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WO1998052577A1 - Apoptose de cellules neuronales induite par un ganglioside gm3 - Google Patents

Apoptose de cellules neuronales induite par un ganglioside gm3 Download PDF

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Publication number
WO1998052577A1
WO1998052577A1 PCT/US1998/010390 US9810390W WO9852577A1 WO 1998052577 A1 WO1998052577 A1 WO 1998052577A1 US 9810390 W US9810390 W US 9810390W WO 9852577 A1 WO9852577 A1 WO 9852577A1
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WIPO (PCT)
Prior art keywords
cells
tumor
ganglioside
cultures
apoptosis
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Application number
PCT/US1998/010390
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English (en)
Inventor
Robert H. Miller
Elizabeth Noll
Yuji Nakasuji
Peter Mclaren Black
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Case Western Reserve University
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Filing date
Publication date
Application filed by Case Western Reserve University filed Critical Case Western Reserve University
Priority to CA002290598A priority Critical patent/CA2290598A1/fr
Priority to EP98922465A priority patent/EP0998294A4/fr
Priority to IL13308598A priority patent/IL133085A0/xx
Priority to AU75003/98A priority patent/AU7500398A/en
Priority to JP55062798A priority patent/JP2002510291A/ja
Publication of WO1998052577A1 publication Critical patent/WO1998052577A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the simple ganglioside GM3, a naturally occurring ligand, has been found to selectively regulate cell proliferation and induce apoptosis of astrocytes.
  • GM3 has been determined to be useful as a selective chemotherapeutic agent for treating high grade gliomas in human patients.
  • Apoptosis plays an important role in the development of the central nervous system (CNS).
  • CNS central nervous system
  • Gangliosides surface components of all mammalian cells, are highly expressed in the CNS compared to many other tissues ( Fishman, P.H. and R.O.
  • gangliosides Brady, Biosynthesis and function of gangliosides, Science, 1976, 194: p.906-915; Ledeen, R.W. and R.K. Yu, Gangliosides: structure, isolation and analysis, Methods Enzymol, 1982, 83: p. 1309-191).
  • Specific ganglioside expression is developmentally regulated (Irwin, L.N. and C.C. Irwin, Developmental changes in ganglioside composition of hippocampus, retina and optic tectum, Dev. Neurosci.,
  • GD3 ganglioside is a glycolipid characteristic of immature neuroectodermal cells, J. Neuroimmunol., 1984, 7: p. 179-192).
  • the highest levels of GD3 and GM3 expression correlate with periods of local cell proliferation suggesting that gangliosides might regulate growth and differentiation of CNS neural cells (Bremer,
  • Gangliosides are present in the plasma membrane of most mammalian cells and are enriched in the central nervous system (CNS) (P.H. Fishman, R.O. Brady, Science 194: p. 906-15 (1976); R.W. Ledeen, R.K. Yu, Methods Enzymol 83: p. 139-91 (1982)).
  • the expression of the gangliosides is developmentally regulated in the brain, and the simplest ganglioside GM3 is expressed predominantly in rat brain until embryonic day 16 (El 6), and at lower levels during further development (R.K. Yu, L.J. Macala, T. Taki, H.M. Weinfield, F.S. Yu, J. Neurochem 50: p. 1825-9 (1988)), with low levels of expression persisting throughout adulthood.
  • GM3 is expressed in the ventricular zone of early human brain development (M.
  • GM3 is intensely expressed in the white matter and layer VI of cerebrum (M. Kotani, et al., Glycobiology, 4: p. 855-65 (1994)).
  • exogenously added gangliosides are rapidly incorporated into the plasma membranes of cells (T.W. Keenan, E. Schmid, W.W. Franke, H. Wiegandt, Exp. Cell Res. 92: p. 259-70 (1975); R.A.
  • BHK fibroblast cell line (E.G. Bremer, S. Hakomori, Biochem. Biophys. Res. Commun. 106: p. 711-8 (1982)), and insulin driven HL-60 leukemia cell line (N. Nojiri, M. Stroud, S. Hakomori, J. Biol. Chem. 266: p. 4531-7 (1991)), are inhibited by exogenously added GM3.
  • the phosphorylation of the appropriate receptors, EGF-receptor (R), PDGF-R, and Insulin-R, are inhibited by GM3 (E.G.
  • GM1 Another ganglioside, GM1 has supportive effects on CNS neurons (C.L. Schengrund, Brain Res. Bull. 24: p. 131-41 (1990)). Less is known about the supportive effects of GM3. GM3 also inhibits cell growth and modulates cell differentiation of the human leukemia cell lines HL-60 and U937, and induces monocytic differentiation (N. Nojiri, F. Takaku, Y. Terui, Y. Miura, M.
  • gangliosides are abundant in brain, little is known about their function on CNS cells especially during development.
  • Gangliosides have been proposed to regulate cellular differentiation in neurons (Cannella, M.S., et al., Comparison of epi-GM3 with GM3 and GM1 as stimulators of neurite outgrowth, Devel. Brain. Res., 1988, 39: p. 137-143;
  • CNS tumors account for approximately 2% of all adult malignancies (Giles, G.G., B.K. Armstrong, and L.N. Smith, Cancer in Australia, 1987), but are responsible for disproportionately high number of years of life lost (Hoffman, R.M., ed. Fertile seed and rich soil; The development of clinically relevant models of human cancer by surgical orthotopic implantation of intact tissue,
  • GBM glioblastoma multiforme
  • the present invention relates to the ability of the ganglioside, GM3 to inhibit proliferation and induce apoptosis in proliferating CNS cells.
  • the present invention further demonstrates the ability for GM3 to reduce cell numbers in primary cultures of rapidly proliferating human glial tumors and the 9L rat gliosarcoma cell line.
