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

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.

• Authors: Michiel S van der Heijden, Jonathan R Brody, David A Dezentje, Eike Gallmeier, Steven C Cunningham, Michael J Swartz, Angelo M DeMarzo, G Johan A Offerhaus, William H Isacoff, Ralph H Hruban, Scott E Kern
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 20 Pg. 7508-15 (Oct 15 2005) ISSN: 1078-0432 [Print] United States
• PMID: 16243825 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 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

Topics

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