Abstract
1577 Background: Treatment for high-grade gliomas represents an area of significant unmet medical need, largely because few agents cross the blood-brain barrier (BBB). RTA 744744 (WP744, 4’-O-benzyldoxorubicin hydrochloride) is a potent topoisomerase II poison and novel anthracycline screened for its ability to circumvent P-gp and MRP1allowing it to cross the BBB. To assess the drug’s potential in gliomas, RTA 744 was tested alone or in combination with temozolomide in an intracranial xenograft model of glioblastoma multiforme (GBM). It was hypothesized that a DNA repair inhibitor such as RTA 744 would enhance the effects of temozolomide. In vitro cell based assays confirmed this hypothesis and led to in vivo testing of this novel combination. Methods: U87MG cells were implanted into the right basal ganglia of nu/nu mice via an implantable screw system. In all studies, groups of 5 or 6 mice received PBS, temozolomide, RTA 744, or the combination of RTA 744 and temozolomide administered IP. PBS and temozolomide were given on a QDx5 schedule, and several schedules were tested for RTA 744. The primary endpoint in these studies was survival. Results: In the single agent study, by day 33, all 5 of the control animals had died compared with just one of the RTA 744-treated animals. Median survival for control animals was 28 days versus 37 for RTA 744-treated animals (T/C=132%). In the combination study, median survival was 30 days for controls, 40 days for temozolomide alone (T/C=133%), and 48 days for animals receiving the optimal combination of RTA 744 and temozolomide (T/C=160%). One animal in the combination group survived to day 78, whereas no control or Temodar treated animals survived past days 32 and 45, respectively. Conclusions: RTA 744 demonstrated potent single agent activity in a rigorous preclinical model of GBM. The combination of RTA 744 and temozolomide produced survival results significantly better than those from any chemotherapeutics tested in this model. This data supports the current Phase 1 trial of RTA 744 in patients with brain tumors as well as future trials testing the combination of RTA 744 and temozolomide. [Table: see text]
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
