RGD Reference Report - In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor. - Rat Genome Database

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In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor.

Authors: Van der Heijden, MS  Brody, JR  Dezentje, DA  Gallmeier, E  Cunningham, SC  Swartz, MJ  Demarzo, AM  Offerhaus, GJ  Isacoff, WH  Hruban, RH  Kern, SE 
Citation: van der Heijden MS, etal., Clin Cancer Res. 2005 Oct 15;11(20):7508-15.
RGD ID: 2317238
Pubmed: PMID:16243825   (View Abstract at PubMed)
DOI: DOI:10.1158/1078-0432.CCR-05-1048   (Journal Full-text)

PURPOSE: BRCA2, FANCC, and FANCG gene mutations are present in a subset of pancreatic cancer. Defects in these genes could lead to hypersensitivity to interstrand cross-linkers in vivo and a more optimal treatment of pancreatic cancer patients based on the genetic profile of the tumor. EXPERIMENTAL DESIGN: Two retrovirally complemented pancreatic cancer cell lines having defects in the Fanconi anemia pathway, PL11 (FANCC-mutated) and Hs766T (FANCG-mutated), as well as several parental pancreatic cancer cell lines with or without mutations in the Fanconi anemia/BRCA2 pathway, were assayed for in vitro and in vivo sensitivities to various chemotherapeutic agents. RESULTS: A distinct dichotomy of drug responses was observed. Fanconi anemia-defective cancer cells were hypersensitive to the cross-linking agents mitomycin C (MMC), cisplatin, chlorambucil, and melphalan but not to 5-fluorouracil, gemcitabine, doxorubicin, etoposide, vinblastine, or paclitaxel. Hypersensitivity to cross-linking agents was confirmed in vivo; FANCC-deficient xenografts of PL11 and BRCA2-deficient xenografts of CAPAN1 regressed on treatment with two different regimens of MMC whereas Fanconi anemia-proficient xenografts did not. The MMC response comprised cell cycle arrest, apoptosis, and necrosis. Xenografts of PL11 also regressed after a single dose of cyclophosphamide whereas xenografts of genetically complemented PL11(FANCC) did not. CONCLUSIONS: MMC or other cross-linking agents as a clinical therapy for pancreatic cancer patients with tumors harboring defects in the Fanconi anemia/BRCA2 pathway should be specifically investigated.




  
Object Symbol
Species
Term
Qualifier
Evidence
With
Notes
Source
Original Reference(s)
FANCCHumanpancreatic cancer  IDA  RGD 
FANCGHumanpancreatic cancer  IDA  RGD 
FanccRatpancreatic cancer  ISORGD:735813 RGD 
FanccMousepancreatic cancer  ISORGD:735813 RGD 
FancgRatpancreatic cancer  ISORGD:1350702 RGD 
FancgMousepancreatic cancer  ISORGD:1350702 RGD 


Genes (Rattus norvegicus)
Fancc  (FA complementation group C) Fancg  (FA complementation group G)

Genes (Mus musculus)
Fancc  (Fanconi anemia, complementation group C) Fancg  (Fanconi anemia, complementation group G)

Genes (Homo sapiens)
FANCC  (FA complementation group C) FANCG  (FA complementation group G)