  • GM3 is shown to have no effect on quiescent cultures of normal human CNS cells.
  • a single injection of GM3 three days after intracranial implantation of tumor cells in a murine xenograft model system resulted in a significant increase in the symptom-free survival period of host animals. Therefore,
  • GM3 is useful as a chemotherapeutic agent for human high grade gliomas.
  • a first aspect of the invention includes a novel chemotherapeutic agent for inducing apoptosis in proliferating neural cells comprising GM3.
  • a second aspect of the invention relates to selective induction of apoptosis in proliferating neural cells using a GM3 chemotherapeutic agent.
  • a further aspect of the invention relates to treatment of a patient having a brain tumor to inhibit proliferation and induce apoptosis of proliferating neural cells in said patient.
  • An additional aspect of the invention relates to a chemotherapeutic regimen to treat patients in need thereof. Therefore, the present invention has the advantage of being able to selectively treat brain tumors including high grade gliomas in patients thereby enhancing the prognosis of the patients by effectively increasing the median survival time for such patients.
  • Another advantage relates to the use of a chemical agent normally produced in the body in a chemotherapeutically effective composition thereby reducing the risk of adverse side effects typically related to such treatments.
  • FIGURE 1 shows TUNEL labeling showing DNA fragmentation for proliferating astrocyte cells treated with 50 ⁇ M GM3.
  • FIGURE 2A and 2B show proliferative astrocyte morphology without
  • FIGURE 3A and 3B show the effect of GM3 on non-proliferative astrocytes.
  • FIGURE 4 shows TUNEL labeling showing DNA fragmentation for proliferating neurons and glial precursor cells treated with GM3.
  • FIGURE 5 shows the effect of GM3 treatment on human glial tumor growth and on rat 9L cell line in vitro.
  • FIGURE 6A-6E show morphological changes in control cell cultures (6A, 6C) and GM3 treated cell cultures (6B, 6D, 6E).
  • FIGURE 7 shows the effect of increasing the concentration of GM3 on human glioblastoma multiforms (GBM's) in vitro.
  • FIGURE 8 shows the effects of GM3 on normal human central nervous system (CNS) tissue cultures.
  • FIGURE 9 shows the effect of GM3 treatment on survival time of animals implanted with 9L rat tumor cells.
  • GM3 treatment of human CNS tumor cells inhibits their growth in vitro and results in prolonged symptom-free post-implant intervals in a xenograft brain tumor model.
  • GM3 may act to both inhibit tumor cells proliferation, as well as to induce apoptosis in actively proliferating cells. Consistent with this hypothesis, GM3 treatment resulted in a significant inhibition of proliferation of rat neural cell precursors and a rapid induction of apoptosis which is correlated with an up regulation of p27 k ⁇ p" ' expression and a reduction of pRb (hyperphosphorylated retinoblastoma protein) expression.
  • pRb hyperphosphorylated retinoblastoma protein
  • the degree of response of cultures to GM3 exposure appears to be cell or tumor specific. While all tumors studied in the present invention were characterized as glioblastoma multiforme (GBM) and where grown at similar densities under identical conditions, their response to GM3 varied. In some cultures the reduction in cell number was greater than 80%, while in parallel experiments using cultures of a different tumor, the reduction in cell number was only 35%. This difference in response to GM3 treatment is unlikely to be due to culture passage number since the seven primary cultures were derived from the original plating, or early passages of the resected tumor.
  • GBM glioblastoma multiforme
  • Non-proliferative rodent CNS cells do not undergo apoptosis in response to GM3 treatment in vitro, but rather become increasingly differentiated.
  • intraventricular injection of GM3 into developing rats results in cell death only in ventricular and subventricular proliferating cell populations.
  • GM3 did not reduce cell number in quiescent cultures of normal human brain cells and there were no changes in neurological behavior associated with injection of GM3 in rats.
  • cells in cultures of different tumors may have different cell cycle times and the response to GM3 may be directly correlated with cell cycle time (i.e. faster cycle times result in increased cell death).
  • the present invention demonstrates that GM3 treatment significantly decreased the growth of primary cultures of human and rodent tumor cells, while not significantly altering cell number in quiescent cultures of normal human brain.
  • a single treatment with GM3 significantly extended the symptom-free, post implant period in nude mice with intracranially implanted rat 9L brain tumor cells.
  • GM3 provides an effective therapeutic treatment for human high grade gliomas.
  • the GM3 used in the examples was obtained from Sigma and was 98% pure from bovine brain. Normal saline (sterile) was used as a carrier.
  • GM3 is shown to induce apoptosis of proliferating astrocytes.
  • Astrocyte cells were prepared from cerebral cortices of newborn (P0) Sprague-Dawley rats as described in Smith et al., Dev.Biol. 138, 377-390 (1990), and maintained in Delbecco's modified Eagles medium (DMEM) supplemented with 10% fetal bovine serum (FBS).
  • DMEM Delbecco's modified Eagles medium
  • FBS fetal bovine serum
  • TUNEL terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick-end labeling
