Conditionally replicating adenoviruses (CRAd's) feature selective replication in and killing of tumor cells. Initial clinical studies with relatively attenuated early generation agents have resulted in promising safety and efficacy data. Nevertheless, increased specificity may be advantageous for an emerging generation of infectivity-enhanced CRAd's. Further, increased specificity could translate into a larger tolerated dose. An approach for increasing specificity is dual control of E1A expression. We constructed six CRAd's featuring two variants of the cyclo-oxygenase 2 (cox2) promoter, combined with three versions of E1A. Transcriptional targeting was supplemented with transductional targeting utilizing the serotype 3 knob. In vivo and in vitro results suggest that cox2 can be utilized for enhancing the specificity of E1A deletion mutants and that combination with the Delta24 mutation increases specificity without reducing potency. Combination with Delta2-Delta24 was specific but somewhat attenuated. The promoter variants behaved similarly, although the longer 1554-bp version displayed a trend for improved specificity. Transcriptional modifications were compatible with transductional targeting and resulted in up to 100,000-fold increase in the therapeutic window for Ad5/3cox2Ld24 vs wild-type adenovirus. Thus, the proposed triple-targeting strategy may be useful for increasing the safety and efficacy of adenoviral gene therapy for ovarian cancer.
Bibliographical noteFunding Information:
This work was supported by the Deutsche Forschungsgemeinschaft, the Academy of Finland, Helsinki University Central Hospital Research Funds, University of Helsinki Internal Funds, the Sohlberg Foundation, Biocentrum Helsinki, the Sigrid Juselius Foundation, the Finnish Cancer Society, the Emil Aaltonen Foundation, the Maud Kuistila Foundation, the Finnish Medical Foundation, the Ida Montin Foundation, the Instrumentarium Research Fund, the Bio-medicum Helsinki Foundation, the Finnish Oncology Association, the Research and Science Foundation of Farmos, and NIH Grant 1 P50 CA83591 (Ovarian Cancer SPORE).
- cyclooxygenase 2
- gene therapy
- ovarian neoplasms
- virus replication