Kooperativer Bibliotheksverbund

Berlin Brandenburg

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  • 1
    In: Anti-Cancer Drugs, 2001, Vol.12(5), pp.467-473
    Description: Treatment failure in most neuroblastoma (NB) patients is related to primary and/or acquired resistance to conventional chemotherapeutic agents. Aphidicolin (APH), a tetracyclic diterpene, exhibits specific cytotoxic action against NB cells. The purpose of this study was to compare antitumoral efficacy of APH in parental NB cell lines and cell subclones that exhibit drug resistance to vincristine (VCR), doxorubicin (DOX) and cisplatin. Due to poor solubility of APH in water, γ-cyclodextrin (γ-CD) inclusion complexes of APH were used for systemic treatment of xenotransplanted parental and VCR-resistant UKF-NB-3 tumours. APH and its γ-CD inclusion complexes inhibited growth of parental and drug-resistant NB cells at equimolar doses in vitro. Growth of VCR-sensitive and -resistant NB tumors was inhibited at equal doses in a dose-dependent fashion in vivo. These results indicate that the specific cytotoxic activity of APH against NB cells in vitro and in vivo is independent of cellular mechanisms facilitating drug resistance to conventional chemotherapeutic drugs. Hence, taking into account our previous findings that APH acts synergistically with VCR and DOX, APH might be an additive tool for the therapy of NB and is suitable for evaluation in clinical studies of NB treatment protocols.
    Keywords: Aphidicolin -- Therapeutic Use ; Cell Survival -- Drug Effects ; Cyclodextrins -- Pharmacology ; Enzyme Inhibitors -- Therapeutic Use ; Neuroblastoma -- Drug Therapy ; Tumor Cells, Cultured -- Drug Effects;
    ISSN: 0959-4973
    E-ISSN: 14735741
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  • 2
    In: Anti-Cancer Drugs, 1997, Vol.8(10), pp.958-963
    Description: Sodium valproate (VPA) belongs to the group of simple branched-chain fatty acids and due its anticonvulsive activity is broadly applied in the treatment of epilepsy. We previously showed that VPA is able to induce cellular differentiation, to enhance immunogenicity and to inhibit proliferation of human neuroblastoma (NB) cells in vitro. Furthermore, we demonstrated that VPA inhibits proliferation, enhances neural cell adhesion molecule expression and decreases CD44 expression of human and rat glioma cells in vitro. In the present study we investigated the anttitumoral effects of VPA on established human NB xenografts from UKF-NB-3 human NB cells in athymic (nude) mice. When the animals developed s.c. tumors of about 100 mm volume they were treated with 400 or 200 mg/kg/day VPA i.p. At the end of the treatment period (40 days) tumor volumes in animals treated with 400 and 200 mg/kg VPA were about 4− (p〈 0.0001) and 2-fold (p〈 0.0005) smaller than in the saline-treated control group, respectively. Histological examination of the remnant tumors of treated animals revealed induction of differentiation by induction of stroma-rich tumors and nodules that contained elongated NB cells. Pyknotic nuclei and apoptotic bodies indicated induction of apoptosis. We conclude that VPA is able to abrogate NB growth in vivo and may therefore be useful in the treatment of NB patients.
    Keywords: Antineoplastic Agents -- Pharmacology ; Neuroblastoma -- Drug Therapy ; Valproic Acid -- Pharmacology;
    ISSN: 0959-4973
    E-ISSN: 14735741
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  • 3
    In: Anti-Cancer Drugs, 2000, Vol.11(6), pp.479-485
    Description: Disseminated neuroblastoma diseases are still indicated by a poor outcome despite treatment regimens including radiation therapy and high-dose chemotherapy with stem cell rescue. Therefore, new substances and treatment regimens are of interest. Aphidicolin (APH), a tetracyclic diterpene antibiotic produced by Cephalosporium aphidicola, has a specific toxicity for neuroblastoma cells. Furthermore, it was shown to enhance the effects of X-ray radiation and chemotherapy on malignant cells. To find new substances, 20 APH derivatives were tested for their anti-neuroblastoma efficacy in vitro in UKF-NB-2 cells. Five derivatives had antitumoral activity in neuroblastoma cells. A relationship between the structure and the antitumoral efficacy showed that the hydroxyl groups at C-3 and C-18 are essential for the antitumoral effects. Furthermore, antitumoral effects of APH in combination with doxorubicin and vincristine, both part of commonly used treatment regimens for disseminated neuroblastoma diseases, were tested in the neuroblastoma cell line UKF-NB-2. APH was found to act synergistically with vincristine and synergistically to additive with doxorubicin depending on the molecular ratio of the substances in combination. This may offer the chance to use APH and its derivatives as additional tools in the treatment of neuroblastomas.
