| 1. |
- Azarbayjani, Faranak
(författare)
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Common mechanism for teratogenicity of antiepileptic drugs : Drug-induced embryonic arrhythmia and hypoxia-reoxygenation damage
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Antiepilptic drugs (AEDs) phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), tri- and dimethadione (TMD and DMD) are known teratogens having a common malformation pattern in human and animal studies. This thesis was designed chiefly to test a hypothesis correlating the teratogenicity of these AEDs to episodes of pharmacologically induced embryonic arrhythmia and hypoxia-reoxygenation damage.Effects on the embryonic heart were studied both after maternal administration in mice and inmouse embryos cultured in vitro. Only AEDs, correlated with the same type of malformation as could be induced by episodes of interrupted oxygen supply to the embryo (e.g. cleft palate) caused concentration dependent bradycardia and arrhythmia. PHT and DMD had the highest potential and affected embryonic heart at clinically relevant concentration, followed by CBZ, TMD and PB. Valproate and vigabatrin not associated with hypoxia-related malformations caused neither arrhythmia nor severe bradycardia.The results showed that the embryonic heart is extremely susceptible to PHT and DMD onlyduring a restricted period of development, between gestational days 9-13 (weeks 5-9 of human pregnancy).An observed genetic susceptibility to react with arrhythmia at low concentrations when exposed to PHT or to external stress, could explain why A/J strain of mice is more susceptible to develop cleft palate compared to other strains. High activities of reactive oxygen species (ROS) capturing antioxidant enzymes observed in untreated A/J embryos supported this assumption. The potential to cause embryonic arrythmia by an AED was related to the potential to inhibit the rapid component of the delayed rectifier potassium channel (I kr ).A marked I kr blocking activity (70%)of DMD in voltage clamping studies was observed. The I kr inhibition occurred at similar concentrations, which causes severe arrhythmia.The idea of a relation between teratogenicity and arrhythmia, resulting in ischemia followed by reperfusion and generation of ROS was supported by mechanistic studies. Pre-treatment with the spin-trapping agent PBN, which has the capacity to capture ROS, markedly reduced the incidence of PHT and DMD-induced cleft palate. In utero exposure to teratogenic doses of DMD and PHT resulted in hemorrhages in the embryonic palatal region. The same type of haemorrhage in the palatal region precedes orofacial clefts induced by episodic hypoxia.
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| 2. |
- Azarbayjani, Faranak, et al.
(författare)
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Embryonic arrhythmia by inhibition of HERG channels : a common hypoxia-related teratogenic mechanism for antiepileptic drugs?
- 2002
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Ingår i: Epilepsia. - : Wiley. - 0013-9580 .- 1528-1167. ; 43:5, s. 457-468
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: There is evidence that drug-induced embryonic arrhythmia initiates phenytoin (PHT) teratogenicity. The arrhythmia, which links to the potential of PHT to inhibit a specific potassium channel (Ikr), may result in episodes of embryonic ischemia and generation of reactive oxygen species (ROS) at reperfusion. This study sought to determine whether the proposed mechanism might be relevant for the teratogenic antiepileptic drug trimethadione (TMO). METHODS: Effects on embryonic heart rhythm during various stages of organogenesis were examined in CD-1 mice after maternal administration (125-1,000 mg/kg) of dimethadione (DMO), the pharmacologically active metabolite of TMO. Palatal development was examined after administration of a teratogenic dose of DMO and after simultaneous treatment with DMO and a ROS-capturing agent (alpha-phenyl-N-tert-butyl-nitrone; PBN). The Ikr blocking potentials of TMO and DMO were investigated in HERG-transfected cells by using voltage patch-clamping tests. RESULTS: DMO caused stage-specific (gestation days 9-13 only) and dose-dependent embryonic bradycardia and arrhythmia at clinically relevant maternal plasma concentrations (3-11 mM). Hemorrhage in the nasopharyngeal part of the embryonic palate (within 24 h) preceded cleft palate in fetuses at term. Simultaneous treatment with PBN significantly reduced the incidence of DMO-induced cleft palate, from 40 to 13%. Voltage patch-clamping studies showed that particularly DMO (70% inhibition), but also TMO, had Ikr blocking potential at clinically relevant concentrations. CONCLUSIONS: TMO teratogenicity, in the same way as previously shown for PHT, was associated with Ikr-mediated episodes of embryonic cardiac arrhythmia and hypoxia/reoxygenation damage.
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| 3. |
- Azarbayjani, Faranak, et al.
(författare)
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Increased susceptibility to phenytoin teratogenicity : Excessive generation of reactive oxygen species or impaired antioxidant defense?
