alpha6 integrin cleavage: sensitizing human prostate cancer to ionizing radiation.

PURPOSE: The goal was to determine if prostate tumor cells containing a mutant alpha6 integrin would be defective in tumor re-population following clinically relevant fractionated ionizing radiation (IR) treatments. MATERIAL AND METHODS: Human prostate cancer cells derived from PC3N cells were used which conditionally expressed a cleavable, wild type form of alpha6 integrin (PC3N-alpha6-WT) or a mutated non-cleavable form of alpha6 integrin (PC3N-alpha6-RR). The resulting tumor growth before, during and after fractionated doses of IR (3 Gyx10 days) was analyzed using the endpoints of tumor growth inhibition (T/C), tumor growth delay (T-C), tumor doubling time (Td) and tumor cell kill (Log(10) cell kill). RESULTS: The T/C values were 36.1% and 39.5%, the T-C values were 20.5 days and 28.5 days and the Td values were 5.5 and 10.5 days for the irradiated PC3N-alpha6-WT and PC3N-alpha6-RR cells, respectively. The Log(10) was 1.1 for the PC3N-alpha6-WT cells and 0.8 for the PC3N-alpha6-RR cells. The tumor response to IR was altered in tumors expressing the mutant alpha6 integrin as indicated by a significant increase in tumor growth inhibition, an increase in tumor growth delay, an increase in tumor doubling time and an increase in tumor cell kill. CONCLUSIONS: Blocking integrin cleavage in vivo may be efficacious for increasing the IR responsiveness of slow growing, pro-metastatic human prostate cancer.