A series of 1,1-dichloro-2,2,3-triarylcyclopropanes (DTACs) was synthesized and evaluated as pure antiestrogens. Addition of 4-methoxy- or 4-(benzyloxy)phenyl Grignard reagents to p-methoxy, p-benzyloxy, or unsubstituted deoxybenzoins, followed by dehydration of the resulting carbinols produced a mixture of E and Z olefins, which were reacted with dichlorocarbene to give O-protected DTACs. The E and Z isomers were separated by fractional crystallization and the central or geminal phenyl ring was deprotected to provide phenolic DTACs. Alkylation with (N,N-dimethylamino)ethyl chloride yielded basic cyclopropanes. Two chlorodiarylindenes were isolated as thermolysis products of the DTACs, and one was converted to a phenol by hydrogenolysis. All DTACs and indenes were competitive inhibitors of [3H]estradiol binding in the immature rat uterine cytosol receptor assay, with relative binding affinities of 0.1-3.6% of estradiol. None of the new compounds were estrogenic in the 3-day immature mouse uterotrophic assay at doses up to 750 micrograms. In the 3-day immature mouse antiuterotrophic assay, five DTACs with either a methoxy (5a), benzyloxy (4d, 5c), or (dimethylamino)ethoxy (7a, 7b) central ring side chain produced significant decreases in uterine weight at doses up to 750 micrograms. One compound, (Z)-1,1-dichloro-2-[4-[2-(dimethylamino)ethoxy]-phenyl]-2-(4- methoxyphenyl)-3-phenylcyclopropane (7b), elicited a dose-dependent decrease in vivo comparable to MER 25. These same five compounds, as well as the lead compound Analog II, were active in vitro against the estrogen-dependent MCF-7 human breast tumor cell line in a dose-dependent fashion.
Abstract.Cancer metastasis is responsible for most of the morbidity and mortality associated with cancer. Cancer metastatic progression is a multiple step process which includes enhanced cell proliferation, release of proteolytic enzymes, cell motility and invasion, angiogenesis and establishment of a supportive microenvironment at the sites of metastatic growth (1, 2).Traditional cancer therapy has focused on removal or destruction of tumour cells by surgery, radiation and rather nonselective types of chemotherapy. Surgery and radiation are often effective with tumours which are localized and have not metastasized to multiple sites throughout the body. Chemotherapy appears to be most effective in the treatment of metastatic cancer; however, typical chemotherapeutic agents such as cisplatin, methotrexate, vincristine, 5-fluorouracil among many others, focus on rapidly growing tissues since cancer cells are relatively rapidly growing. Thus, cancer chemotherapy often results in a high incidence of unwanted and damaging side-effects in rapidly-dividing normal tissues, such as blood cells and cells lining gastrointestinal tract.With a greater understanding of cellular chemistry and genomics during the past twenty years, cellular targets that are unique to cancer cells have been identified and chemotherapeutic agents which specifically bind to, destroy or otherwise inactivate these unique cellular targets have been developed. These agents which impede these unique or overexpressed cancer targets tend to be more selective, -thus more effective with fewer side-effects than traditional, nonselective chemotherapy. They target critical checkpoints which are often overexpressed on rapidly growing and malignant cancer cells, such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and tyrosine kinase. Therefore, cancer Immunotherapy is an exciting and relatively new method to selectively block critical checkpoints in the process of cancer development (3, 4).
The prohibitin 3' untranslated region (3'UTR) belongs to a novel class of non-coding regulatory RNAs. It arrests cell cycle progression by blocking G1-S transition in breast and other cancers. Our previous studies comparing MCF7 derived clones constitutively expressing a common allelic form of prohibitin RNA (UTR/C) to various controls demonstrated that it functions as a tumor suppressor. Here, we further characterized the morphology and motility of these transgenic breast cancer cells when grown in cell culture and on nude mice. In contrast to empty vector (EV) cells, UTR/C cells were observed to grow in an organized manner with more cell-cell contact and differentiate into structures with a duct-like appearance. Computer assisted cytometry to evaluate differences in nuclear morphology was performed on UTR/C and EV tissues from nude mice. Receiver operator curve areas generated using a logistic regression model were 0.8, indicating the ability to quantitatively distinguish UTR/C from EV tissues. Keratinocyte growth factor-induced motility experiments showed that migration of UTR/C cells was significantly reduced (80-90%) compared to EV cells. Together, these data indicate that this novel 3'UTR influences not only the tumorigenic phenotype but also may play a role in differentiation and migration of breast cancer cells.
Dear Editor:In the development of more effective therapeutic strategies for the prevention and treatment of various cancers, it is important to focus on biological characteristics that differentiate benign and malignant neoplasms. A key difference between benign and malignant tumors appears to be related to cellular motility and invasiveness. Since cancer cell movement is an important component of metastatic potential, various in vitro assays have been developed and used to study general cell movement, including chemoinvasion of coated membranes and phagokinetic tracks (1,8). To better define the relationship between cell motility and metastatic potential, the present study used time-lapse videomicroscopy and image analysis to compare and characterize the differences in motile behavior between two human breast cancer cell lines that have been used in numerous in vitro studies. These were MDA-MB-231 (MDA) cells, which display a high metastatic potential and MCF-7 cells, which have a low metastatic potential. Similarly, other investigators have used time-lapse videomicroscopy to quantify the motility of other cancer cells (4,6). MCF-7 human breast cancer cells were provided by Dr. Sam Brooks of the Michigan Cancer Foundation (Detroit, MI), MDA-MB-231 cells were obtained from ATCC (Rockville, MD) and the cells were grown as monolayer cultures in RPMI 1640 media as previously described (3). Cells were plated sparsely in T-25 flasks and their motility was recorded with phase-contrast optics at 400 X with a color video camera (Sony, Model CCD-IRIS/RGB). The microscope stage was maintained at a constant temperature (37 ° C) by a thermostat-controlled stage heater (Fryer, Model A-50-IN). The video signal was fed to a time-lapse videocassette recorder with a time compression ratio of 240:1 (Panasonic, Model AG-6730 S-VHS, Secaucus, N J). Phase-contrast images of each cell line were recorded for 9-10 h in 3-5 replicate experiments. In each recording the movement of 5-10 cells in a microscopic field was analyzed. At least 30 cells from each cell line were analyzed in this study.The video images, at different time intervals (10-60 rain) over a period of 4-8 h, were captured and digitized with video capture software (Apple Video Player, Videocapture) on a Macintosh computer (Quadra 630-AV). Computer-assisted image analysis was accomplished with the NIH Image 1.59 program. Cell contours of the digital images were manually outlined and their x,y coordinates, area, and perimeter were calculated with the NIH Image program.Parameters of cell motility and morphology that were calculated for each cell line included rate of movement, total path length, and perimeter index. Rate of cell movement was determined as the distance traveled by the centroid (geometric center) of individual cells divided by time (gm/h) and plotted at the midpoint between each time interval. Total path length was computed as the total path traveled by the cell centroid (in p.m) during the experimental period. Perimeter index (PI) was caiculated as the perimete...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.