The Experts below are selected from a list of 1428 Experts worldwide ranked by ideXlab platform
Vernon E. Steele - One of the best experts on this subject based on the ideXlab platform.
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Histopathology of human intraepithelial neoplasia with implications for Chemoprevention Strategy.
Basic life sciences, 1993Co-Authors: Charles W. Boone, Gary J. Kelloff, Vernon E. SteeleAbstract:Every epithelial cancer (i.e., invasive neoplasm) is preceded by a preinvasive stage of intraepithelial neoplasia that typically lasts for years. A better understanding of human intraepithelial neoplasia is of critical importance to investigators in the Chemoprevention field; it can assist in the more rational design of drugs that will slow or stop the development of intraepithelial neoplasia and, therefore, the potential for subsequent development of invasive cancer, and also assist in the development of early biomarkers that are modulated by chemopreventive drugs.
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Natural History of Intraepithelial Neoplasia in Humans with Implications for Cancer Chemoprevention Strategy
Cancer research, 1992Co-Authors: Charles W. Boone, Gary J. Kelloff, Vernon E. SteeleAbstract:Abstract Intraepithelial neoplasia is of critical importance to the cancer Chemoprevention field because it is a target condition for which drugs must be sought that will prevent its development or stop its progression. The term “dysplasia” refers to the morphological alterations that characterize intraepithelial neoplasia and according to many authors consists of seven basic morphological changes that occur in the majority of human epithelia, as well as in the epithelium of mouse skin papillomas induced by 7,12-dimethylbenz(a)anthracene and 12- O -tetradecanoylphorbol-13-acetate: increased nuclear size; altered nuclear shape; increased nuclear stain uptake; nuclear pleomorphism (increased variation in nuclear size, shape, and stain uptake); increased mitoses; abnormal mitoses; and disordered or absent maturation. Clonal evolution appears to begin early in the neoplastic process during intraepithelial neoplasia. Aneuploidy has been found during intraepithelial neoplasia in many human epithelia, and, in association with other forms of genetic instability, may provide the increase in genetically variant cells required for clonal evolution to occur. It is postulated that two major factors affecting the rate of progression of intraepithelial neoplasia are the cellular mutation rate, which is enhanced by environmental carcinogens, and the cellular proliferation rate, which is enhanced by agents that include sex hormones, inducers of chronic inflammation, and irritant chemicals which stimulate reactive hyperproliferation. A preferred Chemoprevention Strategy should consist of the development of drugs and drug combinations which will block mutagenic carcinogens or prevent epithelial hyperproliferation or its causes. Two examples of the induction of regression of intraepithelial neoplasia by chemopreventive drugs are the regression of oral leukoplakia produced by β-carotene and the regression of colorectal polyps in patients with familial polyposis produced by sulindac. It is evident that there is a strong need for more research on the induction of regression of intraepithelial neoplasia with chemopreventive agents. There is also a critical need to identify and develop biomarkers that correlate with the appearance and regression of intraepithelial neoplasia.
Charles W. Boone - One of the best experts on this subject based on the ideXlab platform.
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Histopathology of human intraepithelial neoplasia with implications for Chemoprevention Strategy.
Basic life sciences, 1993Co-Authors: Charles W. Boone, Gary J. Kelloff, Vernon E. SteeleAbstract:Every epithelial cancer (i.e., invasive neoplasm) is preceded by a preinvasive stage of intraepithelial neoplasia that typically lasts for years. A better understanding of human intraepithelial neoplasia is of critical importance to investigators in the Chemoprevention field; it can assist in the more rational design of drugs that will slow or stop the development of intraepithelial neoplasia and, therefore, the potential for subsequent development of invasive cancer, and also assist in the development of early biomarkers that are modulated by chemopreventive drugs.
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Natural History of Intraepithelial Neoplasia in Humans with Implications for Cancer Chemoprevention Strategy
Cancer research, 1992Co-Authors: Charles W. Boone, Gary J. Kelloff, Vernon E. SteeleAbstract:Abstract Intraepithelial neoplasia is of critical importance to the cancer Chemoprevention field because it is a target condition for which drugs must be sought that will prevent its development or stop its progression. The term “dysplasia” refers to the morphological alterations that characterize intraepithelial neoplasia and according to many authors consists of seven basic morphological changes that occur in the majority of human epithelia, as well as in the epithelium of mouse skin papillomas induced by 7,12-dimethylbenz(a)anthracene and 12- O -tetradecanoylphorbol-13-acetate: increased nuclear size; altered nuclear shape; increased nuclear stain uptake; nuclear pleomorphism (increased variation in nuclear size, shape, and stain uptake); increased mitoses; abnormal mitoses; and disordered or absent maturation. Clonal evolution appears to begin early in the neoplastic process during intraepithelial neoplasia. Aneuploidy has been found during intraepithelial neoplasia in many human epithelia, and, in association with other forms of genetic instability, may provide the increase in genetically variant cells required for clonal evolution to occur. It is postulated that two major factors affecting the rate of progression of intraepithelial neoplasia are the cellular mutation rate, which is enhanced by environmental carcinogens, and the cellular proliferation rate, which is enhanced by agents that include sex hormones, inducers of chronic inflammation, and irritant chemicals which stimulate reactive hyperproliferation. A preferred Chemoprevention Strategy should consist of the development of drugs and drug combinations which will block mutagenic carcinogens or prevent epithelial hyperproliferation or its causes. Two examples of the induction of regression of intraepithelial neoplasia by chemopreventive drugs are the regression of oral leukoplakia produced by β-carotene and the regression of colorectal polyps in patients with familial polyposis produced by sulindac. It is evident that there is a strong need for more research on the induction of regression of intraepithelial neoplasia with chemopreventive agents. There is also a critical need to identify and develop biomarkers that correlate with the appearance and regression of intraepithelial neoplasia.
