We recently discovered that various human cancer lines (breast MDA-MB-231, prostate PC3, glioblastoma U87, melanoma BLM) respond to a 5-aminolevulinic acid (ALA)-based photodynamic challenge by upregulating inducible nitric oxide synthase (iNOS) to varying extents. Using a novel technique to distinguish photodynamically targeted cells from non-targeted bystander cells, we found that nitric oxide (NO) in the former diffused to the latter, induced iNOS there, and stimulated cell proliferation and migration. The magnitude of these responses for a fixed level of targeted cell death (~25%) varied with the extent of iNOS/NO upregulation in the four cancer lines. Accordingly, PC3 cells with the greatest upregulation were stimulated much more robustly than BLM cells with the smallest upregulation. This, along with our earlier bystander evidence, represents the first known example of a NO “feed-forward field effect” in the context of anti-tumor photodynamic therapy (PDT). In this article, we will review these findings, discuss their potential negative impact on clinical PDT, and how this might be relieved through use of pharmacologic inhibitors of iNOS activity or transcription.
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