Biomedical subjects

Janet E Price

Publications and source records attributed to Janet E Price.

23 records · Page 2Linked to original sources

PubMed2003

Renal cell carcinoma bone metastasis: epidermal growth factor receptor targeting.

Renal cell carcinoma frequently metastasizes to the skeleton in the later stages of the disease. Patients with bone metastasis from renal cell carcinoma experience severe pain, neurologic compromise, and frequent pathologic fractures. These tumors are relatively resistant to chemotherapy and radiation, and the 5-year survival of patients is less than 10%. The epidermal growth factor receptor is overexpressed in human renal cell carcinoma and hypothesized to be a potential target in the treatment of bone metastasis. Using in vitro studies, it was shown that blockade of the epidermal growth factor receptor was effective in decreasing proliferation and receptor autophosphorylation of a human bone-derived renal cell carcinoma cell line. In an experimental nude mouse model, treatment with Taxol and protein tyrosine kinase inhibitor 166, a small molecule receptor tyrosine kinase inhibitor, blocked the growth of renal cell carcinoma in the tibia and resulted in decreased bone destruction. The use of protein tyrosine kinase inhibitor 166 and Taxol was cytostatic and nontoxic in long-term animal experiments. Epidermal growth factor receptor blockade is an exciting potential therapy for renal cell carcinoma bone metastasis in humans, but because it is cytostatic rather than cytotoxic, its optimal role may be as a supplement to cytotoxic chemotherapy. It ultimate role and its relationship to other therapeutic interventions remains to be elucidated and validated.

Animals↗

PubMed2003

Dacarbazine causes transcriptional up-regulation of interleukin 8 and vascular endothelial growth factor in melanoma cells: a possible escape mechanism from chemotherapy.

The incidence of cutaneous malignant melanoma in the United States has increased more than any other cancer in recent years. Chemotherapy for metastatic melanoma is disappointing, there being anecdotal cases of complete remission. Dacarbazine (DTIC) is considered the gold standard for treatment, having a response rate of 15-20%, but most responses are not sustained. The mechanisms for the increased chemotherapeutic resistance of melanoma are unclear. The objective of this study was to determine the mechanisms by which melanoma cells escape the cytotoxic effect of DTIC. Here, we show that DTIC induced interleukin (IL)-8 and vascular endothelial growth factor (VEGF) protein overexpression and secretion via transcriptional up-regulation in the two melanoma cell lines SB-2 and MeWo. Luciferase activity driven by the IL-8 and VEGF promoters was up-regulated by 1.5-2- and 1.6-3.5-fold, respectively, in the SB2 and MeWo melanoma cell lines. The mitogen-activated protein kinase signal transduction pathway seemed to regulate at least partially the activation of IL-8, whereas it was not involved in VEGF promoter regulation. Electrophoretic mobility shift analysis analyses have revealed an increase in binding activity of activator protein 1 (c-Jun) and nuclear factor-kappaB after DTIC treatment for both melanoma cell lines. Metastatic melanoma cell lines secreting high levels of IL-8 and VEGF were more resistant to DTIC than early primary melanomas secreting low levels of the cytokines. In addition, transfection of the primary cutaneous melanoma SB-2 cells with the IL-8 gene rendered them resistant to the cytotoxic effect of the drug, whereas the addition of IL-8-neutralizing antibody to metastatic melanoma cells lowered their sensitivity to DTIC. Taken together, our data demonstrate that DTIC can cause melanoma cells to secrete IL-8 and VEGF, which might render them resistant to the cytotoxic effects of the drug. We propose that combination treatment with anti-VEGF/IL-8 agents may potentiate the therapeutic effects of DTIC.

Cell Line, Tumor↗

PubMed2002

Near real-time in vivo confocal imaging of mouse mammary tumors.

The goal of this study was to evaluate the ability of near real-time reflectance confocal microscopy to image tumor metastasis in vivo in an animal model. We used an epi-illumination confocal microscope to capture images of mouse mammary tumors in nude immunodeficient and Balb/C immunocompetent mice. In vivo confocal images and videos of normal and neoplastic areas were obtained before and after the application of a 6% acetic acid solution, with a lateral resolution of 0.8 microns and an axial resolution of 2-3 microns. Average imaging depths ranged from 150 microns to greater than 300 microns. We were able to differentiate between normal and abnormal tissue areas within the mammary gland, including areas of adipose tissue, fibroblasts and connective tissue, neoplastic tissue, and blood flow within blood vessels. Intravital imaging with reflectance confocal microscopy appears to be a useful tool to study tumor metastasis in vivo.

Animals↗

PubMed2002

Therapeutic intervention with breast cancer metastasis.

Metastatic disease, mainly to the lungs, liver, bone, and brain, is the most common cause of death from breast cancer, despite advances in surgical and clinical management. Two basic principles govern the process of metastasis. First, that tumors are heterogeneous populations of cells, and second, that the process is a sequence of events that depends on tumor cell properties and interactions with the microenvironment at the site of metastasis. Inhibitors targeted at any of these different steps have the potential to inhibit metastatic progression, and examples of key therapeutic targets include overexpression of growth factor receptors, angiogenic factors, matrix metalloproteases, and integrin receptors. The identification of molecular targets for therapy of breast cancer metastasis will be accelerated by DNA array technology, and their selection for use should include evaluation of interactions between tumor cells and normal tissue components. These sorts of inhibitors are likely to target both cancer and normal cell functions, for example, inhibitors of matrix metalloproteases that can potentially inhibit both tumor cell invasion and angiogenesis. The use of appropriate animal models will be necessary to determine the impact of targeted inhibitors on the growth and development of breast cancer metastasis.

Breast Neoplasms↗

PubMed2002

Characterization of a renal cell carcinoma cell line derived from a human bone metastasis and establishment of an experimental nude mouse model.

PURPOSE: We provide the necessary tools to study the biology of bone metastasis using renal cell carcinoma as a model. A relevant renal cell carcinoma cell line developed from a human bone metastasis is described and an experimental model in the nude mouse was established. MATERIALS AND METHODS: The novel cell line RBM1 was developed from bone metastasis from a patient with renal cell carcinoma. In vitro methods used to study the cell line included karyotype analysis, reverse-transcriptase polymerase chain reaction, ribonuclease protection assay and Western blot analysis. An intratibial injection model in the nude mouse resulted in bone lesions similar to those in human patients. RESULTS: Chromosomal analysis of this cell line revealed characteristic cytogenetic abnormalities common in renal cell carcinoma. RBM1 cells expressed parathyroid hormone parathyroid hormone related peptide, interleukin-6 and macrophage colony-stimulating factor, which are cytokines involved in osteoclast activation and subsequent bone resorption. Western blot analysis revealed the presence of high levels of epidermal growth factor receptor and c-MET. Reproducible osteolytic lesions developed in the nude mouse after injecting 1 x 106 cells into the tibia. CONCLUSIONS: This cell line and animal model may allow further study of the biology and mechanism of renal cell carcinoma bone metastasis.

Animals↗