  • GM3 was added to contact-inhibited non-proliferating astrocyte cultures. GM3 did not induce changes in cell morphology or cell death in these contact-inhibited non-proliferating astrocytes ( Figure 3).
  • GM3 selectively induces apoptosis in immature, proliferating astrocytes. Further, the results also demonstrate that active proliferation of neural cells also contributes to the susceptibility of those cells to GM3 treatment.
  • GM3 is shown to induce apoptosis of neurons and glial precursors.
  • Mixed cell cultures post-mitotic neurons, neuronal and glial precursors
  • GBM glioblastoma multiforme
  • Non-neoplastic cells were obtained from a 3 yr. old male that underwent a left hemispherectomy for Rasmussen's disorder.
  • Cultures were grown for at least 24 hours prior to addition of 100 ⁇ M GM3 suspended in media to experimental cultures. Parallel control cultures received media alone at the commencement of the experiment. The majority of assays were performed from cells derived from the original plating or first passage of a tumor sample. Cultures were grown in DMEM media with 10% FBS and N2 supplement containing insulin, transferrin, selenium, progesterone, putrescine, 3, 3 ',5 triiodo-L- thyronine, thyroxine and fraction V BSA.
  • Example 4 In the following example, GM3 is applied to human high grade gliomas in vitro to determine whether GM3 treatment inhibited expansion of primary human tumor cells.
  • Tumor samples used in this example were high grade lesions from a variety of regions of the tumor. Seven independent tumor samples were assayed.
  • Example 5 To determine whether GM3 treatment reduced cell number in quiescent cultures of normal human CNS, exogenous GM3 (100 ⁇ M) was added to cultures derived from non-neoplastic CNS tissue. The density of cells was not significantly altered curing 7 days in vitro. Furthermore, there was no significant difference in the number of cells in GM3 treated cultures compared to controls ( Figure 8), suggesting GM3 was not toxic to normal human CNS cells, consistent with all previous studies.
  • mice 9L rat gliosarcoma cells were transplanted intracranially into mice. Between 1-1.5X10° cells were stereotactically injected into the brain parenchyma of 18 adult Swiss nude mice, in two separate experiments. In each experiment, the animals were randomly assigned to either control or experimental groups immediately following the implantation procedure. Seventy two hours after cell implantation control animals received an intracranial injection of 5 ml of 0.9% sodium chloride while experimental animals received 0.3 mg GM3 in 5 mol of 0.9% sodium chloride.
  • GM3 increases the mean symptom free survival time of host animals following implantation of 9L cells. Based on the in vitro assays, this increased survival time most likely reflects reduction in the rate of growth of implanted tumor cells following GM3 treatment. Since the median survival for a patient diagnosed with a GBM is estimated between 29-36 weeks, any increase in median survival would be beneficial, provided there was little inherent treatment toxicity.
  • GM3 is a naturally occurring molecule that enhances maturation rather than induce cell death in non-proliferative neural cells. Thus GM3 treatment is unlikely to severely compromise the quality of remaining life.
  • GM3 induced cell death is enhanced at higher concentrations. While any effect on non-proliferative neural cells may be more pronounced at higher concentrations, increasing GM3 concentrations may result in extended survival periods.
  • the current studies used a single injection of GM3, 3 days after tumor implantation. Multiple injections of GM3 should result in a greater limitation of tumor growth and concomitant extension of symptom-free survival periods. Recent in vitro studies indicate that sustained application of GM3 over a period of 1 week resulted in greater cell loss in the majority of tumor cultures approaching 100%.
  • GM3 is a treatment agent for patients diagnosed with GBM.
  • Treatment of proliferating CNS cells with GM3 inhibits cell proliferation and induces apoptosis.
  • growth of human primary GBM tumor cells is inhibited by GM3 treatment.
  • normal, non- proliferative CNS cells are not induced to undergo apoptosis following GM3 treatment.
  • This strong proliferation dependence of GM3 responsiveness indicates that GM3 is a powerful agent in the treatment of highly proliferative human CNS malignancies such as GBM.
  • GBMs Glioblastoma multiformes
  • astrocytomas astrogliomas
  • ohgodendrocytomas ependymomas
  • glial tumors glial tumors and other various mixed gliomas
  • GM3 may be in a single application, multiple applications, or as a slow release suspension polymer formulation.
  • the amount to be administered is dictated by the amount needed to inhibit tumor growth. Typical ranges of effective amounts of GM3 to be administered to a patient range from about 5 ⁇ M to 50 ⁇ M (or about lmg to 16g.).
  • the treatment regimen should last at least until tumor growth has been completely inhibited. Generally, this may be from about one day to about six months (or longer, if necessary).
  • chemotherapeutic agents may be used in accordance with practicing the present invention.
  • Such means include direct application of the GM3 to the tumor (either alone or in combination with a slow release polymer), intraarterial injection, and stereotactic injection intratumorally.
  • other adjuvant therapies and chemotherapeutic treatment methods may be used in conjunction with the GM3 treatment.
  • pre- or post- administration of radiation therapy is an effective adjuvant therapy which may be used in conjunction with the GM3 treatment.

