaves BEHAB/brevican protein when grown as an intracranial graft. These results suggest that both synthesis and cleavage of BEHAB/brevican protein may play a role in the invasiveness of gliomas. We report here, using an antibody developed to the neoepitope created by BEHAB/brevican cleavage at the Glu(395)-Ser(396) site, that the CNS-1 cells are able to cleave the protein in vitro. We characterized the CNS-1-derived cleavage activity by assaying its ability to cleave BEHAB/brevican proteoglycan, and determined that the enzyme is a constitutively expressed, secreted activity. Using a variety of protease inhibitors, reverse transcriptase-polymerase chain reaction, and specific antibodies, we determined that this activity is likely to be a member of the ADAMTS family of metalloproteinases, specifically ADAMTS4. These results suggest a novel function for ADAMTS family members in BEHAB/brevican cleavage and glioma and indicate that inhibition of ADAMTS in glioma may provide a novel therapeutic strategy.

ADAM Proteins↗
PubMed2006

Cytotoxicity of doxorubicin bound to poly(butyl cyanoacrylate) nanoparticles in rat glioma cell lines using different assays.

The cytotoxicity of doxorubicin bound to poly(butyl cyanoacrylate) nanoparticles (Dox-PBCA-NP) was investigated in the rat glioma cell lines GS-9L, F-98 and RG-2. MTT and LDH assays were used as cytotoxic assays. In general, the cytotoxicity of nanoparticle-bound doxorubicin (Dox) was enhanced compared to the free drug in solution. However, responses of the cell lines towards the drug effects were different. In the case of free Dox in solution, this difference correlated with different intracellular concentrations of Dox, which in turn, depended on the level of P-glycoprotein (P-gp) expression in these cell lines. Accordingly, the 9L gliosarcoma (GS-9L) cells, which appeared to be most resistant towards Dox, were characterized by the highest P-gp expression.Additionally, the influence of surfactants on the cytotoxic effect was investigated at different Dox concentrations. It was shown that the presence of polysorbate 80 (Tween 80) in the nanoparticle formulation significantly enhanced the cytotoxicity, whereas poloxamer 188 (Pluronic F68) and poloxamine 908 (Tetronic 908) had a negligible influence.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Improved herpes simplex virus type 1 amplicon vectors for proportional coexpression of positron emission tomography marker and therapeutic genes.

For the development of efficient and safe gene therapy protocols for clinical application it is desirable to determine the tissue dose of vector-mediated therapeutic gene expression noninvasively in vivo. The herpes simplex virus type 1 thymidine kinase gene (HSV-1-tk) has been shown to function as a marker gene for the direct noninvasive in vivo localization of thymidine kinase (TK) expression by positron emission tomography (PET). Using bicistronic or multicistronic gene-expressing cassettes with tk as the PET marker gene, the quantitative analysis of tk gene expression may indirectly indicate the distribution and the level of expression of linked and proportionally coexpressed genes. Here, we describe the construction and functional evaluation of HSV-1 amplicon vectors mediating proportional coexpression of HSV-1-tk as PET marker gene and the enhanced green fluorescent protein gene (gfp) as proof of principle and cell culture marker gene and the Escherichia coli cytosine deaminase (cd) as therapeutic gene. Several double-/triple-gene constructs expressing HSV-1-tk, gfp, and E. coli cd were engineered based on gene fusion or the use of an internal ribosome entry site (IRES). Functional analysis in cell culture (green fluorescent protein [GFP] fluorescence and sensitivity to the prodrugs ganciclovir [GCV] and 5-fluorocytosine [5-FC]) and Western blots were carried out after infection of proliferating rat 9L gliosarcoma and human Gli36 glioma cells with helper virus-free packaged HSV-1 amplicon vectors. To study the ability of PET to differentiate various levels of tk expression noninvasively in vivo, retrovirally transduced and selected populations of rat F98 and human Gli36dEGFR glioma cells with defined levels of proportionally coexpressed tk and gfp genes were grown as subcutaneous tumors in nude rats and nude mice, and tk imaging by PET was performed. To study HSV-1 amplicon vector-mediated gene coexpression in vivo, HSV-1 amplicon vectors bearing coexpression constructs were injected (4 x 10(7) to 1 x 10(8) transducing units) into subcutaneously growing Gli36dEGFR gliomas in nude animals, and tk imaging was performed 24 hr later. All vector constructs mediated GFP expression and sensitized 9L and Gli36 cells toward GCV- and 5-FC-mediated cell killing in a drug dose-dependent manner, respectively. The levels of gene expression varied depending on the location of the genes within the constructs indicating the influence of the IRES on the level of expression of the second gene. Moreover, functional proportional coexpression of the PET marker gene HSV-1-tk and the linked therapeutic E. coli cd gene was observed. In selected tumor cell populations, subtle IRES-dependent differences of tk gene expression could be noninvasively distinguished by PET with good correlation between quantitative assays for IRES-dependent attenuated GFP and TK expression in culture and in vivo. After infection of subcutaneously growing gliomas with HSV-1 amplicon vectors, various levels of TK expression were found ranging from 0.011-0.062 percentage injected dose per gram (%ID/g). These values were 4.0- to 5.7-fold lower than positive control tumor cells. TK expression could be imaged by PET in vivo even with the tk gene located at the weak position downstream from the IRES. In conclusion, these HSV-1 amplicon vectors carrying HSV-1-tk as PET marker gene and any linked therapeutic gene will serve an indirect noninvasive assessment of the distribution of therapeutic gene expression by PET. Monitoring the correlation between primary transduction and therapeutic efficiency of a given vector is highly desirable for the development of safe and efficient gene therapy and vector application protocols in clinical applications.

