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The Evolution of Anticancer Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
From the 1960s to the end of the 1980s it was common practice to synthesize novel small-molecule organic compounds and then screen them for pharmacological activity across different therapeutic areas in various screens in a relatively nonrational manner in the hope of identifying a lead molecule. In cancer research, the screening was mainly achieved through in vitro cytotoxicity assays based on tumor cell lines originally derived from patients, and which were immortal due to the overexpression of telomerase, thus allowing indefinite cell division to occur. Although many pharmaceutical companies and academic groups developed their own screens, the National Cancer Institute (NCI) in the US set up a screen based on 60 different cell lines arranged in panels, which has become the “Gold Standard” of in vitro screens. Known as the NCI-60 Human Tumor Cell Line Screen, this resource has served the global cancer research community for nearly 30 years. It was implemented in 1990 and was originally designed to screen up to 3,000 small molecules (synthetic or purified natural products) per year for growth inhibition or killing of tumor cells. The screen is based on 60 different human tumor cell lines divided into panels representing leukemia, melanoma, and cancers of the lung, colon, brain, ovary, breast, prostate, and kidney. The results are provided in graphical format (Figure 2.2) with horizontal bars deflecting to the right of the mean indicating a high sensitivity to the compound being tested, and a deflection to the left a low sensitivity.
Lynch Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Andreas V. Hadjinicolaou, Mashiko Setshedi
Due to the fact that high MSI can be found in a small proportion of sporadic CRC, guidelines have been designed to determine whether an individual is at high risk of LS-associated tumors and therefore needs genetic testing for MSI. These less stringent guidelines are the Bethesda guidelines, devised in 1997 (and revised in 2004) by the National Cancer Institute (NCI) [60]: CRC diagnosed in a patient who is younger than 50 years.Presence of synchronous or metachronous CRC or another LS-associated tumor, regardless of age.CRC with evidence of high MSI on histology (i.e., tumors with changes in two or more of the five NCI-recommended panels of MSI markers (see investigations below), diagnosed in a patient who is younger than 60 years.CRC diagnosed in one or more first-degree relatives with an LS-related tumor with one of the cancers diagnosed in a patient younger than 50 years.CRC diagnosed in two or more first- or second-degree relatives with LS-related tumors, regardless of age.
Radiogenomics
Published in Jun Deng, Lei Xing, Big Data in Radiation Oncology, 2019
Barry S. Rosenstein, Gaurav Pandey, Corey W. Speers, Jung Hun Oh, Catharine M.L. West, Charles S. Mayo
A similar approach was used involving the NCI-60 cell line panel to screen radiation response-associated genes (Amundson et al. 2008) with the discovery of genes whose basal expression differed between the radiosensitive and radioresistant cell lines, with a portion associated with survival following irradiation. Interestingly, genes induced (by RNA expression profiling) by radiation were remarkably consistent between tumor types and were a function of TP53 status, suggesting an underlying conserved set of genes responsible for responding to genotoxic stress. However, there was surprisingly no overlap between the genes identified in these studies, suggesting that the response to radiation treatment is complex and differs under basal and genotoxic conditions.
The efficient design of Nested Group Testing algorithms for disease identification in clustered data
Published in Journal of Applied Statistics, 2023
Ana F. Best, Yaakov Malinovsky, Paul S. Albert
The NCI-60 cell lines encompass 60 different human tumor cell lines that are used to identify and characterize novel compounds for anti-cancer activity, as measured by growth inhibition or killing of tumor cells [27]. These data are publicly available using the online COMPARE database provided by the National Cancer Institute (NCI) Division of Cancer Treatment and Diagnosis (DCTD) Developmental Therapeutics Program (DTP) [28]. Group testing could plausibly be used in this setting as the compounds tested can be rare and difficult to harvest and/or manufacture; it may be feasible to test compounds on groups comprised of pooled cells from lines of the same tumor tissue type (e.g. breast), measure the anti-cancer activity within that pool, and retest individual lines if any activity is seen overall. As heterogeneity is expected across tumor types, we can consider this to be a clustered data setting, where the clusters are defined by the nine types of tumor present in the NCI-60 lines (Breast, Central Nervous System (CNS), Colon, Leukemia, Melanoma, Non-Small-Cell Lung Cancer (NSCLC), Ovarian, Prostate, and Renal).
Development of patient-derived orthotopic xenografts from metastatic colorectal cancer in nude mice
Published in Journal of Drug Targeting, 2019
Bruno Roque-Lima, Caroline Correa de Tulio Augusto Roque, Maria Dirlei Begnami, Patricia Peresi, Eduardo Nobrega Pereira Lima, Celso Abdon Lopes de Mello, Felipe JoséFernandez Coimbra, Rubens Chojniak, Tiago Goss Santos
The use of preclinical models is essential to every aspect of translational research, from elucidating tumour biology to developing new diagnostic and treatment strategies [5]. The NCI-60 cancer cell line panel is the largest collection of tumour cell lines currently available and is the most frequently used resource for in vitro studies of new anti-cancer agents [6]. The cells in this panel are derived from human tumours that have been adapted to grow indefinitely in artificial culture media. Although these cell lines can be used readily, there are important shortcomings with respect to pre-clinical stage drug development. The most relevant limitation of cell line use is the inability to predict clinical activity for specific cancer types. Secondly, tumour cell lines are generally created from the most aggressive tumour components; thus, they do not reflect the complex tumour heterogeneity seen in clinical practice [7]. In contrast, the biologic process of metastasis may be better represented by in vivo murine models, which can then be used to study mechanisms of liver metastasis and develop new treatment strategies [8].
6-(2-Morpholinoethyl)-thiazolo[3,2-a]pyrimidin-5-one: A novel scaffold for the synthesis of potential PI3kα inhibitors
Published in Egyptian Journal of Basic and Applied Sciences, 2018
Ahmed R. Ali, Eman R. El-Bendary, Mariam A. Ghaly, Ihsan A. Shehata
The target compounds 4–6(a–c) were submitted to the National Cancer Institute (NCI) [22], Bethesda, Maryland, USA, under the Developmental Therapeutic Program (DTP). The operation of this screen utilizes 60 different human tumor cell lines, representing leukemia, melanoma and cancers of the lung, colon, brain, ovary, breast, prostate, and kidney. Structures are generally selected for screening based on their ability to add diversity to the NCI small molecule compound collection. Compounds with drug-like properties based on computer-aided design are to be prioritized in the NCI screening service. All compounds submitted to the NCI 60 cell screen were tested initially at a single high dose (10−5 M) in the full NCI 60 cell panel. The compounds were added at a single concentration (10−5 M) and the culture was incubated for 48 h. End point determinations were made with a protein binding dye, Sulforhodamine B [23[24]–25] .