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Abstract

La présente invention concerne l'aptitude du ganglioside, GM3, à inhiber la prolifération et à induire l'apoptose dans des cellules proliférantes CNS. L'invention concerne également l'aptitude de GM3 à réduire le nombre de cellules dans des cultures primaires de tumeurs gliales humaines proliférant rapidement et de la lignée cellulaire 9L du gliosarcome du rat. En outre, GM3 n'a aucun effet sur des cultures quiescentes de cellules CNS humaines. Une injection simple de GM3, trois jours après l'implantation intracrânienne de cellules tumorales dans un système murin constituant une hétérogreffe, provoque une augmentation significative de la période de survie sans symptôme chez des animaux hôtes. GM3 est, en outre, utilisé comme agent chimiothérapeutique destiné au traitement des gliomes très avancés chez l'homme.
PCT/US1998/010390 1997-05-22 1998-05-22 Apoptose de cellules neuronales induite par un ganglioside gm3 WO1998052577A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CA002290598A CA2290598A1 (fr) 1997-05-22 1998-05-22 Apoptose de cellules neuronales induite par un ganglioside gm3
EP98922465A EP0998294A4 (fr) 1997-05-22 1998-05-22 Apoptose de cellules neuronales induite par un ganglioside gm3
IL13308598A IL133085A0 (en) 1997-05-22 1998-05-22 Ganglioside gm3 induced apoptosis of neural cells
AU75003/98A AU7500398A (en) 1997-05-22 1998-05-22 Ganglioside gm3 induced apoptosis of neural cells
JP55062798A JP2002510291A (ja) 1997-05-22 1998-05-22 ガングリオシドｇｍ３によって誘導される神経細胞のアポトーシス

