摘要:

Antisense oligodeoxynucleotides (ODNS) can be used to specifically inhibit hepatitis C viral gene expression. Due to its high degree of conservation and its important function as internal ribosomal entry site, the 5’-non-coding region of the hepatitis C virus has been the most effective target to inhibit translation so far. Inhibition of luciferase reporter gene expression of up to 96 ± 2% has been achieved. Modifications of ODNs like phosphorothioate, methylphosphonate or benzylphosphonate modification of terminal or intramolecular internucleotide phosphates lead to altered lipophilicity and binding stability to its RNA target and resistance against serum nucleases. The mode of action of ODNs is mainly dependent on an efficient induction of RNase H activity. The uptake of ODNs occurs via receptor-mediated or absorptive and fluid-phase endocytosis. After release from the endosomes, ODNs may exert their effects by interaction with cytosolic or nuclear structures. Side effects can occur when this interaction affects intra- or extracellular targets essential for biological cell function. If these problems can be solved, antisense technology has the potential for future therapy of human disea

ISSN:0300-5526    

DOI:10.1159/000150571

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Long-term treatment of HIV-1-infected patients with antiretroviral agents may result in failure of therapy, due to the rapid emergence of resistant virus mutants with decreased susceptibility to therapeutic agents. However, in addition to viral resistance other factors, i.e. cellular factors, may contribute to the waning efficiency of chemotherapy. It has been shown in vitro that continuous treatment of cell lines with nucleoside reverse transcriptase inhibitors, such as S’-azido^’S’-dideoxythymidine (zidovudine, AZT), may induce decreased activity of cellular thymidine kinase (TK). Measurements of TK activity in ex vivo stimulated peripheral blood mononuclear cells of HIV-1-infected patients who undergo AZT long-term monotherapy as well as combination therapy provide evidence that diminished cellular TK activity may develop. This leads to the assumption that due to long-term treatment with nucleoside analogs, altered drug metabolism in host cells may contribute to inefficient activation of chemotherapeutic agents in HIV-1 patients. Thus, intracellular sub-therapeutic levels of the active compounds may develop. In this intracellular environment, selection of resistant virus populations may be promoted. Due to the expanding number of antiretroviral compounds and the requirement for lifelong treatment of HIV-1-infected persons with antiretroviral agents, both viral and cellular resistance mechanisms must be considered in the context of failing chemoth

ISSN:0300-5526    

DOI:10.1159/000150572

出版商:S. Karger AG    

年代:1997

数据来源: Karger

ISSN:0300-5526    

DOI:10.1159/000150573

出版商:S. Karger AG    

年代:1997

数据来源: Karger

ISSN:0300-5526    

DOI:10.1159/000150574

出版商:S. Karger AG    

年代:1997

数据来源: Karger

ISSN:0300-5526    

DOI:10.1159/000150575

出版商:S. Karger AG    

年代:1997

数据来源: Karger

ISSN:0300-5526    

DOI:10.1159/000150560

出版商:S. Karger AG    

年代:1997

数据来源: Karger