Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Chemotherapeutic agent permeability to normal brain and delivery to avian sarcoma virus-induced brain tumors in the rodent: observations on problems of drug delivery. 620 Jul 98

1. After s.c. and intracerebral (i.c.) inoculation, 4 neurogenic tumors of the rat (3 malignant neurinomas, 1 polymorphcellular glioma) revealed an altogether weak response towards a monotherapy with 1,3-bis(2-chloroethyl)-1-nitrosourea(BCNU), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), 1-(2-chloroethyl)-3-(4-Methylcyclohexyl)-1-nitro sourea (MeCCNU), 1-(2-hydroxyethyl)-3-(2-chloroethyl)-3-nitrosourea (OH-ethyl-CCNU), 2-[3-(2-chloroethyl)-3-nitrosoureidol]-D-glucopyranose (chlorozotocin), 5-(3,3-dimethyl-1-triazeno)-imidazol-4-carboxamide (DTIC). Cyclophosphamide (CPA) which was investigated for comparison showed the greatest therapeutic activity; in an equitoxic dosage (less than or equal to LD10), in all 4 s.c. tumors, partial or complete regression were effected only by CPA. 2. If the passage number increases, the response of transplanted neurogenic rat tumors to monochemotherapy can both increase and decrease. 3. In the monotherapy of 3 malignant neurinomas we were unable, on the whole, to observe a higher sensitivity after s.c. inoculation as compared with an i.c. inoculation of the tumor, despite a varying effectiveness of the single substances. 4. In the monotherapy of the polymorphcellular glioma a better response of the i.c. inoculated tumor was recognizable compared to the s.c. inoculated tumor. 5. A combination chemotherapy of a malignant neurinoma after s.c. and i.c. inoculation with vincristine, CPA, OH-ethyl-CNU and MeCcNU yielded a significant increase in life-span of animals with i.c. tumor, whereas s.c. tumors showed no significant growth inhibition. y. Transplanted neurogenic tumors of the rat could serve at less sensitive models for the investigation of new nitrosoureas.
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PMID:[Chemotherapy of transplanted neurogenic tumors in the rat (author's transl)]. 626 27

A 31-year-old female having a family history of neurofibromatosis 1 presented a left CPA tumor. MRI findings showed a completely extraaxial tumor, suggesting an acoustic neurinoma except for the lesion in the acoustic meatus. However, the final diagnosis was of exophytic pontine glioma. When a CPA tumor shows no lesion in the internal acoustic meatus, the possibility of exophytic pontine glioma should be considered in the differential diagnosis, especially in NF-1 patients.
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PMID:Exophytic pontine glioma mimicking acoustic neurinoma: CT and MRI appearance. 829 Jul

Cyclophosphamide is an inactive prodrug which is converted by hepatic cytochrome P450 2B1 to cytotoxic metabolites which produce interstrand DNA cross-linking in a cell cycle-independent fashion. The limited ability of these metabolites to cross the blood-brain barrier contributes to the poor activity of cyclophosphamide against brain tumors. In this study we demonstrate that replication deficient retroviral and adenoviral vector-mediated gene transfer of cytochrome P450 2B1 into 9L glioma cells significantly increases the sensitivity of these tumor cells to cyclophosphamide in vitro, and prolongs the survival of animals bearing intracerebral 9L tumors treated with cyclophosphamide in vivo. Attempts to improve the effectiveness of retrovirally mediated transduction of the P450 2B1 gene by increasing the concentration of cyclophosphamide delivered to the tumors using intracarotid and intratumoral injections did not prolong animal survival, although survival was increased when a second treatment with P450-expressing retroviral vectors and cyclophosphamide was administered. These results suggest that in situ transduction of tumor cells with the P450 2B1 gene using retroviral and adenoviral vectors increases their sensitivity to cyclophosphamide and may have a potential role in the therapy of malignant gliomas.
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PMID:Gene therapy for malignant gliomas using replication incompetent retroviral and adenoviral vectors encoding the cytochrome P450 2B1 gene together with cyclophosphamide. 878 1

