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Experimental Biology and Medicine 231:1283-1286 (2006)
© 2006 Society for Experimental Biology and Medicine

MINIREVIEW

Treatment of Viral and Neoplastic Diseases with Double-Stranded RNA Derivatives and Other New Agents

Julian L. Ambrus, Sr.*,1, Kailash C. Chadha{dagger}, Anwarul Islam*, Selina Akhter* and Julian L. Ambrus, Jr.*

* Department of Internal Medicine, State University of New York at Buffalo, Buffalo General Hospital/Kaleida Health System, Buffalo, New York 14203; and {dagger} Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York 14263

1To whom requests for reprints should be addressed at The Department of Internal Medicine, State University of New York at Buffalo, Buffalo General Hospital/Kaleida Health System, 100 High Street, Buffalo, NY 14203. E-mail: jlambrus{at}netscape.net


   Abstract
Top
 Abstract
Introduction
 RNA Interference
 Studies of Double-Stranded RNA...
 2'-Deoxyoligocytidilates
 Telomerase Inhibitors
 Summary
 References
 
Many attempts have been made to inhibit viral and neoplastic diseases by targeting the RNA system. The pathophysiologic significance of the microRNA system and the therapeutic potential of its manipulation are discussed. Studies of double-stranded RNA derivatives are reviewed. The therapeutic potential of one of these compounds, polyI:MPC, is emphasized. Studies of other related antiviral and antineoplastic agents are discussed, including 2'-deoxyoligocytidilates and telomerase inhibitors.

Key Words: AIDS • double-stranded and single-stranded RNA • HIV infection • neoplastic diseases • thiolated polyI:polyC (pI:MPC) • 2'-deoxyoligocytidilates • telomerase inhibitors • viral diseases


   Introduction
Top
 Abstract
 Introduction
RNA Interference
 Studies of Double-Stranded RNA...
 2'-Deoxyoligocytidilates
 Telomerase Inhibitors
 Summary
 References
 
With the rapidly developing drug resistance of some viruses and the difficulty in the timing of vaccine production and activity, there is great concern about viral disorders. Of particular concern are newly emerging viruses, hybrid viruses, and viruses bioengineered for use in bioterrorism. Similar problems exist with certain types of neoplastic disease. For this reason, there is increasing interest in therapeutic manipulation of the RNA system. We will briefly summarize the related studies.


   RNA Interference
Top
 Abstract
 Introduction
 RNA Interference
Studies of Double-Stranded RNA...
 2'-Deoxyoligocytidilates
 Telomerase Inhibitors
 Summary
 References
 
Gene-silencing techniques (RNA interference) are of particular interest in cancer research. In a series of recent reports (1–5), the roles of interfering RNAs (microRNAs) in cancer development were discussed. It is anticipated that these types of studies may lead to new diagnostic and therapeutic approaches. MicroRNAs are 21- to 25-nucleotide–long regulatory molecules that affect normal growth and development in plants and animals (6). They inhibit the translation of selected mRNAs into proteins. We know little about the normal function of individual microRNAs or about the development and function of abnormal micro-RNAs in neoplastic cells (3, 7). Johnson et al. (8) reported that the let-7 family of microRNAs regulate the expression of the ras oncogene. Michael et al. (9) described two microRNAs that are present in reduced quantities in precancerous and cancerous colorectal tissue. O’Donnell et al. (1) found that some abnormal microRNAs are regulated by a protein encoded by the well-known c-myc oncogene. Preliminary research indicates that microRNAs controlled by c-myc may also inhibit the expression of the E2F gene family, known inducers of apoptosis that encode another protein involved in cellular proliferation (10). The two genes mutually promote a vicious regulatory cycle leading to increased proliferation of neoplastic cells. Years of research may be required before adequate therapy can be developed based on these initial findings. Research along these lines may be of importance in the therapy of certain viral disorders, as well as neoplastic diseases.


   Studies of Double-Stranded RNA Derivatives
Top
 Abstract
 Introduction
 RNA Interference
 Studies of Double-Stranded RNA...
2'-Deoxyoligocytidilates
 Telomerase Inhibitors
 Summary
 References
 
Double-stranded RNA derivatives have experimentally been found to have antiviral and antineoplastic effects, thought to be due in part to their capacity to induce interferons (IFNs). Haines et al. (11), Torrence and DeClereq (12), DeClereq (13), and Sen et al. (14) reported that double-stranded RNA has the capacity to induce IFNs in animal and human cells and to increase resistance to viral infections. A prototype of double-stranded RNA, polyI:polyC, has been reported to inhibit the growth of some tumor cell lines and the growth rate of human tumor xenografts in mice (15, 16). While polyI:polyC is the most potent among the double-stranded RNAs tested, it has proved to be too toxic for therapeutic application (17, 18). Selective thiolation at the 5 position of the cytosine bases in polyI:polyC resulted in partially thiolated double-stranded RNA, polyI:MPC (Fig. 1Go, Refs. 19, 20). PolyI:MPC was found to be an important inducer of IFN-{alpha}, IFN-ß, and IFN-{gamma} (20–29). It is of minimal toxicity in vivo in mice, rabbits, and guinea pigs and is subject to less degradation by plasma ribonucleases than its parent compound (22). PolyI:MPC has significant antitemplate activity against DNA and RNA polymerases, including reverse transcriptase (which is of great significance in the treatment of human immunodeficiency virus [HIV] infection) (23–27). This compound activates IFN-induced double-stranded RNA–dependent protein kinase (which inhibits protein synthesis) and activates 2',5'-oligoadenylate synthetase, which in turn activates a latent endoribonuclease and activates adenylate cyclase, thus increasing the concentration of cAMP. PolyI:MPC activates macrophages and augments the natural killer cell activity (20, 27). In primary human lymphocyte cultures, polyI:MPC was found to be a potent inhibitor of HIV replication in vitro, including multidrug-resistant HIV lines in preliminary results (23). A recent study indicated that 7.5% thiolation is optimal for this compound from the point of view of IFN-{alpha}, IFN-ß, and IFN-{gamma} production and antiviral and antiproliferative activity (25). The effect of polyI:MPC is being explored alone and in combination with other anti-HIV agents, including those reported in the retroviral MAIDS model in mice (30). This model was found to be a useful, inexpensive, and quick early screening approach to acquired immunodeficiency syndrome (AIDS) and AIDS-related lymphoma (31). Investigations will proceed to nonhuman primate models and eventually to clinical studies. We anticipate that these agents and derivatives may contribute to the treatment of viral and neoplastic diseases, overcome disease-related IFN resistance (32), and stimulate other factors of the immune system. Figure 1Go shows the chemical structure and partial 5-thiolation of cytosine residues of polynucleotides.


