Proffered Papers— Medical Oncology

DOMINANT NEGATIVE IkBa POTENTIATES IN ANTI-TUMOR ACTIVITY OF DOXORUBICIN IN A RAT HIND LIMB ISOLATED PERFUSION MODEL

R. Davidson, X. Lu, P. Chiao, R. Pollock, B. Feig. (Univ. of Texas M.D.Anderson Cancer Center, Houston, TX 77030)

Introduction: Inhibition of NF-kB activity has been shown to potentiate apoptotic killing secondary to chemotherapeutic and biologic agents. We hypothesized that direct gene transfer of the dominant negative inhibitor (IkBaM) would potentiate the in vivo tumor response to doxorubicin delivered via isolated perfusion in a rat hind limb fibrosarcoma model.

Methods: Viable tumors were established in the hind limb of Fisher rates weighing 150-250 g using a methylcholanthrene induced rat fibrosarcoma (RFS). When tumors reached 5-10 mm in greatest dimension, direct intra-tumoral injection with 6 x 1010 pfu of either Ad5IkBaM, empty Ad5 vector (EV) or a similar volume of phosphate buffered saline (PBS) was performed serially for 3 days. Rats were then perfused with doxorubicin 1.0mg/gbw/cc for 10 minutes at a perfusion rate of 2.4cc/min. Animals were subsequently observed for 21 days with serial recording of tumor volumes.

Results: There was a reduction in tumor volume from baseline to day 21in the Ad5IkBaM treated group (-21%) as opposed to continued tumor growth in the EV (+58%) and PBS (+457%) treated groups. Overall ANOVA was significant for the three groups (P<0.001). The graph below shows the percent volume change for the three groups.

Conclusions: The addition of Ad5IkBaM potentiates the effect of doxorubicin in this isolated lower extremity perfusion model in the rat. We believe that inhibition of NF-kB activity leads to increased apoptotic sarcoma cell killing in concert with doxorubicin or other effectors that lead to apoptosis. IkBaM may represent an important adjunct to therapies based on the induction of apoptosis in the future.