Immunomodulation and anticytomegalovirus activity of antioxidant metal chelators.
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Antioxidants↗
Biomedical subjects
H W Doerr
Publications and source records attributed to H W Doerr.
[Cytomegalovirus infection as a possible factor in the progression of neuroblastoma].
BACKGROUND: There is evidence that the infection with human cytomegalovirus is clinically associated with enhanced metastasis and progression of neuroblastoma disease. An in vitro model with HCMV-infected neuroblastoma cells (NB) was used to investigate whether HCMV modulates the metastatic potential of NB. METHODS: The neuroblastoma cell line UKF-NB-4 and its productively and persistently HCMV-infected variant UKF-NB-4AD169 were cocultured with human endothelial cells (EC). The rate of NB adherent to the endothelial monolayer and the rate of transmigrating NB was determined by means of combined reflexion interference contrast/phase contrast microscopy. RESULTS: UKF-NB-4AD169 adhered to and transmigrated through cocultured EC monolayer to a significantly higher extent compared with the non-infected cell line UKF-NB-4. At the cell-to-cell contact sites between UKF-NB-4AD169 and EC the intercellular endothelial contacts loosened resulting in the formation of reversible focal openings in the monolayer. This phenomenon was not observed with UKF-NB-4. The transendothelial migration rate of UKF-NB-4AD169 was therefore significantly higher than that of UKF-NB-4. The formation of focal openings in the endothelial monolayer and the enhanced transmigration rate of UKF-NB-4AD169 was suppressed in the presence of phenantroline, suggesting that HCMV-induced proteinases might be responsible for this phenomenon. CONCLUSION: The results confirm our assumption that HCMV has the ability to modulate functional properties of NB which are essential for the interactions with endothelial cells and thus for metastasation. The clinical relevance of these findings has to be further defined yet by means of prospective studies with HCMV-infected neuroblastoma patients. Proteinase inhibitors could be valuable in the therapeutic treatment of these patients.
Cell Migration Inhibition↗
ddC- and 3TC-bis(SATE) monophosphate prodrugs overcome cellular resistance mechanisms to HIV-1 associated with cytidine kinase deficiency.
A 2',3'-dideoxycytidine (ddC)-resistant T-lymphoid cell line (MOLT-4/8rddC250), in which deoxycytidine kinase (dCK) gene-expression was decreased when compared with parental cells, has been selected. Cytotoxic and antiretroviral activity of ddC and 3TC was significantly lower in MOLT-4/8rddC250-than in parental MOLT-4/8 cells. ddC- and 3TC-bis(SATE)phosphotriesters completely overcame cellular resistance mechanisms and showed comparable both cytotoxic and antiretroviral activity in parental and ddC-resistant cells.
Base Sequence↗
Effects of cycloSal-d4TMP derivatives in H9 cells with induced AZT resistance phenotype.
Cytotoxic and antiretroviral activity of cycloSal-d4TMP derivatives were tested in a new AZT-resistant H9 cell subline (H9rAZT250). The results showed, that cycloSal-d4TMP derivatives overcame resistance of HIV-1 to d4T in H9rAZT250 cells, which exert decreased thymidine kinase (TK) gene expression.
Anti-HIV Agents↗
Zidovudine (AZT) resistance in H9 cells due to decreased TK expression is associated with hypermethylation of TK gene.
AZT resistant human T-lymphoid H9 cells, deficient in TK gene expression, re-expressed TK mRNA and regained the ability to metabolize AZT by exposure to the demethylation agent azacytidine (AzaCd). Cytotoxic and anti-HIV-1 effects of AZT were increased in H9 AZT resistant cells treated with AzaCd when compared to untreated cells. This leads to the assumption that drug induced DNA hypermethylation was involved in the TK gene-silencing mechanism. Our results suggest approaches using modulation of gene methylation for increasing antiviral efficiency of drugs.
Anti-HIV Agents↗
Antisense oligonucleotide ISIS 2922 targets IE-expression and prevents HCMV-IE-induced suppression of TSP-1 and TSP-2 expression.
ISIS 2922, but not ganciclovir (GCV), inhibits HCMV immediate early protein (IE) expression in different infected cell lines and prevents down-modulation of extracellular matrix proteins thrombospondin-1 and -2 induced by IE proteins. While action of ISIS 2922 is mainly due to specific inhibition of IE 2 mRNA, there is also evidence for unspecific effects in terms of inhibition of virus adhesion and penetration.
Antigens, Viral↗
Cytarabine treatment of human T-lymphoid cells induces decreased HIV-1 receptor expression and reduced HIV-1 susceptibility.
Continuous cultivation of T-lymphoid C8166 cells in the presence of pharmacological relevant concentration of cytarabine (Ara-C) results in significantly decreased expression of CD4 and CXCR4 molecules, the major cellular receptor and co-receptor of T-lymphotropic HIV-1 isolates. This change in receptor expression leads to decreased susceptibility of Ara-C resistant cells to HIV-1 infection demonstrated by reduced binding and penetration of HI-virus.
Antiviral Agents↗
Aphidicolin glycinate inhibits human neuroblastoma cell growth in vivo.
Aphidicolin is a fungal derived tetracyclic diterpene antibiotic. It is selectively toxic for neuroblastoma (NB) cells in vitro but has no significant effects on the viability of normal human cells and a variety of other tumor entities. We evaluated the antitumoral effects of the water soluble ester aphidicolin glycinate (AphiG) on established human NB xenografts from UKF-NB-3 cells in athymic (nude) mice. Furthermore, we explored the efficacy of direct intraneoplastic and systemic delivery of AphiG. Systemic administration of AphiG (60 mg/kg intraperitoneally, twice per day on 10 consecutive days) significantly suppressed tumor growth but was not able to induce any cures. In contrast, intratumoral AphiG injections (60 or 40 mg/kg/twice a day for 4 days) induced complete tumor regression. Two weeks after the end of treatment no tumor cells were microscopically detectable. Animals were free of tumor for more than 90 days. Histologic examination of inner organs and bone marrow did not reveal any apparent toxic effects of AphiG. These data strongly indicate that AphiG deserves further evaluation as a specific treatment for neuroblastoma.
Animals↗