Figure 1
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  		Figure 1. Chemical structure and partial 5-thiolation of cytosine residues of polynucleotides. MeOBr, methyl hypobromide; NaSH, sodium sulfhydride.

 

   2'-Deoxyoligocytidilates
Top
 Abstract
 Introduction
 RNA Interference
 Studies of Double-Stranded RNA...
 2'-Deoxyoligocytidilates
Telomerase Inhibitors
 Summary
 References
 
Investigators have produced and evaluated a series of polyI:MPC compounds that are closely and distantly related, as well as others in viral and neoplastic pathology. The most effective included oligonucleotides converted to 4 thio-deoxyuridylic acid (s4d UMP)35 (Fig. 2Go) containing oligomers of the 4 amino group of the cytosine bases, which were converted to the corresponding 4-thio group in 2'-deoxyoligocytidilates. 2'-Deoxyoligocytidilates inhibited a number of established tumor cell lines in vitro and was not cytotoxic to human granulocyte-macrophage progenitor cells. It was effective in vitro against multidrug-resistant HIV lines (23). 2'-Deoxyoligocytidilates also appeared to inhibit attachment of HIV to target cell receptors and viral fusion to cell membranes. In a series of publications, the chemistry and the antiviral effects (29, 33, 34) of this agent were discussed. Further in vivo studies of the possible role of 2'-deoxyoligocytidilates in oncology are under way.


Figure 2
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  		Figure 2. Chemical structure of (s4d UMP)35 (Suligovir).

 

   Telomerase Inhibitors
Top
 Abstract
 Introduction
 RNA Interference
 Studies of Double-Stranded RNA...
 2'-Deoxyoligocytidilates
 Telomerase Inhibitors
Summary
 References
 
Other synthesized compounds are telomerase inhibitors (35, 36). Telomerase, a ribonucleoprotein complex, includes an RNA template and a catalytic subunit with reverse transcriptase activity and is responsible for the maintenance of normal telomere structure (37). In contrast to healthy adult somatic cells (38–40), most human neoplastic cells exhibit high telomerase activity, with some exceptions, including stem cells of renewable tissues and activated lymphocytes (41). Telomerases thus protect cells against apoptosis (40). Telomerase inhibitors have been described previously (41). Matthes and Lehmann (42) were the first to propose the evaluation of antitelomerase chimeric oligonucleotides, which contain a moiety targeting the primer binding sites and a sequence targeting the RNA as well. One compound that is fairly effective in inhibiting telomerases is a chimeric oligonucleotide composed of an antisense sequence directed against RNA template regions and a base modified moiety. The chemical synthesis has been described (29, 33, 35). Evaluation in several biological model studies is under way, including studies of various therapeutic combinations. In a recent study, retinoid and arsenic combination therapy was effective in patients with active promyelocytic leukemia, including those who were resistant to retinoic acid alone (43). This appears to be due in part to partial telomerase inhibition. Future studies will investigate specific telomerase inhibitors relative to their effect in combination therapy of promyelocytic leukemia and related diseases.


   Summary
Top
 Abstract
 Introduction
 RNA Interference
 Studies of Double-Stranded RNA...
 2'-Deoxyoligocytidilates
 Telomerase Inhibitors
 Summary
References
 
This brief review demonstrates the potent antiviral activity (such as agents to treat multidrug-resistant HIV) and antineoplastic effects of new therapies that are based on double-stranded RNA derivatives (including polyI:polyC), deoxyoligocytidilate compounds, and telomerase inhibitors (such as those containing methylated deoxyuridine moiety). Further in vitro studies are planned to investigate the effects of these agents in animal and human models.


   Acknowledgments
 
We thank S. Grochowski for technical assistance; students K. Lillie and S. Lillie for participation in these projects; and Dr. T. J. Bardos, Professor of Medicinal Chemistry at the State University of New York at Buffalo, and members of his staff for advice and collaboration.


   Footnotes
 
Original studies by the authors were supported in part by the John R. Oishei Foundation, the Margaret Duffy and Cameron Troup Foundation for Cancer Research, and the Hyde Foundation.


   References
Top
 Abstract
 Introduction
 RNA Interference
 Studies of Double-Stranded RNA...
 2'-Deoxyoligocytidilates
 Telomerase Inhibitors
 Summary
 References
 

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