Signal transduction inhibitors as modifiers of radiation therapy in human prostate carcinoma xenografts

Radiation therapy is very useful in the treatment of prostate cancer; however, local treatment failure still occurs in the majority of patients with locally advanced disease. The growth and progression of tumors involve signaling through protein growth factors and small molecules such as arachidonic acid cascade products. In order to develop novel agents to enhance the efficacy of radiation therapy for patients with prostate cancer, the ability of signal transduction inhibitors including (1) the antiandrogen, flutamide; (2) the anti-inflammatory agent, ibuprofen; (3) the growth factor receptor antagonist, suramin; (4) the retinoid, all-trans-retinoic acid; and (5) the calcium pump inhibitor, thapsigargin to enhance the response of the human prostate carcinoma xenografts DU-145 and LN-CaP, was assessed. Flutamide acted as a radiation protector of the androgen independent DU-145 tumor but produced an additive antitumor effect in combination with fractionated radiation therapy in the androgen dependent LNCaP tumor. Administration of suramin or thapsigargin along with radiation therapy provided little or no tumor growth delay compared with radiation therapy alone. Treatment with all-trans-retinoic acid did not alter the response of the DU-145 to radiation therapy but increased the response of LNCaP tumor to radiation therapy. Administration of ibuprofen along with radiation therapy was most effective. The radiation dose modifying factor for ibuprofen in the DU-145 tumor was 1.8 and 1.7 for a 1-week and a 2-week fractionated regimen, respectively. Administration of ibuprofen along with radiation therapy to animals bearing the LNCaP tumor resulted in a 2-fold increase in tumor growth delay compared with radiation therapy alone. Further investigation of inhibitors of the arachidonic acid cascade as radiation modifiers is warranted.