    Keywords: Antineoplastic Agents -- Pharmacology ; Antineoplastic Agents, Phytogenic -- Pharmacology ; Aphidicolin -- Pharmacology ; Cell Survival -- Drug Effects ; Doxorubicin -- Pharmacology ; Enzyme Inhibitors -- Pharmacology ; Neuroblastoma -- Drug Therapy ; Tumor Cells, Cultured -- Drug Effects ; Vincristine -- Pharmacology;
    ISSN: 0959-4973
    E-ISSN: 14735741
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  • 4
    Language: English
    In: Cancer research, 01 April 2003, Vol.63(7), pp.1508-14
    Description: Replication restricted oncolytic viruses such as multimutated herpes simplex virus type 1 (HSV-1) G207 represent a novel and attractive approach for cancer therapy, including pediatric solid tumors. Rhabdomyosarcoma is the most common soft-tissue sarcoma of childhood and is often diagnosed already as an advanced disseminated disease. Despite aggressive therapeutic approaches, the prognosis for patients with metastatic rhabdomyosarcoma remains grim. Therefore, there is a need for novel effective drugs with superior safety and efficacy profile. In this study, we showed marked in vitro activity of HSV-1 G207 against embryonal and alveolar rhabdomyosarcoma cells. All human embryonal (KF-RMS-1, RD, and CCA) and alveolar RMS (KFR, Rh28, Rh30, and Rh41) cell lines were highly sensitive to cytotoxic and replicative effects of G207 even at a multiplicity of infection of 0.01, except embryonal Rh1 rhabdomyosarcoma cells, which were efficiently killed only upon multiplicity of infection of 1.0. i.v. G207 treatment of xenotransplanted KFR and KF-RMS-1 tumors in mice led to significant tumor growth inhibition of both tumor entities, whereas intraneoplastic G207 treatment additionally resulted in complete tumor disappearance in 25% of animals. No difference has been found between alveolar and embryonal types of rhabdomyosarcoma. Combination treatment of both cell lines with G207 and vincristine led to strongly enhanced in vitro cytotoxicity without affecting infection efficiency and replication of G207 in KFR as well as in KF-RMS-1 cells. In vivo combination treatment using i.v. G207 and vincristine resulted in complete regression of alveolar rhabdomyosarcoma in five of eight animals and significant growth inhibition of embryonal rhabdomyosarcoma. Taking into consideration the proven safety of G207 in humans, we suggest that G207 alone and in combination with vincristine should be additionally evaluated as a potential agent against human rhabdomyosarcoma.
