Invited Presentation: Sequencing Effects of a Superoxide Dismutase Mimetic on Tumor Radioresponsiveness

Abstract: ID # 230007 aperr savage 2 41 2003-11-04T22:22:00Z 2003-11-12T20:35:00Z 2003-11-12T20:35:00Z 1 582 3319 Computer Services 27 6 4075 9.3821 6 pt 2 2 Purpose: A recent study demonstrated that a novel small molecular weight mimetic of Superoxide Dismutase (SOD), AEOL-10113, can serve as a normal tissue radioprotectant. Its radioprotective properties presumably derive from its ability to efficiently scavenge a variety of reactive oxygen species (ROS), blocking initiation and progression of chronic inflammatory changes induced by ionizing radiation. Interestingly, AEOL-10113 also has anti-tumor effects. The overall effects of this compound on tumor radioresponsiveness, given its simultaneous ROS scavenging and anti-tumor mechanisms, would be difficult to predict. We, therefore, sought here to investigate whether AEOL-10113 would serve to increase tumor radioresponsiveness while protecting normal tissues. Using two distinct combinations of AEOL-10113 with radiotherapy (RT), i.e., administering the drug either before or after radiation, we examine the potential for additive tumor control, as well as the effects of differential sequencing on the overall treatment outcome. Materials and Methods: First flank tumors were established in the flank of Fischer-344 rats by transplanting an excised portion (a 0.5x0.5x0.5mm cube) of a “donor” R3230 tumor, a syngeneic mammary carcinoma. Tumors were allowed to reach a mean diameter of 6-8mm before randomization to treatment groups. Rats were randomized to: (1) no treatment, (2) AEOL-10113 alone (6mg/kg/day, intraperitoneal), (3) radiation alone (21Gty, or (4) AEOL-10113 (6mg/kg/day, intraperitoneal) and radiation (21Gy). Treatment with AEOL-10113 began 15 minutes prior to radiation/sham-irradiation. Radiation was delivered to the tumor-bearing leg, under anesthesia using a single dorsal-ventral field with 4-MV photons, in a single dose, with a 0.5cm bolus placed over the tumor. Growth was followed until tumors reached approximately 5 times the original treatment volume. Next, flank tumors were established in the flank of Balb/C mice by injecting 104 4T1 cells (a syngeneic mammary carcinoma) subcutaneously. Mice were randomized to +/- AEOL-10113 (6mg/kg/day), +/- radiation (15Gy in 3 fractions, spaced by 12 hours) once tumors reached a mean volume of 200mm. Treatment with AEOL-10113 began 15 minutes following the last dose of radiation/sham-irradiation and continued either: (1) for 3 days, or (2) for the duration of the study. Growth was followed until tumors reached approximately 5 times the original treatment volume. Results: AEOL-10113 alone was more effective in the R3230 model (Tumor Growth Delay = 5 days) than the 4T1 model (Tumor Growth Delay = 2 days). When administered prior to irradiation, AEOL-10113 was as effective as radiation alone (Tumor Growth Delay = 12 days), but demonstrated no additivity. When administered after irradiation, AEOL-10113 achieved supra-additive growth delay in both short-term administration (Tumor Growth Delay = 20 days) and long-term administration (Tumor Growth Delay = 24 days). Conclusion: These studies demonstrate that AEOL-10113, an effective normal tissue protectant, can also serve to increase tumor radioresponsiveness. However, the sequencing of its administration with radiation is important. When AEOL-10113 is administered prior to RT, the potential additivity of this combination is lost. When given after radiation is complete, AEOL-10113 causes a marked tumor growth delay, significantly greater than either modality, alone. Interestingly, the crucial window of activity for AEOL-10113 appears to be in the first few days after RT is complete, as 3 days of dosing was as effective as an indefinite dosing schedule. As this SOD mimetic can both protect normal tissues and enhance the anti-tumor effect of radiation, more investigation is warranted to determine whether (1) simultaneous administration of AEOL-10113 with fractionated RT, or (2) sequential administration of RT followed by AEOL-10113 can protect normal tissues while enhancing tumor curability. (Funding was received from NIH Grant P30CA14236 and Incara Pharmaceuticals.)

A17-148

Invited Presentation: Sequencing Effects of a Superoxide Dismutase Mimetic on Tumor Radioresponsiveness