In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3580-3580
Abstract:
Studies of cells harboring Fanconi anemia (FA) pathway defects have aided clinical understanding of inherited cancer risks and therapeutic strategies. Here, we observed a novel and large (27X) hypersensitivity of BRCA2- and PALB2-null genotypes to the epidemiologically important ethanol metabolite, acetaldehyde. This prominent acetaldehyde sensitivity may hold evolutionary and clinical significance. Interrogation of a novel panel of cells engineered to be null for various FA genes also revealed two classes of chemical hypersensitivities: the shared and divergent phenotypes. Prominent chemical hypersensitivities to various interstrand crosslinking (ICL) agents in vitro (melphalan, mitomycin C, and cisplatin), to γ-radiation in vitro, and to mitomycin C in vivo were essentially similar among the tested genotypes. A large divergence of responsiveness existed, however, between the cell lines when using the PARP inhibitor KU0058948, the topoisomerase II inhibitor etoposide, and acetaldehyde. These results indicate that, toward some agents, not all FA defects are necessarily equivalent; this divergence among phenotypes may dissect functions differing among FA genes and may presage differing clinical and epidemiological implications. We additionally present the first engineered PALB2-null human cancer cells. The results suggest new applications in cancer epidemiology, prevention, and targeted therapy. Citation Format: Soma Ghosh, Surojit Sur, Sashidhar R. Yerram, Carlo Rago, Anil K. Bhunia, M. Zulfiquer Hossain, Bogdan C. Paun, Yunzhao R. Ren, Christine A. Iacobuzio-Donahue, Nilofer A. Azad, Scott E. Kern. Acetaldehyde and drug hypersensitivities of Fanconi anemia defects: Implications for cancer initiation, prevention, and therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3580. doi:10.1158/1538-7445.AM2013-3580
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2013-3580
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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