    Keywords: Antineoplastic Agents, Phytogenic -- Pharmacology ; Rhabdomyosarcoma -- Therapy ; Simplexvirus -- Physiology ; Vincristine -- Pharmacology
    ISSN: 0008-5472
    E-ISSN: 15387445
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 5
    Language: English
    In: International Journal of Cancer, 10 March 2003, Vol.104(1), pp.36-43
    Description: Cytotoxic drug treatment of neuroblastoma often leads to the development of drug resistance and may be associated with increased malignancy. To study the effects of long‐term cytotoxic treatment on malignant properties of tumor cells, we established 2 neuroblastoma cell sublines resistant to vincristine (VCR) and doxorubicin (DOX). Both established cell lines (UKF‐NB‐2VCR and UKF‐NB‐2DOX) were highly resistant to VCR, DOX and vice‐versa but retained their sensitivity to cisplatin. UKF‐NB‐2VCR and UKF‐NB‐2DOX expressed significant amounts of P‐glycoprotein, while parental cells were P‐glycoprotein negative. GD2 expression was upregulated, whereas NCAM expression was decreased in both resistant cells. Spectral karyotype (SKY) analysis revealed complex aberrant karyotypes in all cell lines and additional acquired karyotype changes in both resistant cells. All cell lines harbored high levels of N‐myc amplification. Compared to parental cells, UKF‐NB‐2VCR and UKF‐NB‐2DOX exhibited more than 2‐fold increase in clonal growth , accelerated adhesion and transendothelial penetration and higher tumorigenicity . We conclude that development of drug resistance and acquisition of certain karyotypic alterations is associated with an increase of additional malignant properties that may contribute to the poor prognosis in advanced forms of NB. The 2 novel neuroblastoma cell sublines also provide useful models for the study of drug resistance in aggressive forms of neuroblastoma. © 2002 Wiley‐Liss, Inc.
    Keywords: Neuroblastoma ; Drug Resistance ; Mdr‐1 ; Ncam ; Gd2 ; Karyotype
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 6
    Language: English
    In: International journal of oncology, December 2004, Vol.25(6), pp.1795-9
    Description: Valproic acid (VPA) as a differentiation inducing anti-neoplastic substance is currently tested in solid tumour and leukaemia patients. Previously, we were able to show that the anti-cancer activity of VPA was synergistically increased by interferon-alpha (IFN-alpha) in Be(2)-C neuroblastoma (NB) cells. Now, we studied the effects of VPA in combination with IFN-alpha on two other NB cell lines. UKF-NB-2 and UKF-NB-3 cell growth was synergistically inhibited by VPA and IFN-alpha. Cell cycle investigations revealed massive accumulation of cells in G0/G1-phase after a combined treatment with VPA and IFN-alpha. The VPA-induced accumulation of acetylated histones in NB cell nuclei that indicates inhibition of histone deacetylases was not further enhanced by the combination treatment with IFN-alpha. Most strikingly, VPA plus IFN-alpha synergistically inhibited growth of UKF-NB-3 xenograft tumours in nude mice and induced complete cures in two out of six animals, while single treatment merely inhibited tumour growth. The results of this study together with our previous report strongly encourage the clinical evaluation of VPA and IFN-alpha for NB patients.
    Keywords: Enzyme Inhibitors -- Pharmacology ; Interferon-Alpha -- Pharmacology ; Neuroblastoma -- Pathology ; Valproic Acid -- Pharmacology
    ISSN: 1019-6439
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  • 7
    Language: English
    In: International journal of oncology, January 2002, Vol.20(1), pp.97-106
    Description: Valproic acid (VPA) has been shown to induce growth-arrest and differentiation of human neuroectodermal tumors similarly to several other fatty acids. In the present study, we show that continuous VPA treatment together with Interferon-alpha (INF-alpha) synergistically inhibited cell growth of a well-established model of neuroblastoma (NB) differentiation using the human N-myc amplified cell line BE(2)-C. Suppression of tumor growth was accompanied by morphological features of neuronal differentiation and inhibition of histone deacetylase activity. Furthermore, induction of differentiation was concomitant with altered expression of genes related to malignant phenotype such as down-regulation of N-myc, induction of bcl-2 and neural cell adhesion molecule. Production of inhibitors of angiogenesis like thrombospondin-1 and activin A was up-regulated in differentiated NB cells. Treatment with VPA alone decreased the ability of BE(2)-C cells to adhere to and penetrate human endothelium. All these effects of VPA were significantly enhanced when combined with INF-alpha which on its own had little or no effect. These results suggest that combination of VPA and INF-alpha may provide a novel therapeutic strategy for NB due to enhanced inhibition of tumor cell growth, induction of tumor differentiation and suppression of malignant biology by reduced angiogenic and decreased metastatic potentials.