- 2006
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 99:4, s. 305-311
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Tidskriftsartikel (refereegranskat)abstract
- Phenytoin is a human and animal teratogen. Accumulating evidence suggests that the teratogenicity is associated with a potential of phenytoin to cause embryonic cardiac arrhythmia and resultant generation of toxic reactive oxygen species via hypoxia-reoxygenation mechanisms. The A/J mouse is more susceptible to phenytoin teratogenicity than other mouse strains. The aim of this study was to investigate whether A/J mice have other antioxidant enzyme activities than C57BL/6J and CD-1 mice. Also, strain differences in phenytoin effects on embryonic heart rate and rhythm were determined. Another objective was to determine whether a spin trapping agent with capacity to capture reactive oxygen species alter the developmental toxicity of phenytoin. Treatment with this agent resulted in a marked decrease in phenytoin teratogenicity, which supports the idea that reactive oxygen species are important mediators for the teratogenic action of phenytoin. The A/J mice embryos were most susceptible to the adverse cardiac effects of phenytoin and had the highest activity of superoxide dismutase and glutathione peroxidase, while the activity of catalase was the same in embryos of the three different strains. The high activities of antioxidant enzymes in the A/J stain indicate that the sensitivity to develop malformations is caused by excessive arrhythmia-related generation of reactive oxygen species rather than impaired antioxidant defense.
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| 4. |
- Bäckman, Ulrika, et al.
(författare)
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The Bisphosphonate Zoledronic Acid Reduces Experimental Neuroblastoma Growth by Interference with Tumor Angiogenesis
- 2008
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 28:3A, s. 1551-1557
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Tidskriftsartikel (refereegranskat)abstract
- Background: Zoledronic acid is a new member of the bisphosphonate (BP) class of compounds, a family of closely related synthetic molecules originally derived from the naturally occurring pyrophosphate. These compounds that are potent inhibitors of bone resorption, have been shown to reduce the growth of several cancer cell lines in vitro, and can act as inhibitors of angiogenesis. The angiogenesis inhibitor TNP-470, a synthetic analogue of the fungal antibiotic fumagillin, has been shown to inhibit the growth of multiple tumors in vivo, and is currently in Phase H clinical trials for cancer. Materials and Methods: The effects of daily subcutaneous (s.c.) administration of zoledronic acid (0.1 mg/kg) were compared with those of TNP-470 (15 mg/kg/day and 30 mg/kg every other day, s.c.) in a nude mouse xenograft model for the childhood cancer, neuroblastoma (NB). Results: Zoledronic acid reduced the tumor growth by 33% whereas TNP-470 was less effective and reduced the tumor growth by 26% and 11% for animals treated with 15 mg/kg/day and 30 mg/kg every other day, respectively. Analysis of angiogenesis showed a significant reduction of the number of vessels per grid and in vessel length in all the treatment groups. Conclusion: Zoledronic acid shows tumoristatic and angiostatic properties that might be beneficial in the treatment of solid tumors such as neuroblastoma.
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| 5. |
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| 6. |
- Danielsson, Christian, et al.
(författare)
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Polytherapy with hERG-blocking antiepileptic drugs : Increased risk for embryonic cardiac arrhythmia and teratogenicity
- 2007
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Ingår i: Birth defects research. Clinical and molecular teratology. - : Wiley. - 1542-0752 .- 1542-0760. ; 79:8, s. 595-603
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The antiepileptic drugs (AEDs) phenytoin, phenobarbital, dimethadione, and carbamazepine cause a similar pattern of malformations in humans, with an increased risk after polytherapy. The teratogenicity has been linked to cardiac rhythm disturbances and hypoxic damage as a consequence of their common potential to inhibit a specific potassium ion current (IKr). The IKr is of major importance for embryonic cardiac repolarization and rhythm regulation. This study investigated whether these AEDs cause irregular rhythm and if various combinations of AEDs result in higher arrhythmia risk than exposure to a single AED. METHODS: The effects on heart rhythm of a single AED (monotherapy), and of various combinations (polytherapy) of AEDs, in gestational day 10 C57BL mouse embryos in culture were analyzed and graphically illustrated during a 25 s recording with a digitalization technique. RESULTS: All of the studied AEDs caused increased intervals between heartbeats (resulting in bradycardia) and large variations in the interval between heartbeats (resulting in irregular rhythm) in a concentration-dependent manner in cultured mouse embryos. Dimethadione caused irregular rhythm at concentrations within and phenytoin slightly above the therapeutic ranges. Polytherapy resulted in more substantial prolongation of the mean interval between heartbeats (>60 ms) than monotherapy at clinically relevant concentrations. CONCLUSIONS: The results suggest that polytherapy more than monotherapy causes substantial prolongation of the cardiac repolarization, a marker associated with high risk of developing irregular rhythm during longer exposure periods (days to months). This supports the idea that the increased risk for malformations following polytherapy is linked to an increased risk for cardiac rhythm disturbances.
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| 7. |
- Fuchs, Dieter, et al.
(författare)
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Metronomic administration of the drug GMX1777, a cellular NAD synthesis inhibitor, results in neuroblastoma regression and vessel maturation without inducing drug resistance
- 2010
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 126:12, s. 2772-2789
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Tidskriftsartikel (refereegranskat)abstract
- High-risk neuroblastoma is a rapidly growing tumor with a survival rate below 50%. A new treatment strategy is to administer chemotherapeutic drugs metronomically, i.e. at lower doses and frequent intervals. The aim of the study was to investigate the effects of GMX1777, a chemotherapeutic drug affecting cellular energy metabolism, in a mouse model for high-risk neuroblastoma.Female SCID mice were injected s.c. with MYCN-amplified human neuroblastoma cells and randomized to either treatment with GMX1777 or vehicle. In some animals, treatment was discontinued allowing tumor relapse. Treatment response was evaluated using the Pediatric Preclinical Testing Program (PPTP). Immunohistochemistry and qRT-PCR was performed on tumor cryosections to investigate the microscopic and molecular changes in tumors in response to GMX1777.Despite an increase in vessel density, tumor regression and a high group response score according to PPTP criteria was induced by GMX1777 without inducing drug resistance. Treatment resulted in inhibition of tumor cell proliferation, vessel maturation, reduced hypoxia, increased infiltration of MHC class II negative macrophages and expansion of the non-vascular stromal compartment. Decreased stromal VEGF-A and PDGF-B mRNA in response to treatment together with the structural data suggest a "deactivation" or "silencing" of the tumor stroma as a paracrine entity.In conclusion, GMX1777 was highly efficient against high-risk neuroblastoma xenografts through modulation of both the tumor cell and stromal compartment.
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| 8. |
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| 9. |
- Fuchs, Dieter, 1979-
(författare)
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Novel Treatment Modalities for High-Risk Neuroblastoma : Studies in Animal Models
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neuroblastoma, the most common extracranial solid tumor of childhood, is a heterogeneous tumor. In some patients, the tumor can go into spontaneous regression and disappear whereas other patients have rapidly growing tumors with a poor prognosis. The overall long-term survival rate in patients with high-risk neuroblastoma is less than 30%, indicating the need for new treatment strategies. Angiogenesis inhibition hampers the formation of new blood vessels, thereby limiting the tumors’ metabolic exchange. Neuroblastoma is rapidly growing and high tumor angiogenesis has been associated with poor outcome. Therefore, the aim of this thesis was to investigate the effect of novel treatment modalities for angiogenesis inhibition on high-risk neuroblastoma xenografts. For that purpose, we used subcutaneous mouse models and characterized orthotopic mouse models for high-risk neuroblastoma. We found that xenotransplantation of neuroblastoma cells into the adrenal gland of SCID and SCID beige mice resulted in orthotopic tumors resembling clinical neuroblastoma in respect to tumor site, growth and spread. Using contrast-enhanced ultrasound, we observed that the receptor tyrosine kinase inhibitor SU11248 reduced orthotopic neuroblastoma growth and spread by reducing tumor angiogenesis.In subcutaneous xenografts for high-risk neuroblastoma, valuable for studies requiring continuous assessment of tumor volume, we demonstrated that immune-neutralizing VEGF with the anti-VEGF antibody bevacizumab significantly reduced neuroblastoma growth. Finally, we found that formulations of the chemotherapeutic drug GMX1778 inhibited angiogenesis and induced tumor regression in a dose dependent manner without host toxicity. We showed that relapsing tumors remained responsive to GMX-therapy without accelerated growth or induced drug resistance.In conclusion, SU11248, bevacizumab, and formulations of the active compound GMX1778 may become useful for treating high-risk neuroblastoma.
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| 10. |
- Fuchs, Dieter, et al.
(författare)
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Regression of orthotopic neuroblastoma in mice by targeting the endothelial and tumor cell compartments
- 2009
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 7, s. 16-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: High-risk neuroblastoma has an overall five-year survival of less than 40%, indicating a need for new treatment strategies such as angiogenesis inhibition. Recent studies have shown that chemotherapeutic drugs can inhibit angiogenesis if administered in a continuous schedule. The aim of this study was primarily to characterize tumor spread in an orthotopic, metastatic model for aggressive, MYCN-amplified neuroblastoma and secondarily to study the effects of daily administration of the chemotherapeutic agent CHS 828 on tumor angiogenesis, tumor growth, and spread. METHODS: MYCN-amplified human neuroblastoma cells (IMR-32, 2 x 10(6)) were injected into the left adrenal gland in SCID mice through a flank incision. Nine weeks later, a new laparotomy was performed to confirm tumor establishment and to estimate tumor volume. Animals were randomized to either treatment with CHS 828 (20 mg/kg/day; p.o.) or vehicle control. Differences between groups in tumor volume were analyzed by Mann-Whitney U test and in metastatic spread using Fisher's exact test. Differences with p < 0.05 were considered statistically significant. RESULTS: The orthotopic model resembled clinical neuroblastoma in respect to tumor site, growth and spread. Treatment with CHS 828 resulted in tumor regression (p < 0.001) and reduction in viable tumor fraction (p < 0.001) and metastatic spread (p < 0.05) in correlation with reduced plasma levels of the putative tumor marker chromogranin A (p < 0.001). These effects were due to increased tumor cell death and reduced angiogenesis. No treatment-related toxicities were observed. CONCLUSION: The metastatic animal model in this study resembled clinical neuroblastoma and is therefore clinically relevant for examining new treatment strategies for this malignancy. Our results indicate that daily scheduling of CHS 828 may be beneficial in treating patients with high-risk neuroblastoma.
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