Comparative toxicity and efficacy of combined radioimmunotherapy and antiangiogenic therapy in carcinoembryonic antigen-expressing medullary thyroid cancer xenograft.
A significant antitumor effect was previously observed with radioimmunotherapy using anti-carcinoembryonic antigen (131)I-F6 monoclonal antibody in medullary thyroid cancer-bearing nude mice. Nevertheless, no complete response was observed. As seen with chemotherapy, drugs targeting the tumor microenvironment might improve radioimmunotherapy efficacy. This study evaluated the toxicity and efficacy of combining radioimmunotherapy with thalidomide or a cyclopeptidic vascular endothelial growth inhibitor (CBOP11) in mice grafted with the TT human medullary thyroid cancer cell line.


METHODS
Six to 10 nude mice treated with 92.5 MBq of (131)I-F6 in association with 200 mg/kg/d of oral thalidomide during 20 d by force-feeding or 0.45 mg/kg/d of CBOP11 during 25 d using subcutaneous minipumps were compared with control mice receiving either treatment or naked F6 or nonspecific (131)I-734. Combined therapies included (131)I-F6 at day 0 followed by thalidomide between days 20 and 40, thalidomide between days 0 and 20 followed by (131)I-F6 at day 25, (131)I-F6 at day 0 and CBOP11 between days 0 and 25, CBOP11 between days 0 and 25 followed by (131)I-F6 at day 25, and (131)I-F6 at day 0 followed by CBOP11 between days 20 and 45. Animal weight, hematologic toxicity, tumor volume, and serum calcitonin were monitored for the following 3 mo. Improvement of (125)I-F6 tumor biodistribution by antiangiogenic drug was studied after pretreatment by thalidomide. Follow-up of the tumor after combined antiangiogenic and radioimmunotherapy therapies was performed by histology studies.


RESULTS
Combined associations, as compared with radioimmunotherapy alone, increased leukopenia but not thrombocytopenia. Tumor volume-quadrupling time (TVQT) was 22.8 +/- 3.3 d in the control group, 29.9 +/- 3.6 d in the group treated with thalidomide, 34.6 +/- 4.4 d in the group treated with CBOP11, and 51.0 +/- 2.8 d after radioimmunotherapy alone. As compared with radioimmunotherapy, TVQT was significantly longer (P < 0.01) after thalidomide followed by radioimmunotherapy (69.83 +/- 3.9), CBOP11 followed by radioimmunotherapy (71.3 +/- 6.1), and CBOP11-radioimmunotherapy in concomitance (64.2 +/- 6.1). Nevertheless, TVQT was not increased after radioimmunotherapy followed by thalidomide (48.8 +/- 4) and radioimmunotherapy followed by CBOP11 (56.8 +/- 4.8). Surprisingly, pretreatment by CBOP11 or thalidomide sensitized larger tumors (>300 mm(3)) to radioimmunotherapy. Change in calcitonin levels confirmed morphologic tumor response. Tumor uptake 24 h after injection of (125)I-F6 was 4.5 +/- 0.6 percentage injected dose per gram (%ID/g) without pretreatment and 8.7 +/- 1.3 %ID/g with pretreatment by thalidomide. An increase of the antitumor effect observed using the antiangiogenic drug combined with radioimmunotherapy was correlated with a decrease of blood vessels shown by von Willebrand immunostaining.


CONCLUSIONS
Pretreatment with antiangiogenic therapies improved radioimmunotherapy efficacy, with acceptable toxicity. Future investigations will be performed to understand how antiangiogenic agents sensitize large tumors to radioimmunotherapy.
Kraeber-Bodéré
Françoise
F
INSERM UMR 892-Cancer Research Center, Université de Nantes, Nantes, France. francoise.bodere@chu-nantes.fr
Bodet-Milin
Caroline
C
Niaudet
Colin
C
Saï-Maurel
Catherine
C
Moreau
Anne
A
Faivre-Chauvet
Alain
A
Thomare
Patrick
P
Deleris
Gerard
G
Estieu-Gionnet
Karine
K
Bikfalvi
Andréas
A
Barbet
Jacques
J
Paris
François
F
D020533:Angiogenesis Inhibitors / Q000276:immunology / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002272:Carcinoembryonic Antigen / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D016228:Endothelial Growth Factors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry; D051379:Mice; D010456:Peptides, Cyclic / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016499:Radioimmunotherapy; D013792:Thalidomide / Q000494:pharmacology / Q000627:therapeutic use; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D014018:Tissue Distribution; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D016228:Endothelial Growth Factors; D007457:Iodine Radioisotopes; D010456:Peptides, Cyclic; D042461:Vascular Endothelial Growth Factor A; C478485:cyclo-VEGI; D013792:Thalidomide