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Tracey,
You may want to look into this.
Antifolate Activity of Pyrimethamine Enhances Temozolomide-Induced Cytotoxicity in Melanoma Cells.
Authors
Chen M, Osman I, Orlow SJ
Institution
Departments of Medicine and Cell Biology, and the New York University Cancer Institute Clinical Cancer Center, New York, New York.
Source
Mol Cancer Res 2009 May 12.
Abstract
Most metastatic melanoma patients fail to respond to available therapy, underscoring the need to develop more effective treatments. We screened 2,000 compounds from the Spectrum Library in human melanoma cell lines to identify compounds that enhanced the cytotoxic effect of temozolomide, a drug used to treat metastatic melanoma. Screening was done with the temozolomide-resistant melanoma cell line SK-MEL-19, and six compounds were identified that had little or no inherent cytotoxicity but significantly enhanced growth-inhibition by temozolomide. These compounds were tested in five additional melanoma cell lines. Cell proliferation and death assays were used to compare the efficacy of single agent temozolomide versus combination treatments. Effects of combination treatment on levels of DNA double-strand breaks, the DNA repair protein O(6)-methylguanine-DNA-methyltransferase, apoptosis [measured by cleaved caspase-3 and poly(ADP-ribose) polymerase], and cell cycle were examined. Pyrimethamine, an antiparasitic, sensitized melanoma cells to temozolomide. Temozolomide combined with Pyrimethamine synergistically inhibited cell proliferation in melanoma cells with combination index values of 0.7 or less. In addition, combination treatment induced cell cycle arrest and increased both DNA damage and apoptosis. The increase in cell death due to combination treatment was rescued by leucovorin. Other folate antagonists were also effective enhancers of temozolomide-induced cytotoxicity, and the effects of antifolates were also evident in gliomas. Our screening approach led to the identification of Pyrimethamine, an orally available drug that efficiently crosses the blood-brain barrier, as a potent enhancer of the efficacy of temozolomide as an antineoplastic agent via inhibition of folate metabolism.(Mol Cancer Res 2009;7(5):703-12).
Dying Tumor Cells Attracts Dendritic Cells That Activates T cells
More interestingly, the researchers discovered that tumors cells dying from the viral attack secreted a protein called HMGB1. This protein is specifically recognized by the receptor TLR2 present at the surface of another particular class of white blood cells called myeloid dendritic cells. The presence of HMGB1 attracts and activates the dendritic cells into the brain which, in turn, activate the T lymphocyte cells essential in killing other tumors growing in the brain.
New Treatment for Brain Tumors ?
While the effectiveness of such an immunotherapy approach still needs to be proven in humans as a potential treatment against cancer, this study presents a very elegant demonstration of using the specialized mechanisms of the immune system in conjunction with chemotherapy to deliver effective treatment against cancer. It would be interesting to know if such approach could ultimately be considered for the eradication of other types of cancer.
Read more at Suite101: Anti-Tumor Immunotherapy for Brain Cancer: HMGB1 from Tumor Cells Activates TLR2 Signaling in Dendritic Cells http://www.suite101.com/content/antitumor-immunotherapy-for-brain-cancer-a90636#ixzz1946SNsts
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Tracey,
You may want to look into this.
Antifolate Activity of Pyrimethamine Enhances Temozolomide-Induced Cytotoxicity in Melanoma Cells.
Authors
Chen M, Osman I, Orlow SJ
Institution
Departments of Medicine and Cell Biology, and the New York University Cancer Institute Clinical Cancer Center, New York, New York.
Source
Mol Cancer Res 2009 May 12.
Abstract
Most metastatic melanoma patients fail to respond to available therapy, underscoring the need to develop more effective treatments. We screened 2,000 compounds from the Spectrum Library in human melanoma cell lines to identify compounds that enhanced the cytotoxic effect of temozolomide, a drug used to treat metastatic melanoma. Screening was done with the temozolomide-resistant melanoma cell line SK-MEL-19, and six compounds were identified that had little or no inherent cytotoxicity but significantly enhanced growth-inhibition by temozolomide. These compounds were tested in five additional melanoma cell lines. Cell proliferation and death assays were used to compare the efficacy of single agent temozolomide versus combination treatments. Effects of combination treatment on levels of DNA double-strand breaks, the DNA repair protein O(6)-methylguanine-DNA-methyltransferase, apoptosis [measured by cleaved caspase-3 and poly(ADP-ribose) polymerase], and cell cycle were examined. Pyrimethamine, an antiparasitic, sensitized melanoma cells to temozolomide. Temozolomide combined with Pyrimethamine synergistically inhibited cell proliferation in melanoma cells with combination index values of 0.7 or less. In addition, combination treatment induced cell cycle arrest and increased both DNA damage and apoptosis. The increase in cell death due to combination treatment was rescued by leucovorin. Other folate antagonists were also effective enhancers of temozolomide-induced cytotoxicity, and the effects of antifolates were also evident in gliomas. Our screening approach led to the identification of Pyrimethamine, an orally available drug that efficiently crosses the blood-brain barrier, as a potent enhancer of the efficacy of temozolomide as an antineoplastic agent via inhibition of folate metabolism.(Mol Cancer Res 2009;7(5):703-12).
Dying Tumor Cells Attracts Dendritic Cells That Activates T cells
More interestingly, the researchers discovered that tumors cells dying from the viral attack secreted a protein called HMGB1. This protein is specifically recognized by the receptor TLR2 present at the surface of another particular class of white blood cells called myeloid dendritic cells. The presence of HMGB1 attracts and activates the dendritic cells into the brain which, in turn, activate the T lymphocyte cells essential in killing other tumors growing in the brain.
New Treatment for Brain Tumors ?
While the effectiveness of such an immunotherapy approach still needs to be proven in humans as a potential treatment against cancer, this study presents a very elegant demonstration of using the specialized mechanisms of the immune system in conjunction with chemotherapy to deliver effective treatment against cancer. It would be interesting to know if such approach could ultimately be considered for the eradication of other types of cancer.
Read more at Suite101: Anti-Tumor Immunotherapy for Brain Cancer: HMGB1 from Tumor Cells Activates TLR2 Signaling in Dendritic Cells http://www.suite101.com/content/antitumor-immunotherapy-for-brain-cancer-a90636#ixzz1946SNsts
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