Seventeen patients less than or equal to 20 years of age with newly diagnosed (n = 10) or recurrent (n = 7) malignant gliomas (anaplastic astrocytoma and glioblastoma multiforme) were treated with cyclophosphamide in association with hematopoietic cytokines (GM-CSF or G-CSF). Cyclophosphamide was given at a dose of 2 g/m2 daily for 2 days at 4-week intervals. Toxicity consisted of grade IV neutropenia and thrombocytopenia in 95% and 48% of cycles, respectively. There were no cyclophosphamide-related cardiac, pulmonary, or urothelial toxicities observed. Four of 10 patients with newly diagnosed disease demonstrated responses (three complete and one partial responses; one CR was only of 2 months duration). None of the seven patients with recurrent tumors demonstrated a response. We conclude that high-dose cyclophosphamide warrants further evaluation in children with newly diagnosed malignant glioma.
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PMID:Activity of high-dose cyclophosphamide in the treatment of childhood malignant gliomas. 940 13

Toward the goal of developing an optical imaging contrast agent that will enable surgeons to intraoperatively distinguish cancer foci from adjacent normal tissue, we developed a chlorotoxin:Cy5.5 (CTX:Cy5.5) bioconjugate that emits near-IR fluorescent signal. The probe delineates malignant glioma, medulloblastoma, prostate cancer, intestinal cancer, and sarcoma from adjacent non-neoplastic tissue in mouse models. Metastatic cancer foci as small as a few hundred cells were detected in lymph channels. Specific binding to cancer cells is facilitated by matrix metalloproteinase-2 (MMP-2) as evidenced by reduction of CTX:Cy5.5 binding in vitro and in vivo by a pharmacologic blocker of MMP-2 and induction of CTX:Cy5.5 binding in MCF-7 cells following transfection with a plasmid encoding MMP-2. Mouse studies revealed that CTX:Cy5.5 has favorable biodistribution and toxicity profiles. These studies show that CTX:Cy5.5 has the potential to fundamentally improve intraoperative detection and resection of malignancies.
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PMID:Tumor paint: a chlorotoxin:Cy5.5 bioconjugate for intraoperative visualization of cancer foci. 1763 99

Despite recent technical improvements in surgical excision techniques and adjuvant radio- and chemotherapy, the clinical outcome of patients with grade IV astrocytoma (glioblastoma) remains very poor, with a median survival of less than 12 months. A promising approach to therapy employs gene-engineered neural stem/progenitor cells (NSCs) as a cellular therapeutic delivery system, to track glioblastoma cells and deliver anticancer molecules. However, most results on their tumor tropism have been derived by immortalized NSCs. We now report that primary murine gene-engineered NSCs displayed in vivo tropism for glioblastoma cells. Ten days after injection into the brain, many NSCs continued to express the transgene and the NSC marker, nestin. NSCs transduced with a retroviral vector co-expressing a secretable form of human endostatin and eGFP (NSC/endo-eGFP) released potentially antiangiogenetic concentrations of endostatin into the culture medium. Conditioned medium of NSC/endo-eGFP cells inhibited the growth of mouse pulmonary microvascular endothelial cells (PMVECs). A good correlation between endostatin levels and PMVEC growth inhibition was observed. In NSCs co-expressing cytochrome P450 2B6 (CYP2B6) and eGFP (NSC/CYP2B6-eGFP), the forced expression of CYP2B6 resulted in intracellular activation of CPA and subsequent cell death. In the presence of NSC/CYP2B6-eGFP, we observed CPA cytotoxicity to DsRed-expressing U87Mg glioma cells. In vivo treatment of intracranial GL-261 glioblastoma with NSC/endo-eGFP caused a 65% reduction in tumor size, compared to untreated control mice or mice treated with NSC/eGFP cells. Our data suggest that primary NSCs transduced with retroviral vectors expressing endostatin and/or CYP2B6 have a potential role in glioblastoma therapy.
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PMID:Primary neural stem/progenitor cells expressing endostatin or cytochrome P450 for gene therapy of glioblastoma. 1842 9