    Keywords: Antineoplastic Agents -- Therapeutic Use ; Brain Neoplasms -- Drug Therapy ; Cell Differentiation -- Drug Effects ; Enzyme Inhibitors -- Therapeutic Use ; Interferon-Alpha -- Therapeutic Use ; Neuroblastoma -- Drug Therapy ; Valproic Acid -- Therapeutic Use
    ISSN: 1019-6439
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  • 8
    Language: English
    In: Neoplasia, November 2004, Vol.6(6), pp.725-735
    Description: The mode of the antitumoral activity of multimutated oncolytic herpes simplex virus type 1 G207 has not been fully elucidated yet. Because the antitumoral activity of many drugs involves the inhibition of tumor blood vessel formation, we determined if G207 had an influence on angiogenesis. Monolayers of human umbilical vein endothelial cells and human dermal microvascular endothelial cells, but not human dermal fibroblasts, bronchial epithelial cells, and retinal glial cells, were highly sensitive to the replicative and cytotoxic effects of G207. Moreover, G207 infection caused the destruction of endothelial cell tubes . In the Matrigel plug assay in mice, G207 suppressed the formation of perfused vessels. Intratumoral treatment of established human rhabdomyosarcoma xenografts with G207 led to the destruction of tumor vessels and tumor regression. Ultrastructural investigations revealed the presence of viral particles in both tumor and endothelial cells of G207-treated xenografts, but not in adjacent normal tissues. These findings show that G207 may suppress tumor growth, in part, due to inhibition of angiogenesis.
    Keywords: Angiogenesis ; Hsv-1 ; G207 ; Human Rhabdomyosarcoma ; Ribonucleotide Reductase ; Medicine
    ISSN: 1476-5586
    E-ISSN: 1476-5586
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  • 9
    Language: English
    In: Cell Communication & Adhesion, 01 January 2002, Vol.9(3), pp.131-147
    Description: The precise function of cell adhesion molecules in the hematogenous phase of neuroblastoma metastasis is poorly understood. The aim of this study was to investigate whether neural cell adhesion molecule (NCAM) modulates neuroblastoma cell (NB) adhesion and transendothelial penetration in a...
    Keywords: Ncam ; Neuroblastoma ; Adhesion ; Biology
    ISSN: 1541-9061
    E-ISSN: 1543-5180
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  • 10
    Language: English
    In: International journal of oncology, October 2005, Vol.27(4), pp.1029-37
    Description: Acquisition of P-gp-mediated multidrug-resistance does not always correlate with observed malignant behavior of NB. To characterize alterations accompanying development of multidrug-resistance in NB we established two neuroblastoma cell sublines resistant to vincristine (UKF-NB-3rVCR10) and doxorubicin (UKF-NB-3rDOX20). UKF-NB-3rVCR10 and UKF-NB-3rDOX20 overexpressed functional P-gp and developed an increased malignant phenotype: presented constitutive phosphorylation of AKT, resistance to gamma-irradiation, and had increased survival in serum-free medium. Inhibition of P-gp restored chemosensitivity but did not affect increased survival in serum-free medium and sensitivity to gamma-irradiation. Inhibition of AKT had no influence on chemoresistance but restored sensitivity to serum starvation. Both resistant cell lines acquired additional chromosomal changes. UKF-NB-3rVCR10 cells acquired a missense P53 mutation in exon 5, an increased MYCN amplification, an enhanced adhesion to endothelium, a decreased NCAM expression, a distinctly higher clonogenicity, and an increased in vivo tumorigenicity. We conclude that acquisition of increased malignant behavior in neuroblastoma occurs concomitantly with multidrug-resistance and is P-gp-independent.
    Keywords: Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; ATP Binding Cassette Transporter, Subfamily B, Member 1 -- Metabolism ; Neuroblastoma -- Pathology
    ISSN: 1019-6439
    E-ISSN: 17912423
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