Urokinase Antisense Oligodeoxynucleotides as a Novel Therapeutic Agent for Malignant Glioma:In Vitroandin VivoStudies of Uptake, Effects and Toxicity

Engelhard, Herbert H.; Narang, Carol; Homer, Ronald J.; Duncan, Holly A.

doi:10.1006/bbrc.1996.1519

Cited by 23 publications

(18 citation statements)

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“…Studies of intraventricular phosphorothioate ODN infusion lasting 1 week did not show any evidence of toxicity, yet the ODNs permeated the brain extensively and were taken up by astrocytes [60,62]. Other investigators have confirmed the superiority of phosphorothioate ODNs for CNS administration, the cellular uptake and biodistribution of intracranially administered ODNs, and their apparent lack of adverse effects [16,[63][64][65][66]. ODNs may be more stable within the CNS than in other bodily compartments [67].…”

Section: Odn Targeting Of Brain Tumorsmentioning

confidence: 84%

“…Animal studies of ODN biodistribution have shown that ODNs administered systemically (as negatively charged molecules of approximately 5 kDa) enter the brain only in extremely small quantities [5,32,37,58,59]. Because of this, direct injection (or osmotic minipump infusion) into the CSF, brain parenchyma or tumor bed has been advocated [4,10,16,18,60,61]. Figure 3 shows a nude rat being implanted subcutaneously with an Alizet TM osmotic minipump, for the purpose of delivering antisense ODNs directly into the bed of an implanted brain tumor.…”

Section: Odn Targeting Of Brain Tumorsmentioning

confidence: 99%

“…Nonspecific effects of ODN treatment of cells have been reported, particularly for phosphorothioated ODNs used at concentrations above 20-50 ÌM [4,16,54,70,71,[86][87][88][89]. Nonspecific effects may in some cases be advantageous, such as the inhibition of the proliferation and/or migration of glioblastoma cells [70].…”

Section: Obstacles To Clinical Use Of Odns In Neuro-oncologymentioning

confidence: 99%

“…Reported target genes for antisense ODN therapy in glioma cells in vitro have included bFGF, c-erb B, c-myb, c-myc, c-sis, CD44, p34cdc2, mdm2, IGF-1, PDGF, TGF-ß, PKC·, tumor necrosis factor, urokinase, the urokinase receptor and S100ß protein [10,16,52,54,55,[68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83]. For cultured medulloblastoma cells, Liu et al [84] used antisense ODNs to block expression of leukemia inhibitory factor (LIF).…”

Section: Odn Targeting Of Brain Tumorsmentioning

confidence: 99%

“…Antisense therapy is attractive due to its theoretical specificity [12][13][14][15], and (to date) relative lack of known adverse effects, particularly when the vector or ODN is administered directly into the CNS [7,[16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

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Use of Antisense Vectors and Oligodeoxynucleotides in Neuro-Oncology

1998

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Section: Odn Targeting Of Brain Tumorsmentioning

confidence: 84%

Section: Odn Targeting Of Brain Tumorsmentioning

confidence: 99%

Section: Obstacles To Clinical Use Of Odns In Neuro-oncologymentioning

confidence: 99%

Section: Odn Targeting Of Brain Tumorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Use of Antisense Vectors and Oligodeoxynucleotides in Neuro-Oncology

1998

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Regulation of urokinase plasminogen activator (uPA) activity by E-cadherin and hormones in mammary epithelial cells

1999

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Urokinase plasminogen activator (uPA) is involved in proteolysis of extracellular matrix during development and tumor cell invasion. In the present study, we examined the regulation of uPA in hormone-responsive, noninvasive mammary epithelial cells by using fibrinolytic and caseinolytic enzyme activity assays. Urokinase PA expression was activated after contact with fibrin and initiation of cell-cell interactions that were mediated by E-cadherin. Fibrinolysis occurred in zones surrounding cellular aggregates. Stromal matrix proteins that disrupted aggregation or anti-E-cadherin antibodies that inhibited cellular compaction inhibited fibrinolysis perhaps by increasing cell-matrix adhesion or preventing E-cadherin signaling, respectively. Aggregation required the presence of divalent cations and was inhibited by serum and ethylene diaminetetraacetic acid, whereas serine protease inhibitors reduced uPA activity without affecting aggregation. Inhibitors of PA (type 2; PAI-2) and a specific antisense uPA oligonucleotide also reduced enzymatic activity, suggesting that fibrinolysis depends on translational regulation of uPA. In addition, the activation of plasmin from plasminogen was inhibited by anti-E-cadherin antibodies and PAI-2, consistent with a role for uPA. The data also support a role for transcriptional regulation of uPA activity because treatment of cells with progesterone, hydrocortisone, or dexamethasone inhibited uPA activation on fibrin without affecting cellular aggregation. Estradiol and insulin did not alter, whereas human chorionic gonadotropin and prolactin increased uPA activity. The expression of the 55-kDa uPA activity was consistent with specific hormone action and correlated with protein expression by immunoblotting. Therefore, the alteration of downstream signaling events by hormones may affect uPA production. These results indicate that uPA is an enzyme that may be important in the degradation of extracellular matrix during development and that specific E-cadherin interactions and hormones can regulate its activity. Investigation of the regulation of uPA in these cells may be useful in understanding and manipulating mammary gland remodeling. J. Cell. Physiol. 181:1-13, 1999. Published 1999 Wiley-Liss, Inc.

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Leptomeningeal Metastasis of Primary Central Nervous System (CNS) Neoplasms

Engelhard

Corsten

2005

Cancer Treatment and Research

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Abstract:Leptomeningeal dissemination of primary CNS tumors varies widely by histologic subtype. In certain tumors including medulloblastoma, ependymoma, germ cell tumors, and primary CNS lymphoma, seeding of the cerebrospinal fluid space is a critical factor in determining stage, prognosis and appropriate therapy. Other tumor types, such as glioma, may have radiographic evidence of leptomeningeal metastases without clear impact on prognosis or therapy.

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Urokinase Antisense Oligodeoxynucleotides as a Novel Therapeutic Agent for Malignant Glioma:In Vitroandin VivoStudies of Uptake, Effects and Toxicity

Cited by 23 publications

References 0 publications

Use of Antisense Vectors and Oligodeoxynucleotides in Neuro-Oncology

Use of Antisense Vectors and Oligodeoxynucleotides in Neuro-Oncology

Regulation of urokinase plasminogen activator (uPA) activity by E-cadherin and hormones in mammary epithelial cells

Leptomeningeal Metastasis of Primary Central Nervous System (CNS) Neoplasms

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