The use of conditional replication-competent adenoviruses (CRADs) for cancer gene therapy gained much attention after a report published in 1996 stated that an adenovirus with a mutation in the E1B region (designated dl1520 or ONYX-015) replicates specifically in p53-mutated tumors (73). It is therefore conceivable that the destructive effect of a replication-competent adenovirus would be beneficial for cancer therapy as long as this destructive effect was limited to tumors. Because p53 is the most frequently mutated gene in human cancers (74), an adenovirus that would specifically destroy p53-negative or-mutant cells would thus be regarded as a powerful anticancer agent. However, subsequent studies indicated that a lytic infection of cells with an E1B-mutated adenovirus did not depend on the cellular p53 status and that p53 might play a necessary part in mediating cellular destruction via a productive adenovirus infection (75,76). Nevertheless, the notion that in situ amplification of CRADs and the resulting burst of viral progeny from the lysed cancer cells could enhance the local spread and penetration of these vectors, thereby greatly increasing therapeutic efficacy, spurred the creation and testing of various other CRADs for cancer therapy. This is because pre-clinical and clinical studies have shown that one of the major limitations of a replication-defective adenovector was the incomplete transduction of target cells because of poor vector penetration in tumor tissue. Indeed, the intratumoral injection of E1-deleted vectors often resulted in the transduction of only a small portion of the tumor cells surrounding a needle track. CRADs are believed to overcome this problem by producing cycles of replication, oncolysis, and local dissemination within tumor tissues that will ultimately eradiate all the cancer cells. It is noteworthy that CRAD and E1-deleted vectors are alike in most ways except for replication capability. Thus, resistance to an adenovirus infection resulting from lack of CAR expression, inflammatory response, or immune response which have all been observed in E1-deleted vectors, may also cause resistance to CRADs. However, these problems may be overcome through use of the same strategies used to enhance the transduction efficiency of E1-deleted vectors.
Two techniques have been used to create CRADs. In the first, a tumor-specific promoter is used to control the expression of an essential early gene, most frequently E1A. Several CRADs whose E1A gene is driven by a tissue-specific promoter have been reported to elicit tumor-specific cell lysis (77). The promoters used in these studies included the prostate-specific antigen (PSA) promoter for prostate cancer (77), the a-fetoprotein promoter for liver cancer, and human telomerase reverse transcriptase for various cancers (78). Similarly, expressing the viral E1B and E2 genes from the promoters controlled by the Tcf4 transcription factor targeted CRADs to colon cancers, which resulted in the constitutive activation of the wnt signaling pathway (79).
In the second approach, viral mutants with defective functions that are required for viral replication in normal cells but that are dispensable for replication in cancer cells are explored for virotherapy. Because mutations or deletions of the p53 and retinoblas-toma (Rb) genes are frequently found in cancers, CRADs that selectively replicate in cells with p53 or Rb defects have been sought for anticancer therapy (19,73,80). For example, E1A protein binds to Rb to trigger cell-cycle progression into the S phase. An adenovirus (Ad-824) with a deletion of eight animo acids from the Rb binding region of the E1A protein was reported to replicate specifically in Rb-defective cells (80). It was also reported that a virus associated-I (VAI) RNA mutant adenovirus can be used for Ras-dependent oncolytic virotherapy (81). It is noteworthy, however, that even though the E1-deleted adenovirus is generally regarded as replication defective, certain cancer cells may express E1-like factors that can accommodate replication of the E1-defective vectors (51,82,83). In fact, it has been reported that E1-deleted adenoviruses were able to replicate in HeLa and H1299 cells when the cells were infected with high multiplicities of infections (51,82).
It should be noted, however, that the outburst, or release, of CRADs from the cells in which they replicate may also depend on their ability to induce cell death during a late stage of infection. Indeed, it has been found that many cancer cells that have a defective p53 pathway do not support CRAD-induced cell death, whereas exogenous expression of p53 in human cancer cells during adenovirus replication augmented viral progeny release and increased antitumor potency. For example, a clinical trial of the ONYX-O15 vector showed that even though the vector was present and replicating in tumors as much as a week after intralesional injection, no obvious tumor necrosis or apoptosis was detected (84), suggesting that replication alone is not sufficient to induce cell death. On the other hand, a p53-expressing CRAD, Addl24-p53, was shown to have an advantage over Addl24, which does not express p53 (85,86). Similarly, a CRAD over-expressing the adenovirus death protein (ADP), a 11.6-kDa protein from the E3 region, was found to be more effective in killing tumor cells than the CRAD lacking ADP (87).
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