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US4743097P 1997-05-22 1997-05-22
US60/047,430 1997-05-22

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AU (1) AU7500398A (fr)
CA (1) CA2290598A1 (fr)
IL (1) IL133085A0 (fr)
WO (1) WO1998052577A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002534359A (ja) * 1998-12-22 2002-10-15 ジェネンテック・インコーポレーテッド 血管内皮細胞増殖因子アンタゴニストとその用途
WO2004080960A2 (fr) 2003-03-06 2004-09-23 Neose Technologies Inc. Procedes et compositions pour la synthese enzymatique de gangliosides
EP2573567A4 (fr) * 2010-05-17 2014-01-08 Tokyo Inst Tech Procédé de détection du cancer de l'estomac
EP3175857A1 (fr) 2009-03-25 2017-06-07 Seneb Biosciences Inc. Glycolipides en tant que traitement de maladies

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4744187B2 (ja) * 2005-05-10 2011-08-10 オリンパス株式会社 細胞観察装置

Citations (1)

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US4710490A (en) * 1985-10-01 1987-12-01 Angio Medical Corporation Compositions containing ganglioside molecules with enhanced angiogenic activity

Family Cites Families (3)

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JPS61227531A (ja) * 1985-03-30 1986-10-09 Sankyo Co Ltd 抗腫瘍剤
JPH06145069A (ja) * 1992-11-06 1994-05-24 Nisshin Oil Mills Ltd:The ガングリオシドｇｍ３またはその類縁体を有効成分とする血管新生阻害剤
JP3141693B2 (ja) * 1994-08-16 2001-03-05 ダイキン工業株式会社 シアル酸の９位をフッ素で置換したガングリオシドｇｍ３類縁体及びその中間体

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4710490A (en) * 1985-10-01 1987-12-01 Angio Medical Corporation Compositions containing ganglioside molecules with enhanced angiogenic activity
US4710490B1 (fr) * 1985-10-01 1989-08-29

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002534359A (ja) * 1998-12-22 2002-10-15 ジェネンテック・インコーポレーテッド 血管内皮細胞増殖因子アンタゴニストとその用途
JP4731016B2 (ja) * 1998-12-22 2011-07-20 ジェネンテック， インコーポレイテッド 血管内皮細胞増殖因子アンタゴニストとその用途
US7998931B2 (en) 1998-12-22 2011-08-16 Genentech, Inc. Vascular endothelial cell growth factor antagonists and uses thereof
US8007799B2 (en) 1998-12-22 2011-08-30 Genentech, Inc. Vascular endothelial cell growth factor antagonists and uses thereof
US8287873B2 (en) 1998-12-22 2012-10-16 Genentech, Inc. Vascular endothelial cell growth factor antagonists and uses thereof
WO2004080960A2 (fr) 2003-03-06 2004-09-23 Neose Technologies Inc. Procedes et compositions pour la synthese enzymatique de gangliosides
EP3175857A1 (fr) 2009-03-25 2017-06-07 Seneb Biosciences Inc. Glycolipides en tant que traitement de maladies
US10555959B2 (en) 2009-03-25 2020-02-11 La Jolla Pharmaceutical Company Glycolipids as treatment for disease
EP2573567A4 (fr) * 2010-05-17 2014-01-08 Tokyo Inst Tech Procédé de détection du cancer de l'estomac

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EP0998294A1 (fr) 2000-05-10
EP0998294A4 (fr) 2001-02-07
IL133085A0 (en) 2001-03-19
AU7500398A (en) 1998-12-11
JP2002510291A (ja) 2002-04-02
CA2290598A1 (fr) 1998-11-26

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