Balgangadhar Karthik Grandhi - One of the best experts on this subject based on the ideXlab platform.
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abstract b64 a novel Chemoprevention Strategy using nanotechnology based delivery of combinations of piroxicam curcumin and sulforaphane pcs on human pancreatic cancer cell lines
Cancer Prevention Research, 2011Co-Authors: Sunil Prabhu, Dhruvitkumar S Sutaria, Balgangadhar Karthik GrandhiAbstract:According to the American Cancer Society (ACS), an estimated 37,660 deaths will occur in 2011 due to complications from pancreatic cancer. The onset of pancreatic cancer is often devoid of symptoms and is mostly diagnosed at a stage where survival rate is less than 5%. Thus, Chemoprevention could play an important role in the fight against this silent yet deadly disease. The objective of our study was to use combinations of chemopreventive agents namely piroxicam (a non-steroidal anti-inflammatory drug), curcumin (a natural spice with significant cancer chemopreventive properties) and sulforaphane (a potent broccoli extract) in very low doses to inhibit cell proliferation and promote apoptosis on two human pancreatic cancer cell lines, MIA PaCA-2 and Panc-1. More importantly, we compared the effects of the chemopreventive combinations in both, unmodified (free drug) and modified forms, encapsulated within solid-lipid nanoparticles (SLNs). SLNs were prepared using a process of hot-melt oil in water (o/w) emulsion technique using stearic acid as the lipid backbone to which the chemopreventive agents were added and then recovered as nanoparticles (∼200 nm size) after a process of freeze-drying. MTS cell proliferation, apoptosis and cell colony forming assays were conducted on cultured cells. For the MTS assay, upon 75 % confluence, 2.5 × 103 cells for MIA PaCa-2 and 4 × 103 cells for Panc-1 were transferred into each well of 96-well plates. The PCS chemopreventive agents alone or in combination were added to the cells and incubated for 72 h. Absorbance was recorded at 490 nm using an ELISA plate reader. For the apoptosis assay, 3 × 105 cells were cultured in 6-well plates for both MIA PaCa-2 and Panc-1 cell-lines. PCS, individual or combinations, were added and the plates were incubated for 72 h. Cells were analyzed using flow cytometry, measuring the fluorescence emission at 530 nm (FL1) and >575 nm (FL3). For the cell colony formation assays, MIA PaCa-2 and Panc-1 cells were seeded at a density of 1 ml containing 3 × 104 cells, incubated for a period of 24 h. After treatment with PCS alone and in combinations, cells were trypsinized then incubated for a period of 10 days. The number of colonies with >50 cells were counted under a dissecting microscope. IC50 values obtained for the unmodified and modified forms of piroxicam were (663.1μM; 52.85μM), curcumin (16.05μM; 4.93μM) respectively and free sulforaphane at 11.82 μM/L for MIA PaCa-2 cells. For Panc-1 cells, the IC50 values for unmodified and modified piroxicam were (389.3μM; 66.96μM), curcumin (24.01μM; 7.5μM) respectively and free sulforaphane at 17.81μM/L. For MIA PaCa-2 cell line, unmodified combinations of piroxicam (250μM) with curcumin (10μM) and sulforaphane (5μM) showed significant reduction in cell viability of > 60% using MTS assay. In comparison, lower concentrations of piroxicam SLN (25μM) and curcumin SLN (2.5μM) with free sulforaphane (5μM) mixtures showed decrease in cell viability by >47.4%. Flow cytometry analysis demonstrated apoptosis of 71% (unmodified) and 38.4% (modified) for the combinations, at the same concentration ranges as above. Panc-1 cell line treated with similar concentrations of unmodified and modified SLN combinations showed a >82% and >45.79% decrease in cell viability and 91% and 54.6% apoptotic cells, respectively. Colony formation assays in both cell lines showed a significant decrease (p value Citation Information: Cancer Prev Res 2011;4(10 Suppl):B64.
James M Ford - One of the best experts on this subject based on the ideXlab platform.
