Translational strategies exploiting TNF-alpha that sensitize tumors to radiation therapy.
TNFerade is a radioinducible adenoviral vector expressing tumor necrosis factor-alpha (TNF-alpha) (Ad.Egr-TNF) currently in a phase III trial for inoperable pancreatic cancer. We studied B16-F1 melanoma tumors in TNF receptor wild-type (C57BL/6) and deficient (TNFR1,2-/- and TNFR1-/-) mice. Ad.Egr-TNF+IR inhibited tumor growth compared with IR in C57BL/6 but not in receptor-deficient mice. Tumors resistant to TNF-alpha were also sensitive to Ad.Egr-TNF+IR in C57BL/6 mice. Ad.Egr-TNF+IR produced an increase in tumor-associated endothelial cell apoptosis not observed in receptor-deficient animals. Also, B16-F1 tumors in mice with germline deletions of TNFR1,2, TNFR1 or TNF-alpha, or in mice receiving anti-TNF-alpha exhibited radiosensitivity. These results show that tumor-associated endothelium is the principal target for Ad.Egr-TNF radiosensitization and implicate TNF-alpha signaling in tumor radiosensitivity.
Mauceri
H J
HJ
Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, USA.
Beckett
M A
MA
Liang
H
H
Sutton
H G
HG
Pitroda
S
S
Galka
E
E
Efimova
E
E
Darga
T
T
Khodarev
N N
NN
King
C R
CR
Posner
M C
MC
Hellman
S
S
Kufe
D W
DW
Weichselbaum
R R
RR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D000068800:Etanercept; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000628:therapy*; D051379:Mice; D009368:Neoplasm Transplantation; D011838:Radiation-Sensitizing Agents; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014964:X-Ray Therapy
D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D011838:Radiation-Sensitizing Agents; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept