| Summary: | 碩士 === 國立清華大學 === 生醫工程與環境科學系 === 104 === Malignant glioma is one of the toughest tumors to be treated at present due to the complexity of the tumor microenvironment and the intrinsic resistant to therapy. Previous studies have shown that CD11b+ myeloid cells play essential role in recurrent prostate and brain tumors following radiation therapy. In this study, the CD11b-diphtheria toxin receptor (CD11b-DTR) transgenic mouse model was used to evaluate the role of CD11b+ myeloid cells in TK/GCV suicide gene therapy for brain tumor using a murine astrocytomal tumor model, ALTS1C1-TK. The results show that the depletion of peritoneal macrophages (CD11b+F4/80+) and blood monocyte (CD11b+Ly6G-Ly6C-) could be achieved after two injections of DT, but the neutrophil (CD11b+Gr-1+) were increased transiently. Results also found that the depletion of CD11b+ myeloid cells enhanced the efficacy of TK/GCV therapy as shown by the increase of median surviving time of GCV-treated ALTS1C1-TK tumor-bearing mice from 30.6 days to 37.6 days with significant tumor growth reduction. Interestingly, the depletion of CD11b+ myeloid cells did not benefit the surviving time of tumor-bearing mice after receiving two doses of DT injections compared to the control PBS group (22.4 days vs 25.0 days, respectively). The immunohistological analysis of the tumor tissues revealed that F4/80+ macrophages were significantly increased after GCV administration associated with increasing micro-vascular density (MVD) of the tumor. Selective depletion of these macrophages resulted in reduced MVD and increasing iNOS+ macrophages and myeloid cells. On the other hand, selective depletion of the macrophages without GCV treatment resulted in the increase of the ARG-1+ myeloid cells in the tumor. These results indicate that macrophages could change their roles from the anti-tumor activity in the primary tumor to the pro-tumor function in the therapy-induced recurrent tumors. This study also found the best time for macrophages/monocytes depletion was performed during the administration of GCV, but not before or after GCV treatment. In summary, this study demonstrates that macrophages play different roles in the primary and the recurrent tumors. This study also provides a feasible strategy for combining conventional therapies with macrophage targeting for brain tumor therapy.
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