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At least 469 records · Page 26Linked to original sources
PubMed2002

Expression of HIF-1alpha by human macrophages: implications for the use of macrophages in hypoxia-regulated cancer gene therapy.

Large numbers of monocytes extravasate from the blood into human tumours, where they differentiate into macrophages. In both breast and prostate carcinomas, these cells accumulate in areas of low oxygen tension (hypoxia), where they respond to hypoxia with the up-regulation of one or more hypoxia-inducible factors (HIFs). These then accumulate in the nucleus and bind to short DNA sequences called hypoxia-response elements (HREs) near or in such oxygen-sensitive genes as that encoding the pro-angiogenic factor vascular endothelial growth factor (VEGF). This stimulates gene expression and could explain why, in part, macrophages express abundant VEGF only in avascular, hypoxic areas of breast carcinomas. It also suggests that macrophages could be used to deliver HRE-regulated therapeutic genes specifically to hypoxic tumour areas. A recent study suggested that hypoxic macrophages accumulate HIF-2 rather than HIF-1, prompting the search for HRE constructs that optimally bind HIF-2 for use in macrophage-based gene therapy protocols. However, the present study shows that human macrophages accumulate higher levels of HIF-1 than HIF-2 when exposed to tumour-specific levels of hypoxia in vitro; that macrophages in human tumours express abundant HIF-1; and that expression from HRE-driven reporter constructs in the human macrophage-like cell line MonoMac 6 correlates more closely with HIF-1 than with HIF-2 up-regulation under hypoxia. Taken together, these findings suggest that HIF-1 may be the major hypoxia-inducible transcription factor in macrophages and that HIF-1-regulated constructs are likely to be effective in macrophage delivery of hypoxia-regulated gene therapy to human tumours.

Antigens, CD↗
PubMed2000

Design and testing of ribozymes for cancer gene therapy.

This chapter describes procedural aspects for development of ribozymes in general, and specifically, that cleave mRNA to an essential cellular gene, the AC40 subunit of RNA pol I. Ribozyme design includes functional selection of binding sites followed by computer modeling. These ribozymes are being used in vectors that target expression to the prostate via tissue specific promoters (Voeks, Norris, and Clawson, 1998) and have demonstrated efficacy.

Animals↗
PubMed1996

An in vitro nucleoside analog screening method for cancer gene therapy.

Suicide genes that sensitize cells to drugs that are normally nontoxic at therapeutic levels represent an important approach in human gene therapy research. We have developed an in vitro screening assay to assess the modulation of nucleoside analogs after transfection of a vector expressing the herpes simplex virus thymidine kinase gene (HSV-TK). The thymidine kinase gene enhances nucleoside phosphorylation to nucleotides that kill cells by blocking DNA elongation. Cells lines used are 3T3-NIH fibroblasts (parental cells) and 3T3-TKc3 (HSV-TK gene-transfected 3T3-NIH). Two types of analysis are performed: a cytotoxicity assay, the neutral red uptake assay to assess the IC50 on the two cell lines, and an HPLC analysis coupled to a radiochemical flow detector to evaluate metabolic profiles after incubation of cells with tritiated analogs. Results show that cells expressing the HSV-TK gene are more sensitive than the parent cells to the effect of acyclovir or ganciclovir, the reference purine analog drugs, and also to the effect of pyrimidine analogs, bromodeoxyuridine, bromovinyldeoxyuridine, and ethyldeoxyuridine. Promising nucleoside analogs for gene therapy that can be achieved by HSV-TK could be evaluated using this model.

3T3 Cells↗