Viral oncogenesis

A. R. Mattocks, Proc. 11th Internat. Cancer Congr. , Florence, 1974, Excerpta Med. Internat. Congr. Ser. No. 350, Excerpta Medica, Amsterdam, 1975, Vol. 2, Chem. Viral Oncogenesis, p. 20. 

The inhibitory effect of the various daunomycin derivatives on viral oncogenesis by FL VandRSVis shown in Table 15. FLV suspensions, prepared as described above, were incubated with and without the antibiotic (50 pg/ml) for 1 h at 37 °C and 0.1 ml of this suspension (ID90) was injected intraperito-neally into mice. Each experimental group contained six animals five of the six control animals died after 13 days of infection at which time all the animals... 

Table 15. Effect of daunomycin and its derivatives on viral oncogenesis in mice and chickens...

The inhibitory activity of daunomycin and its structural analogues on viral oncogenesis by FLV and RSV, and on in vitro transformation by MSV (M) suggests that it is the activity of the virus-associated enzymes which is sensitive to these antibiotics. The RNA-dependent DNA polymerase of the virions is responsible for the synthesis of viral DNA. Table 16 shows how the reverse-transcriptase activity of MSV (M), FLV and RSV is inhibited by various daunomycin derivatives. 

In addition to these genes there are other genes playing important role in the viral oncogenesis like interferon regulatory factor, G protein-coupled receptor, as well as DNA synthesis proteins including dihydrofolate reductase, thymidine kinase, thy-midylate synthetase and DNA polymerase. 

Besides the cytokine receptors that lack intrinsic kinase activity but have associated JAK kinases, STAT proteins can be activated by a variety of G-protein coupled receptors and growth factor receptors with intrinsic tyrosine kinase activity (for example EGF, PDGF, CSF-1, and angiotensin receptor). Increasing evidence suggests a critical role for STAT family members in oncogenesis and aberrant cell proliferation. Constitutively activated STATs have been found in many transformed cell lines and a wide variety of human tumor entities. Numerous non-receptor tyrosine kinases and viral oncoproteins, such as v-Src, v-Abl, v-Sis, and v-Eyk, have been identified to induce DNA-binding activity of STAT proteins. 

These clinical trials have pointed to a number of adverse effects, problems with in vivo administration of viral vectors and the severe concerns of insertional oncogenesis. Several problems associated with in vivo administration of viral vectors have been identified, which includes the following ... 

The viral vector infects nontarget cells also resulting in oncogenesis or severe inflammatory responses. 

Adeno-associated virus + + + Life-long +++ Quiescent and dividing Oncogenesis Viral mutation +... 

Much of the interest in Abelson (Abl) tyrosine kinase (review Smith and Mayer, 2002) stems from its involvement in oncogenesis in rodents and in humans. Like many other nonreceptor tyrosine kinases, Abl tyrosine kinase may be converted by mutations into a dominant oncoprotein and may thus contribute to tumor formation. The wild-type form of the Abelson kinase is termed c-Abl the viral, oncogenic form is termed v-Abl. This mutated enzyme was first discovered as the oncogene of murine Abelson leukemia virus. Apart from the v-Abl enzymes, other oncogenic forms of the Abelson kinase exist. Chronic myelogenic leukemia in humans is caused by a chromosome translocation in which a fusion protein is created from Abl tyrosine kinase and a Bcr protein (cf. Chapter 14). The result is a greatly increased tyrosine kinase activity with very different regulatory properties, to which a causal role in the occurrence of this leukemia is attributed. 

Recently, it has been suggested that viral infections play an important role in cancer or other chronic diseases (Danesh et al., 1997). Evidence for their involvement comes partly from epidemiological studies, focusing on the detection of viruses in (cancer) patients. Herpesviruses, papillomaviruses and hepadnaviruses (Hepatitis B) are all associated with transformation of cells and, along with other factors, initiate oncogenesis (Table 1). CMV has been reported to play a role in artherosclerosis (Persoons et al, 1994). 

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