The overall hypothesis of this project is that subcurative PDT of certain tumor types/sites may increase distant metastasis despite reasonable local control, and thus be detrimental to long-term cure. This will be tested in 5 aims examining 4 sub-hypotheses: (a) The site of implantation (environment) of tumors in experimental models for different cancers is critical for a reasonable evaluation of long-term cure. This effect may be related to or be distinct from factors that affect local control. This will be tested in rat and murine (human cells) models of prostate cancer (PCa) and in a murine model for lung cancer. (b) The nature of the photosensitizer (PS), localization and action in vivo are important determinants of whether or not metastasis occurs consequent to PDT: PS acting primarily by tumor cell toxicity are more likely to lead to metastasis than PS which eradicate tumors by vascular shutdown. The PS, BPD will be established. The effect on metastasis of varying times post-PS administration, PS concentration and the extent of local control will be examined. The induction of hypoxia following PDT could favor metastasis. The effect of fluence rate and of light fractionation on local control on tumor and on distant metastasis will be evaluated collaboratively with Project 3. (d) PDT can trigger molecular processes that might facilitate metastasis: effect of PDT on tumor. Tu cell shedding, Tu cell-extracellular matrix binding, E-cadherin expression and transcriptional and post-transcriptional activation of HIF1a and VEGF will be correlated with the extent of metastasis. Immunocytochemical and biochemical techniques involving ELISAs, Northern and Western blots, in situ hybridization and RT-PCR will be used. (e) Finally, combination protocols will be explored where PDT-based local and metastasis control are enhanced. (I) With Project 1, treatment protocols that combine differentiation therapy with PDT will be tested in vivo in the murine model for human prostatic cancer. (ii) A combination of an antiangiogenic peptide and PDT which is expected to prevent disaggregated tu cells from colonizing distant organs will be evaluated. (iii) Macrophage targeting protocols will be evaluated in the orthotopic rat prostate cancer model. It is anticipated that despite the focus on prostate cancer models, data obtained in this project will enhance our understanding of the connection between PDT and metastasis in a more general fashion. Such long-term effects become relevant as PDT is applied to early cancers and cure becomes the goal.
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