Because of the specificity of Watson-Crick base pairing, attempts are now being made to use oligodeoxynucleotides (oligos) in the therapy of human disease. However, for a successful outcome, the oligo must meet at least six criteria: (i) the oligos can be synthesized easily and in bulk; (ii) the oligos must be stable in vivo; (iii) the oligos must be able to enter the target cell; (iv) the oligos must be retained by the target cell; (v) the oligos must be able to interact with their cellular targets; and (vi) the oligos should not interact in a non-sequence-specific manner with other macromolecules. Phosphorothioate oligos are examples of oligos that are being considered for clinical therapeutic trials and meet some, but not all, of these criteria. The potential use of phosphorothioate oligos as inhibitors of viral replication is highlighted.

https://science.sciencemag.org/content/sci/261/5124/1004.full.pdf

Antisense oligonucleotides as therapeutic agents--is the bullet really magical?

The zinc finger transcription factor Egr-1 is essential for and restricts differentiation along the macrophage lineage

Cell-restricted membrane antigens have made it possible to map the distribution of mature macrophages in many murine tissues. Monoclonal antibodies (mAbs) have been used to define the appearance of macrophages dusing foetal and postnatal development, to establish the anatomic relationships between macrophages and other cells in the normal and diseased adult, and to investigate cellular modulation and heterogeneity within different microenvironments. Current studies have illustrated the complex differentiation pathway of mononuclear phagocytes in vivo and have raised questions concerning the mechanisms that determine monocyte entry, migration and fate within tissues. Macrophages constitute a major, widely dispersed system of cells that regulate homeostasis in the normal host and respond to tissue injury by contributing essential functions during inflammation and repair. In this review we consider several membrane marker antigens which have proved useful in studying the life history and biologic properties of macrophages, and relate immunochemical studies on antigen expression to lineage analysis and macrophage differentiation in vivo. We restrict our discussion to the mouse, in which it is possible to manipulate the system in its entirety. Where known, properties of macrophages in other species are broadly similar.

Antigen markers of macrophage differentiation in murine tissues.

Rational design of sequence-specific oncogene inhibitors based on antisense and antigene oligonucleotides☆

Antisense RNA and its derivatives may provide the basis for highly selective gene inhibition therapies of virus infections. In this review, I concentrate on advances made in the study of antisense RNA and ribozymes during the last five years and their implications for the development of such therapies. It appears that antisense RNAs synthesized at realistic levels within the cell can be much more effective inhibitors than originally supposed. Looking at those experiments that enable comparisons to be made, it seems that inhibitory antisense RNAs are not those that are complementary to particular sites within mRNAs but those that are able to make stable duplexes with their targets, perhaps by virtue of their secondary structure and length. The inclusion of ribozyme sequences within antisense RNAs confers RNA-cleaving activity upon them in vitro and possibly in cells, thereby offering the possibility of markedly increasing their therapeutic potential. The varieties of natural ribozyme and their adaptation a...

Towards Gene-Inhibition Therapy: A Review of Progress and Prospects in the Field of Antiviral Antisense Nucleic Acids and Ribozymes:

Human promyelocytic leukemia HL-60 cells were induced to differentiate into macrophages by PMA (phorbol 12-myristate-13-acetate), 1-alpha-25-(OH)2D3(1-alpha-25-dihydroxyvitamin D3, hrGM-CSF (human recombinant granulocyte-macrophage colony-stimulating factor) and into granulocytes by DMSO (dimethylsulfoxide). We found that the differentiation of HL-60 cells into macrophages was accompanied by transcription of the c-fms oncogene, which was assessed by a modified PCR (polymerase-chain reaction) method. After treatment with a c-fms anti-sense oligomer, the PMA and hrGM-CSF induced macrophage differentiation of HL-60 cells was significantly inhibited, whereas either 1-alpha-25-(OH)2D3 induced macrophage or DMSO and hrGM-CSF induced granulocytic differentiation was not inhibited. Furthermore, we treated the HL-60 cells with M-CSF (macrophage-colony stimulating factor or CSF-1) anti-sense N degrees 2 (see Figure 1) in the presence of PMA, hrGM-CSF, 1-alpha-25-(OH)2D3 and DMSO. The results showed that this treatment leads to a significant inhibition of PMA and hrGM-CSF-induced macrophage differentiation, but has no influence on the 1-alpha-25-(OH)2D3-induced macrophage differentiation and DMSO-induced granulocytic differentiation. It was further demonstrated that the M-CSF (or CSF-1) and c-fms antisense oligomers acted synergistically on inhibition of macrophage formation induced by PMA and hrGM-CSF, but had no inhibitory effect on the macrophage formation induced by 1-alpha-25-(OH)2D3. Thus we concluded firstly, that HL-60 cells differentiate into macrophages along two different pathways: one is involved in the action of the c-fms oncogene and the other is not. Secondly, an autocrine circuit of M-CSF (or CSF-1) action may exist in the macrophage formation induced by PMA and hrGM-CSF.

Zhu Dx

Papers

The role of the c-fms oncogene in the regulation of HL-60 cell differentiation.