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abstract 2966 targeting defective dna repair as a novel Chemoprevention Strategy for brca1 mutated breast cancer
Cancer Research, 2014Co-Authors: Elizabeth Alli, David E Solowcordero, Stephanie C Casey, James M FordAbstract:Carriers of germline mutations in the Breast Cancer Susceptibility Gene 1 (BRCA1) have an increased risk for developing breast cancer. Unfortunately, BRCA1-mutated cancers are not amenable to current Chemoprevention options, often associate with an aggressive clinical course, and thus, are in need of an effective prevention Strategy. We previously found that BRCA1 plays a role in DNA base-excision repair (BER) of oxidative DNA damage, and that BRCA1-mutated breast cancers exhibit a compromised ability for BER of oxidative DNA damage. Given that excessive oxidative DNA damage leads to tumorigenesis, we hypothesized that small molecules may be used to enhance the repair of oxidative DNA damage, and in turn, prevent tumorigenesis of BRCA1-mutated breast cancer cells. First, a high-throughput chemical screen identified small molecules that enhance BER of oxidative DNA damage in the presence of mutant BRCA1. These molecules have been termed DNA repair-activating agents. At least two DNA repair-activating agents significantly enhanced BER in mutant BRCA1 but not wild-type BRCA1 cell lines. These molecules also decreased basal levels of oxidative DNA damage as determined by flow cytometry using a FITC-conjugated 8oxoG-binding protein and decreased H 2 O 2 -induced oxidative DNA damage as determined by the alkaline comet assay modified for detection of oxidized lesions. Both DNA repair-activating agents directly activated BER, rather than indirectly as a result of induction of DNA damage, as evidenced by the alkaline comet assay for DNA strand breaks. Both agents also showed no cytotoxicity at concentrations that enhanced BER of oxidative DNA damage, which is ideal for Chemoprevention. Finally, at least one of the DNA repair-activating agents decreased BRCA1-associated tumorigenesis in vitro and in vivo. The DNA repair-activating agent decreased anchorage-independent growth of BRCA1-mutant/deficient cells without a significant effect on cell viability, as well as delayed tumor formation and decreased tumor burden in a dose-response manner in a xenograft mouse model. Taken together, these data suggest that enhancing DNA base-excision repair of oxidative DNA damage may be a novel Strategy for the targeted Chemoprevention of BRCA1-associated breast cancers. Citation Format: Elizabeth Alli, David Solow-Cordero, Stephanie C. Casey, James M. Ford. Targeting defective DNA repair as a novel Chemoprevention Strategy for BRCA1-mutated breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2966. doi:10.1158/1538-7445.AM2014-2966
H Gomez - One of the best experts on this subject based on the ideXlab platform.
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a numerical simulation study of the dual role of 5α reductase inhibitors on tumor growth in prostates enlarged by benign prostatic hyperplasia via stress relaxation and apoptosis upregulation
Computer Methods in Applied Mechanics and Engineering, 2020Co-Authors: Guillermo Lorenzo, Thomas J R Hughes, Alessandro Reali, H GomezAbstract:Abstract 5 α -reductase inhibitors are regarded as a promising Chemoprevention Strategy to reduce the incidence and delay the progression of prostate cancer. Landmark clinical trials have shown the chemopreventive potential of these drugs, but they appear to be mostly effective in mild tumors and have also been correlated with a higher prevalence of advanced prostate cancer. Hence, the use of 5 α -reductase inhibitors for prostate cancer Chemoprevention has become a controversial issue. The effects of these drugs on prostate cancer growth remain incompletely understood, but they are thought to promote apoptosis in the tumor. Additionally, 5 α -reductase inhibitors induce global prostate shrinkage, which decreases the tumor-inhibiting effect of the mechanical stress accumulated in prostatic tissue due to common prostate enlargement with age. Thus, the competition between this mechanical effect and apoptotic upregulation may explain the controversial outcomes of 5 α -reductase inhibitors on prostate cancer. Here, we extend our mechanically-coupled model of prostate cancer growth by including the mechanical and apoptotic action of 5 α -reductase inhibitors and explore their combined effect on an aggressive tumor in silico. Our simulations show that the apoptotic boost dominates in the first months of therapy but the long-term outcome of 5 α -reductase inhibitors depends on its competition with a decrease in hydrostatic stress caused by prostate shrinkage, which favors tumor growth. By combining moderate or strong prostate shrinkage with mild or intense apoptotic upregulation, our simulations show different tumor growth dynamics ranging from long-term inhibition of prostate cancer growth to rapidly growing large tumors, which may evolve towards advanced disease. Thus, our proposed mechanism for the action of 5 α -reductase inhibitors may contribute to resolve the controversy around the use of these drugs for Chemoprevention and to gain insight on prostate cancer dynamics during its use. The computational technology used herein could also assist physicians to monitor prostatic tumors during 5 α -reductase inhibitor therapy and enable the early identification of responders from non-responders in a patient-specific manner.