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

Clin Cancer Res. 2005 Oct 15;11(20):7508-15. doi: 10.1158/1078-0432.CCR-05-1048.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • BRCA2 Protein / deficiency
  • BRCA2 Protein / genetics
  • Caspases / metabolism
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chlorambucil / pharmacology
  • Cisplatin / pharmacology
  • Cross-Linking Reagents / pharmacology*
  • Cross-Linking Reagents / therapeutic use
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Dose-Response Relationship, Drug
  • Doxorubicin / pharmacology
  • Etoposide / pharmacology
  • Fanconi Anemia Complementation Group C Protein / deficiency
  • Fanconi Anemia Complementation Group C Protein / genetics
  • Fanconi Anemia Complementation Group G Protein / deficiency
  • Fanconi Anemia Complementation Group G Protein / genetics
  • Fanconi Anemia Complementation Group Proteins / deficiency
  • Fanconi Anemia Complementation Group Proteins / genetics*
  • Female
  • Fluorouracil / pharmacology
  • Gemcitabine
  • Humans
  • Inhibitory Concentration 50
  • Melphalan / pharmacology
  • Mice
  • Mice, Nude
  • Mitomycin / pharmacology*
  • Mitomycin / therapeutic use
  • Mutation
  • Paclitaxel / pharmacology
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • Time Factors
  • Vinblastine / pharmacology
  • Xenograft Model Antitumor Assays / methods

Substances

  • Antineoplastic Agents
  • BRCA2 Protein
  • Cross-Linking Reagents
  • FANCC protein, human
  • FANCG protein, human
  • Fanconi Anemia Complementation Group C Protein
  • Fanconi Anemia Complementation Group G Protein
  • Fanconi Anemia Complementation Group Proteins
  • Deoxycytidine
  • Chlorambucil
  • Mitomycin
  • Vinblastine
  • Etoposide
  • Doxorubicin
  • Caspases
  • Paclitaxel
  • Cisplatin
  • Melphalan
  • Fluorouracil
  • Gemcitabine