The effect of the immunomodulatory chemotherapeutic agent cyclophosphamide (CTX) on tumor growth was investigated in primary and metastatic intracerebral and subcutaneous rat xenograft models. Nude rats were treated with CTX (100 mg/kg, intraperitoneally) 24 hours before human ovarian carcinoma (SKOV3), small cell lung carcinoma (LX-1 SCLC), and glioma (UW28, U87MG, and U251) tumor cells were inoculated subcutaneously, intraperitoneally, or in the right cerebral hemisphere or were infused into the right internal carotid artery. Tumor development was monitored and recorded. Potential mechanisms were further investigated. Only animals that received both CTX and Matrigel showed consistent growth of subcutaneous tumors. Cyclophosphamide pretreatment increased the percentage (83.3% vs 0%) of animals showing intraperitoneal tumors. In intracerebral implantation tumor models, CTX pretreatment increased the tumor volume and the percentage of animals showing tumors. Cyclophosphamide increased lung carcinoma bone and facial metastases after intra-arterial injection, and 20% of animals showed brain metastases. Cyclophosphamide transiently decreased nude rat white blood cell counts and glutathione concentration, whereas serum vascular endothelial growth factor was significantly elevated. Cyclophosphamide also increased CD31 reactivity, a marker of vascular endothelium, and macrophage (CD68-positive) infiltration into glioma cell-inoculated rat brains. Cyclophosphamide may enhance primary and metastatic tumor growth through multiple mechanisms, including immune modulation, decreased response to oxidative stress, increased tumor vascularization, and increased macrophage infiltration. These findings may be clinically relevant because chemotherapy may predispose human cancer subjects to tumor growth in the brain or other tissues.
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PMID:Cyclophosphamide enhances human tumor growth in nude rat xenografted tumor models. 1917 3

As the main effector-cell population of the central nervous system, microglia (MG) are considered to play an important immunoregulatory function in a number of pathological conditions such as inflammation, trauma, degenerative disease, and brain tumors. Recent studies, however, have suggested that the anti-neoplastic function of MG may be suppressed in malignant brain tumors. Considering the proposed suppressive role of signal transducers and activators of transcription 3 (Stat3) in antitumor immunity, we evaluated the role of Stat3 inhibition on MG and macrophage (MP) activation and tumor growth in a murine glioma model. N9 MG cells were exposed to GL261 glioma conditioned medium (GL261-CM) and evaluated for Stat3 activity and cytokine expression. Furthermore, the role of Stat3 inhibition on MG and MP activation was studied both in vitro and in vivo. Finally, the effect of Stat3 inhibition on tumor growth was assessed in intracranial GL261 gliomas. GL261-CM increased Stat3 activity in N9 cells in vitro and resulted in overexpression of IL-10 and IL-6, and downregulation of IL1-beta, a pro-inflammatory cytokine. Inhibition of Stat3 by CPA-7 or siRNA reversed glioma-induced cytokine expression profile in N9 cells. Furthermore, inactivation of Stat3 in intracranial GL261 tumors by siRNA resulted in MG/MP activation and tumor growth inhibition. Glioma-induced MG and MP suppression may be mediated thorough Stat3. Inhibition of Stat3 function in tumor MG/MP may result in their activation and can potentially be used as an adjunct immunotherapy approach for gliomas.
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PMID:Stat3 inhibition activates tumor macrophages and abrogates glioma growth in mice. 1930 72

Development of glioma-specific nanoparticles has been an area of intense research over the past several years. Iron oxide, multifunctional superparamagnetic, and NaYF(4):Yb,rare-earth upconversion nanoparticles, conjugated with chlorotoxin (CTX, a key toxin in scorpion venom which has been shown to bind specifically to glioma cell surface as a specific chloride channel and matrix metalloproteinase-2 blocker), exhibit high affinity for glioma and direct tumor visualization. We review the latest improvements of CTX-modified nanoparticle platforms which might enable development of more effective therapeutic agents in clinical treatment of glioma.
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PMID:Chlorotoxin-conjugated nanoparticles as potential glioma-targeted drugs. 2210 16


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