Combined treatment with lexatumumab and irradiation leads to strongly increased long term tumour control under normoxic and hypoxic conditions.
OBJECTIVE
The combination of ionizing radiation with the pro-apoptotic TRAIL receptor antibody lexatumumab has been shown to exert considerable synergistic apoptotic effects in vitro and in short term growth delay assays. To clarify the relevance of these effects on local tumour control long-term experiments using a colorectal xenograft model were conducted.


METHODS
Colo205-xenograft bearing NMRI (nu/nu) nude mice were treated with fractionated irradiation (5x 3 Gy, d1-5) and lexatumumab (0.75 mg/kg, d1, 4 and 8). The tumour bearing hind limbs were irradiated with graded single top up doses at d8 under normoxic (ambient) and acute hypoxic (clamped) conditions. Experimental animals were observed for 270 days. Growth delay and local tumour control were end points of the study. Statistical analysis of the experiments included evaluation of tumour regrowth and local tumour control.


RESULTS
Combined treatment with irradiation and lexatumumab led to a pronounced tumour regrowth-delay when compared to irradiation alone. The here presented long-term experiments revealed a highly significant rise of local tumour control for normoxic (ambient) (p = 0. 000006) and hypoxic treatment (p = 0. 000030).


CONCLUSIONS
Our data show that a combination of the pro-apoptotic antibody lexatumumab with irradiation reduces tumour regrowth and leads to a highly increased local tumour control in a nude mouse model. This substantial effect was observed under ambient and more pronounced under hypoxic conditions.
Marini
Patrizia
P
CCC Tübingen, Dept of Radiation Oncology, University of Tübingen, Hoppe-Seyler-Str 3, 72076 Tübingen, Germany. patrizia.marini@uni-tuebingen.de
Junginger
Dorothea
D
Stickl
Stefan
S
Budach
Wilfried
W
Niyazi
Maximilian
M
Belka
Claus
C
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D015687:Cell Hypoxia / Q000187:drug effects* / Q000528:radiation effects*; D003131:Combined Modality Therapy; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; C510234:lexatumumab