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Original Research |
, a Promoter That Protects Cells, in Response to Chemotherapy
1 Department of Radiology, Duke University Medical Center, Durham, NC
27710.
2 Department of Radiation Oncology, University of Colorado Health Sciences
Center, Aurora, CO.
3 University of North Carolina, Chapel Hill, NC.
4 Duke University School of Medicine, Durham, NC.
5 Department of Radiation Oncology, Duke University Medical Center, Durham,
NC.
OBJECTIVE. Bioluminescence imaging is a powerful technique that has
shown that hypoxia-inducible factor 1 (HIF-1), a transcription factor that
protects tumor cells from hypoxia, is up-regulated in tumors after radiation
therapy. We tested the hypothesis that bioluminescence imaging would
successfully and noninvasively depict an increase in HIF-1 in the novel
therapeutic environment of chemotherapy and that, as in radiation therapy, the
underlying mechanism involves inducible nitric oxide synthase originating in
macrophages. Active HIF-1 consists of 
and β subunits that bind to
promoter sequences in many genes, including those that protect endothelial
cells, promote angiogenesis, and alter metastasis and tumor cell
metabolism.
MATERIALS AND METHODS. We grew 4T1 murine breast carcinoma cells
with an HIF-1 luciferase reporter construct to 7 mm in the right rear
flanks of 18 Balb-C mice. The mice were evenly randomized to receive one of
the following single intraperitoneal doses: maximum tolerated dose
cyclophosphamide (231.5 mg/kg), maximum tolerated dose paclitaxel (10 mg/kg),
or control saline solution. Immunohistochemical analysis of tumor sections
from the cyclophosphamide and control groups was performed 10 days after
treatment to assess the intensity and distribution of HIF-1 expression,
hypoxia, macrophage infiltration, and expression of macrophage-derived
inducible nitric oxide synthase in tumor tissues treated with maximum
tolerated dose cyclophosphamide compared with control tumors.
RESULTS. Cyclophosphamide, but not paclitaxel, significantly
inhibited tumor growth and caused a significant increase in HIF-1
protein levels, which peaked at a 10-fold increase from baseline on day 10
after administration. In contrast, paclitaxel did not have an antitumor effect
in this model and did not cause a significant increase in HIF-1.
Immunohistochemical analysis showed increased and more evenly dispersed levels
of HIF-1 protein, macrophage infiltration, and expression of inducible
nitric oxide synthase originating in macrophages after cyclophosphamide
treatment.
CONCLUSION. We successfully monitored increased expression of a
tumor protective protein in a noninvasive manner. Such monitoring may be a
means of detection of resistance to therapy, and it may be possible to use the
monitoring findings to alter treatment strategies in real time. The tumor
microenvironment seen at immunohistochemical analysis supports the
hypothesized mechanism that the cytotoxic effects of radiation therapy that
attract macrophages, causing the release of macrophage-derived inducible
nitric oxide synthase and production of HIF-1 under aerobic conditions,
also underlie chemotherapy. Such noninvasive imaging may be a means to
development of therapeutic strategies that prevent HIF-1 up-regulation after
chemotherapy treatments.
Keywords: bioluminescence imaging • molecular imaging • tumors
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