Conditionally replicating adenoviruses

Oncolytic Adenoviruses. A class of AdVs has been developed to specifically kill cancer cells, an approach that has been termed virotherapy [56]. Contrary to the approach pursuedi with first-, second-, and third-generation adenovirus vectors, these oncolytic or conditionally replicating adenoviruses (CRAds) are engineered in such a way that they retain the ability to replicate. This replication however, is tumor selective—the virus will only infect and proli-ferate in malignant cells with mutations in specific tumor suppressor genes [2, 19, 56]. Thus, a transgene is actually not required for the therapeutic effect to take place. 

Lamfers ML, Grill J, Dirven CM, Van Beusechem VW, Geoerger B, Van Den Berg J et al. Potential of the conditionally replicative adenovirus Ad5-Delta24RGD in the treatment of malignant gUomas and its enhanced effect with radiotherapy. Cancer Res 2002 62 5736 5742. 

Ylosmaki, E., Hakkarainen, T., Hemminki, A., Visakorpi, T., Andino, R., and Saksela, K. 2008. Generation of a conditionally replicating adenovirus based on targeted destruction of El A mrna by a cell type-specific Microrna./ournoJ of Virology, 82,11009-11015. 

Suzuki K, Fueto J, Krasnykh V, Reynolds PN, Curiel DT, Alemany R. A conditionally replicative adenovirus with enhaneed infeetivity shows improved oncolytic potency. Clin Cancer Res 2001 7 120-126. 

Hernandez-Alcoceba R, PihaljaM, WichaMS, Clarke MF. A novel, conditionally replicative adenovirus for the treatment of breast cancer that allows controlled replication of El a-deleted adenoviral vectors. Hum Gene Ther 2000 11(14) 2009-2024. 

AAV-specific RNA synthesis does not precede AAV DNA synthesis (Rose and Koczot, 1972). AAV RNA synthesis is first detectable approximately 2 hours after the onset of AAV DNA synthesis when AAV and adenovirus are used simultaneously to infect a cell. This is true even under conditions where adenovirus early messenger RNA synthesis is readily measurable. Thus the possibility exists that there is no class of AAV RNA synthesized prior to the onset of DNA replication. Again, if adenovirus infection preceded AAV infection by 10 hours, AAV-specific RNA could be detected starting at Shours after AAV infection at the time of onset of AAV DNA synthesis (Carter et al, 1973). 

In addition to the antineoplastic activity, camptothecin was found to be an effective inhibitor of adenovirus replication [268, 269] and herpes virus replication [252, 270]. 10-Methoxycamptothecin is about 8-times more potent than camptothecin as an inhibitor of herpes virus [252]. A combination of camptothecin and dimethyl sulphoxide is very effective for the topical treatment of psoriasis [271]. Since, in the goldfish brain, camptothecin blocks RNA synthesis in eucaryotic cells by blocking the incorporation of uridine into RNA, this alkaloid can block the memory of conditioned avoidance and produces no measurable effect on retention of the learned response [272]. 

Temperature-sensitive ts) mutants have proven to be the most useful type of mutants for a number of viruses and bacteria because of their conditional-lethal phenotype. The (ts) mutants are produced by alteration in the nucleotide sequence of a gene so that the resulting protein product of the gene is unable to assume or maintain its functional configuration at the non-permissive (37-39°C) temperature. The protein, however, is able to assume a functional configuration at the permissive temperature (32-34° C), e.g., herpesviruses, adenoviruses, and influenza viruses. Thus, these mutants can replicate in mucosal sites with a lower temperature, e.g., the nasal cavity, but are unable to cause systemic infections and disease. 

It seems only reasonable to suppose that the ability of adenoviruses to induce cellular DNA synthesis and entry into the cell cycle in mammalian cells is of advantage to the virus replication cycle such a property could hardly have evolved for any other purpose. Bellett and colleagues (see, for example, Murray et al., 1982a) have pointed out the particular relevance of this ability to the natural conditions of infection. By contrast to the artificial laboratory situation in which the virus is usually provided with cells that are partially transformed (they are immortal) and undergoing rapid growth and division, most cells encountered by the virus in the natural host are likely to be arrested at the Gl/GO boundary. Thus, it would seem to be of considerable advantage to the virus to possess a mechanism that, soon after an adenovirus enters such a relatively inactive host cell, induces that cell to enter its most active biosynthetic state and, thus, provide maximal quantities of those cellular proteins upon which viral DNA synthesis and gene expression depend. 

Interestingly, Jablons and colleagues have also investigated the efficacy of the ON YX-015 adenovirus in mesothelioma cells, and they found that the cytolytic effect of this agent in mesothelioma is dependent upon absence of pl4(ARF) expression. ONYX-015 is a conditionally rejjication-competent adenovirus lacking the Elb-55-kDgene, and therefore can only replicate in tumor cells lacking functional p53. (One of the functions of Elb-55-kD is to bind and inactivate... 

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