UBC Theses and Dissertations
Humatopoietic effects of photofrin Hunt, David William Carey
In the presence of visible light, certain naturally-occurring and synthetic non-metallic porphyrins and their derivatives can cause toxic effects within cells. This aspect of these compounds has been harnessed for the elimination of malignant tissue, a therapeutic approach termed photodynamic therapy (PDT). The likelihood that photosensitizing porphyrins might significantly influence the status of tissues other than those targeted by PDT, has not been rigorously investigated. When given to normal male mice, the photosensitizer Photofrin® (dihematoporphyrin ether) produced significant increases in spleen weight, nucleated cell numbers, indices of cell proliferation, and levels of granulocyte-macrophageand erythroid progenitors. Concordant with these changes, was an increase in the number of spleen cells which expressed the receptor (CD71) for the iron transport protein transferrin but no change in expression of the receptor (CD25) for the T cell growth factor interleukin-2, suggesting that the compound had not effected splenic lymphocyte activation. Further flow cytometric studies demonstrated that Photofrin® elevated the number of nucleated spleen cells which expressed antigens recognized by the monoclonal antibody LR-1, the erythroid lineage-specific antibody TER-119, and those that did not express the leukocyte common antigen CD45 or major histocompatibility Class I molecules. The antigen recognized by the LR-1 antibody was subsequently identified as the glycosylphosphatidylinositol-anchoredheat stable antigen (HSA) by enzyme digest, f l ow cytometric and Western immunoblot studies. The increased expression of HSA in the spleens of Photofrin®-treated mice was associated with heightened erythropoiesis in t he organ. Granulopoiesis was the dominant activity in the marrow of mice given Photofrin®. This was represented by a large increase in the proportion of cells which expressed the myeloid-associated Gr-1 and CD11b antigens and a decrease in the proportion of cells which expressed CD71 or the B cell-restricted isofo rm of CD45 (B220). In contrast to Photofrin®, other photosensitizing porphyrins including benzoporphyrin derivative (BPD, verteporfin), hydroxyethyl vinyl deuteroporphyrin, hematoporphyrin IX, and protoporphyrin IX had no discernable hematostimulatory effect. Culture of murine erythroleukemic cells with Photofrin®, but not BPD, increased cell surface CD71 levels and binding of transferrin to these cells, but did not cause erythroid differentiation. Photofrin® also increased surface CD71 expression by non-erythroid P815 mastocytoma cells, suggesting that Photofrin® can influence cellular iron status. Although the mechanism by which Photofrin® influences hematopoiesis was not identified, it nevertheless will be an interesting agent with which to study murine hematopoiesis.
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