Animals↗
PubMed1976

Dianhydrogalactitol (NSC-132313): pharmacokinetics in normal and tumor-bearing rat brain and antitumor activity against three intracerebral rodent tumors.

Dianhydrogalactitol (DAG; NSC-132313), a hexitol epoxide, was used to treat intracerebral rodent tumors. DAG was most active against the murine ependymoblastoma [treated/controls (T/C)greater than 440%], less active against murine glioma 26 (T/C approximately 112-150%), and least active against rat 9L gliosarcoma (T/C approximately 100%). Application of a two-compartment open model for plasma disappearance of 14C-DAG in rats gave a volume of distribution at steady state of approximately 872 ml, a clearance of approximately 9.4 ml/minute, and an elimination constant of 0.025/minute. Entry of 14C-DAG was more rapid into the 9L tumor than into the normal brain. When a two-compartment series model for brain and tumor entry was applied, the t1/2 (half-time) for compartmental equilibrium was approximately 22 and 105 minutes in the brain, and 4 and 56 minutes in the 9L tumor. The drug rapidly entered the brain and tumor intracellular compartments. Binding to RNA was linear with time, and the absolute amount of binding was approximately six times greater for RNA than for DNA.

Animals↗
PubMed1979

Human brain tumor transplantation into nude mice.

Seven human brain tumors were transplanted into the brains (6/7 takes) and subcutaneous tissues (7/7 takes) of athymic nude mice. Compared to experimental animal brain tumors, these tumors, taken directly from patients in the operating room and transplanted, grew more slowly in the mice; their growth rates following explant generally paralleled those in the patients. A rough correlation was seen between the degree of the tumor's malignancy and both successful take and rate of growth following explant. The tumors' growth rates increased during serial transplantation after explant. Two tumors developed into long-term serial lines; both came from gliosarcomas. Preliminary chemotherapy experiments with these two lines demonstrated different chemosensitivities. One line was very sensitive to the nitrosoureas and resistant to procarbazine; the other line was more sensitive to procarbazine than to the nitrosoureas. This model permits study of the biologic behavior of human brain tumors growing intracerebrally and subcutaneously in nude mice.

Animals↗
PubMed1989

5-Iodo-2-deoxyuridine administered into the lateral cerebral ventricle as a radiosensitizer in the treatment of disseminated glioma.

A rat brain tumor model (Fischer 344 rats) with the clinical and pathological features of dissemination via the cerebrospinal fluid (CSF) pathways was used to demonstrate the efficacy of 5-iodo-2-deoxyuridine (IUDR) as a radiosensitizer when it is administered directly into the CSF. Stereotaxic implantation of 9L gliosarcoma cells (5 X 10(5) into the CSF of the lateral cerebral ventricle resulted in widespread dissemination and median survival of 18.5 and 20 days (range, 10-22) in two experiments. A continuous 7-day infusion of IUDR into the CSF starting on the day of tumor implantation did not provide any beneficial effect. Irradiation of the cranial spinal axis with 800 rad on days 4, 6, and 7 after implantation achieved an increase in survival time that was modest but statistically significant. However, the combination of IUDR infusion and radiotherapy resulted in marked improvement in survival time and a 10% cure rate (two of 20 rats). This is the first demonstration in vivo that IUDR administered into the CSF can be a potent radiosensitizer.

Animals↗