Successful anticancer strategies require a differential response between tumor and normal tissue (i.e., a therapeutic index). Replication-competent, E1B-attenuated adenoviruses represent a means of achieving a therapeutic index by selectively destroying tumor cells with minimal toxicity to normal cells (90-92). The prototype virus, ONYX-015, is deleted for the E1B protein that binds to and inactivates cellular p53 (90,93). As a result, ONYX-015 viral therapy was initially regarded as a potentially significant advancement in cancer treatment because of its ability to destroy p53-mutated tumors, which comprise approx 50% of all human cancers (94). In addition, p53 mutation often correlates with resistance to conventional therapies (94,95). However, subsequent studies have called into question the host range specificity originally described for ONYX-015 (91,96-101). Multiple groups have recently demonstrated in vitro that ONYX-015 can lyse tumor cells having a wild-type or mutant p53 status. Because most of these studies used heterogeneous cell lines having diverse genetic backgrounds, it is possible that these conflicting observations were, in part, attributable to differences other than p53 status.
Because ONYX-O15 virus has proven to be biologically active and safe in cancer patients (102), several investigators have evaluated the possible radiosensitizing effect of ONYX-O15 on human tumor cells. ONYX-O15 has been suggested as an effective neoadjuvant to radiation therapy in a human colon carcinoma model and malignant glioma (103,104). These studies provide evidence that ONYX-O15 has an additive, even potentiating antitumor effect on irradiated human tumor xenografts supporting the use of combined treatment with this attenuated replicative adenovirus and radiation therapy.
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