PMID- 14751531
OWN - NLM
STAT- MEDLINE
DCOM- 20040308
LR  - 20190708
IS  - 0360-3016 (Print)
IS  - 0360-3016 (Linking)
VI  - 58
IP  - 2
DP  - 2004 Feb 1
TI  - A bispecific antibody to enhance radiotherapy by tumor necrosis factor-alpha in 
      human CEA-expressing digestive tumors.
PG  - 580-8
AB  - Tumor necrosis factor-alpha (TNF-alpha) enhances X-ray killing of human tumor 
      cells in vitro and enhances tumor control when combined with radiotherapy (RT) in 
      animal tumor models. In multiple Phase I studies, intravenous injection of 
      TNF-alpha appeared to have severe systemic side effects. To overcome these 
      limitations, we used a bispecific antibody (BAb) directed against 
      carcinoembryonic antigen and human TNF-alpha to target this cytokine in human 
      digestive carcinoma treated with simultaneous RT. We used human digestive 
      carcinoma cell lines (colon cancer, LS174T, and pancreatic cancer, BxPC-3) to 
      determine the interaction of TNF-alpha and RT on clonogenic cytotoxicity. 
      Isobolograms were established to confirm additive or supra-additive effects 
      between both treatments. LS174T and BxPC-3 cells were grafted subcutaneously at 
      Day 0 into female nude mice (7-8 weeks old). When the tumors reached a volume of 
      about 80 mm(3), the mice were randomly assigned to treatment: Group 1, normal 
      saline i.v. injection (control group); Group 2, TNF-alpha at 1 microg/i.v. 
      injection; Group 3, BAb at 25 microg/i.v. injection; Group 4, BAb plus TNF-alpha 
      (ratio 25 microg to 1 microg) i.v. injection; Group 5, local RT plus normal 
      saline (0.5 Gy. min(-1)) at a total dose of 30 Gy delivered in five fractions; 
      Group 6, local RT plus TNF-alpha injections 3 h before RT; Group 7, local RT plus 
      BAb plus TNF-alpha co-injected 24 h before RT. Tumor growth delay was used as the 
      end point for all groups. In the LS174T experiments, TNF-alpha added 12 h before 
      RT showed a statistically significant decrease in the survival fraction at 2 Gy 
      compared with RT alone (0.23 vs. 0.42 Gy, p = 0.0017). These results were largely 
      confirmed with the BxPC-3 cell lines (0.29 vs. 0.72, p <0.00001). Isobolograms 
      confirmed the additivity between TNF-alpha and RT in both cell lines. At 50% 
      survival, the data points were within the envelope of additivity. In the LS174T 
      and BxPC-3 xenografts, RT as a single agent (Group 5) slowed tumor progression 
      compared with Group 1 (p <0.027 and p = 0.00001, respectively). TNF-alpha alone, 
      BAb alone, or BAb plus TNF-alpha (Groups 2, 3, and 4) had no effect. In the 
      LS174T model, TNF-alpha plus RT enhanced the delay to reach 2000 mm(3) compared 
      with RT alone but without statistical significance. This delay was significantly 
      longer when BAb was added (p = 0.0033, for Group 6 vs. Group 7). In the BxPC-3 
      experiments, the median delay to reach 2000 mm(3) was similar between the RT and 
      TNF-alpha plus RT groups (93 days). The use of our BAb in combination with 
      TNF-alpha and RT dramatically enhanced this median delay (177 days, p = 0.0013). 
      No body weight loss was observed in any group. Our data could be used as a solid 
      preclinical rationale on which to base a clinical study of locally advanced 
      pancreatic or rectal cancers in the near future.
FAU - Azria, David
AU  - Azria D
AD  - Tumor Immunotargeting and Antibody Engineering, INSERM EMI 0227, 34298 
      Montpellier Cedex 5, France. azria@valdorel.fnclcc.fr
FAU - Larbouret, Christel
AU  - Larbouret C
FAU - Garambois, Veronique
AU  - Garambois V
FAU - Gourgou, Sophie
AU  - Gourgou S
FAU - Martineau, Pierre
AU  - Martineau P
FAU - Robert, Bruno
AU  - Robert B
FAU - Dubois, Jean-Bernard
AU  - Dubois JB
FAU - Pelegrin, Andre
AU  - Pelegrin A
LA  - eng
PT  - Journal Article
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 (Antineoplastic Agents)
RN  - 0 (Carcinoembryonic Antigen)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Radiation-Sensitizing Agents)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Animals
MH  - Antibodies, Bispecific/*pharmacology
MH  - Antineoplastic Agents/adverse effects/*therapeutic use
MH  - Carcinoembryonic Antigen/*immunology/metabolism
MH  - Cell Line, Tumor
MH  - Colonic Neoplasms/metabolism/*radiotherapy
MH  - Female
MH  - Humans
MH  - Mice
MH  - Mice, Nude
MH  - Neoplasm Proteins/*antagonists & inhibitors/metabolism
MH  - Pancreatic Neoplasms/metabolism/*radiotherapy
MH  - Radiation-Sensitizing Agents/adverse effects/*therapeutic use
MH  - Radiotherapy Dosage
MH  - Tumor Necrosis Factor-alpha/adverse effects/antagonists & inhibitors/*therapeutic 
      use
MH  - Tumor Stem Cell Assay
EDAT- 2004/01/31 05:00
MHDA- 2004/03/09 05:00
CRDT- 2004/01/31 05:00
PHST- 2004/01/31 05:00 [pubmed]
PHST- 2004/03/09 05:00 [medline]
PHST- 2004/01/31 05:00 [entrez]
AID - S0360301603019904 [pii]
AID - 10.1016/j.ijrobp.2003.09.051 [doi]
PST - ppublish
SO  - Int J Radiat Oncol Biol Phys. 2004 Feb 1;58(2):580-8. doi: 
      10.1016/j.ijrobp.2003.09.051.