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• W1451528488 abstract "Proc Amer Assoc Cancer Res, Volume 47, 2006 240 Background: Flexible Heteroarotinoids (Flex-Hets) are a novel class of compounds that induce differentiation and apoptosis in cancer cells with little effect on normal cells. SHetA2 was chosen as the lead Flex-Het, because it induced the highest levels of apoptosis in multiple cancer types. Microarray analysis identified, and RT-PCR analysis validated that expression of thymidine phosphorylase (TP) and thrombospondin 4 (TSP-4) are down-regulated by SHetA2 in ovarian cancer cell lines. Because TP and TSP-4 are involved in blood vessel formation, the ability of SHetA2 to inhibit endothelial tube formation was tested in vitro and was found to occur in a dose-dependent manner. The objectives of this study were to validate the down-regulation of TP and TSP-4 at the protein level and evaluate the anti-angiogenesis activity of SHetA2 in vivo . Methods: Ovarian cancer cell lines (A2780 and OVCAR-3) were treated with 1 or 10 μM SHetA2 for various times ranging from 30 minutes to 24 hours. Proteins were isolated and evaluated by Western blot for TP and TSP-4 expression levels. The B16 melanoma line was injected subcutaneously into syngeneic C57BL mice, which were divided into 4 treatment groups: SHetA2 gavage (12 mice) SHetA2 intratumoral (12 mice), solvent control gavage (6 mice) and solvent control intratumoral (6 mice). Mice were euthanized when tumor reached 10% body weight and tumors were fixed, embedded and sectioned. Mitoses were counted in 10 high powered fields in H&E stained sections and tumor vessels were visualized in CD34 stained sections. Results: SHetA2 inhibited TP and TSP-4 protein expression as early as 30 minutes and throughout the 24 hour evaluation period. One mouse survived in each of the SHetA2 treated groups, while none survived in the control groups. The average mitotic indices in the intratumoral and gavage control groups were 13.3 ± 1.0 and 12.1 ± 1.1, and in the SHetA2 intratumoral and gavage groups were 5.3 ± 1.6 and 3.0 ± 0.8, respectively. Control tumors had arterioles extending from a large peripheral vessel with tumor cells surrounded the arterioles. These arterioles largely disappeared in the SHetA2 treated tumors and the cancer cells were arranged into poorly formed nests that were supplied by small tenuous blood vessels. Massive necrosis was present. Discussion: These studies demonstrate that SHetA2 inhibits TP and TSP-4 protein expression in vitro , and tumor cell proliferation and angiogenesis in vivo . The inhibition of angiogenesis appears to have contributed to the inhibition of proliferation and massive necrosis in the SHetA2 treated tumors. Studies are planned to validate the functional roles of TP and TSP-4 in SHetA2 inhibition of angiogenesis. Supported by NCI grant CA106713." @default.
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• W1451528488 date "2006-04-15" @default.
• W1451528488 modified "2023-09-23" @default.
• W1451528488 title "Inhibition of thymidine phosphorylase (TP), thombospondin 4 (TSP-4) and angiogenesis by flexible heteroarotinoid (Flex-Het), SHetA2" @default.
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