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  • 1
    ISSN: 1432-1335
    Keywords: Ammine/amine platinum complex ; Structure/efficacy relationship ; Drug resistance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Three homologous series, each differing from the other in the coordinated amine ligand class, namely alicyclic, heterocyclic or isoaliphatic, were highly effective against wild-type murine leukemia L1210/0 cells in vivo (T/C=171%–426% at optimal doses). Of the 13 complexes comprising the three series, 3 were inactive in the cisplatin-resistant L1210/DDP model, but the other 10 maintained good efficacy (T/C=131%–167%). Longterm survivors, frequently observed with these complexes in the L1210/0 model, were also seen in the L1210/DDP model but to a lesser extent. In the homologous alicyclic series, which contained six analogs, as the alicyclic ring size increased, potency against L1210/0 and L1210/DDP cells also increased up to cyclohexylamine, and then declined. Four ammine/alicyclic amine analogs were evaluated against L1210/DACH cells, which are cross-resistant to tetraplatin, and the clinically predictive M5076 reticulosarcoma. Although the congeners were ineffective or minimally effective in prolonging the survival time of L1210/DACH-bearing mice (T/C=111%–134%), 20%–40% cure rate was consistently observed and suggested that the compounds possessed a low inherent ability to circumvent resistance in these tumor cells also. In the solid M5076 model, activity was greatest (tumor growth delays of about 25 days) for the alicyclic homologs containing the ammine/cyclobutylamine or ammine/cyclopentylamine carrier ligand combination. In summary, ammine/amine platinum (II) analogs have demonstrated promise at the preclinical level in their ability to circumvent acquired resistance, which is a major drawback of cisplatin use in treating cancer.
    Type of Medium: Electronic Resource
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  • 2
    Publication Date: 2022-05-25
    Description: Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of National Academy of Sciences for personal use, not for redistribution. The definitive version was published in Proceedings of the National Academy of Sciences 108 (2011): 4352-4357, doi:10.1073/pnas.1016106108.
    Description: Harmful algal blooms (HABs) cause significant economic and ecological damage worldwide. Despite considerable efforts, a comprehensive understanding of the factors that promote these blooms has been lacking because the biochemical pathways that facilitate their dominance relative to other phytoplankton within specific environments have not been identified. Here, biogeochemical measurements demonstrated that the harmful 43 Aureococcus anophagefferens outcompeted co-occurring phytoplankton in estuaries with elevated levels of dissolved organic matter and turbidity and low levels of dissolved inorganic nitrogen. We subsequently sequenced the first HAB genome (A. anophagefferens) and compared its gene complement to those of six competing phytoplankton species identified via metaproteomics. Using an ecogenomic approach, we specifically focused on the gene sets that may facilitate dominance within the environmental conditions present during blooms. A. anophagefferens possesses a larger genome (56 mbp) and more genes involved in light harvesting, organic carbon and nitrogen utilization, and encoding selenium- and metal-requiring enzymes than competing phytoplankton. Genes for the synthesis of microbial deterrents likely permit the proliferation of this species with reduced mortality losses during blooms. Collectively, these findings suggest that anthropogenic activities resulting in elevated levels of turbidity, organic matter, and metals have opened a niche within coastal ecosystems that ideally suits the unique genetic capacity of A. anophagefferens and thus has facilitated the proliferation of this and potentially other HABs.
    Description: Joint Genome Institute is supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231. Efforts were also supported by awards from New York Sea Grant to Stony Brook University, National Oceanic and Atmospheric Administration Center for Sponsored Coastal Ocean Research award #NA09NOS4780206 to Woods Hole Oceanographic Institution, NIH grant GM061603 to Harvard University, and NSF award IOS-0841918 to The University of Tennessee.
    Keywords: Harmful algal blooms ; HABs ; Genome sequence ; Ecogenomics ; Metaproteomics ; Eutrophication ; Aureococcus anophagefferens
    Repository Name: Woods Hole Open Access Server
    Type: Preprint
    Format: application/pdf
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