PMID- 17967312
OWN - NLM
STAT- MEDLINE
DCOM- 20071213
LR  - 20071030
IS  - 0360-3016 (Print)
IS  - 0360-3016 (Linking)
VI  - 69
IP  - 4
DP  - 2007 Nov 15
TI  - Radiocurability by targeting tumor necrosis factor-alpha using a bispecific 
      antibody in carcinoembryonic antigen transgenic mice.
PG  - 1231-7
AB  - PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) enhances radiotherapy (RT) 
      killing of tumor cells in vitro and in vivo. To overcome systemic side effects, 
      we used a bispecific antibody (BsAb) directed against carcinoembryonic antigen 
      (CEA) and TNF-alpha to target this cytokine in a CEA-expressing colon carcinoma. 
      We report the evaluation of this strategy in immunocompetent CEA-transgenic mice. 
      METHODS AND MATERIALS: The murine CEA-transfected colon carcinoma MC-38 was used 
      for all experiments. In vitro, clonogenic assays were performed after RT alone, 
      TNF-alpha alone, and RT plus TNF-alpha. In vivo, the mice were randomly assigned 
      to treatment groups: control, TNF-alpha, BsAb, BsAb plus TNF-alpha, RT, RT plus 
      TNF-alpha, and RT plus BsAb plus TNF-alpha. Measurements of endogenous TNF-alpha 
      mRNA levels and evaluation of necrosis (histologic evaluation) were assessed per 
      treatment group. RESULTS: In vitro, combined RT plus TNF-alpha resulted in a 
      significant decrease in the survival fraction at 2 Gy compared with RT alone (p < 
      0.00001). In vivo, we observed a complete response in 5 (50%) of 10, 2 (20%) of 
      10, 2 (18.2%) of 11, and 0 (0%) of 12 treated mice in the RT plus BsAb plus 
      TNF-alpha, RT plus TNF-alpha, RT alone, and control groups, respectively. This 
      difference was statistically significant when TNF-alpha was targeted with the 
      BsAb (p = 0.03). The addition of exogenous TNF-alpha to RT significantly 
      increased the endogenous TNF-alpha mRNA level, particularly when TNF-alpha was 
      targeted with BsAb (p < 0.01). The percentages of necrotic area were 
      significantly augmented in the RT plus BsAb plus TNF-alpha group. CONCLUSION: 
      These results suggest that targeting TNF-alpha with the BsAb provokes RT 
      curability in a CEA-expressing digestive tumor syngenic model and could be 
      considered as a solid rationale for clinical trials.
FAU - Larbouret, Christel
AU  - Larbouret C
AD  - INSERM, Centre de Recherche en Cancerologie de Montpellier, Universite de 
      Montpellier, CRLC Val d'Aurelle-Paul Lamarque, Montpellier, France.
FAU - Robert, Bruno
AU  - Robert B
FAU - Linard, Christine
AU  - Linard C
FAU - Teulon, Isabelle
AU  - Teulon I
FAU - Gourgou, Sophie
AU  - Gourgou S
FAU - Bibeau, Frederic
AU  - Bibeau F
FAU - Martineau, Pierre
AU  - Martineau P
FAU - Santoro, Lore
AU  - Santoro L
FAU - Pouget, Jean-Pierre
AU  - Pouget JP
FAU - Pelegrin, Andre
AU  - Pelegrin A
FAU - Azria, David
AU  - Azria D
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Int J Radiat Oncol Biol Phys
JT  - International journal of radiation oncology, biology, physics
JID - 7603616
RN  - 0 (Antibodies, Bispecific)
RN  - 0 (Carcinoembryonic Antigen)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Animals
MH  - Antibodies, Bispecific/*therapeutic use
MH  - Carcinoembryonic Antigen/*immunology
MH  - Cell Survival
MH  - Colonic Neoplasms/immunology/*radiotherapy
MH  - Combined Modality Therapy/methods
MH  - Drug Evaluation, Preclinical/methods
MH  - Humans
MH  - Immunocompromised Host
MH  - Mice
MH  - Mice, Transgenic
MH  - RNA, Messenger/drug effects/metabolism
MH  - Random Allocation
MH  - Tumor Necrosis Factor-alpha/immunology/metabolism/*therapeutic use
MH  - Tumor Stem Cell Assay/methods
EDAT- 2007/10/31 09:00
MHDA- 2007/12/14 09:00
CRDT- 2007/10/31 09:00
PHST- 2007/03/23 00:00 [received]
PHST- 2007/07/09 00:00 [revised]
PHST- 2007/07/11 00:00 [accepted]
PHST- 2007/10/31 09:00 [pubmed]
PHST- 2007/12/14 09:00 [medline]
PHST- 2007/10/31 09:00 [entrez]
AID - S0360-3016(07)03771-6 [pii]
AID - 10.1016/j.ijrobp.2007.07.2372 [doi]
PST - ppublish
SO  - Int J Radiat Oncol Biol Phys. 2007 Nov 15;69(4):1231-7. doi: 
      10.1016/j.ijrobp.2007.07.2372.