Radiosensitisation of U87MG brain tumours by anti-epidermal growth factor receptor monoclonal antibodies.
As epidermal growth factor receptor (EGFR) has been reported to be a radiation response modulator, HER inhibitors are regarded to act as potential radiosensitisers. Our study examined the role of nimotuzumab and cetuximab both, the two monoclonal antibodies (mAbs) to EGFR, as radiosensitisers in a murine glioma model in vivo. Co-administration of both the antibodies with radiation increased the radiosensitivity of U87MG, resulting in a significant delay of subcutaneous (s.c.) tumour growth. Furthermore, the addition of antibodies to the radiation decreased brain tumour sizes and is inhibited by 40-80% the increased tumour cell invasion provoked by radiotherapy, although promoted tumour cell apoptosis. Whereas nimotuzumab led to a reduction in the size of tumour blood vessels and proliferating cells in s.c. tumours, cetuximab had no significant antiangiogenic nor antiproliferative activity. In contrast, cetuximab induced a more marked inhibition of EGFR downstream signalling compared with nimotuzumab. Moreover, both antibodies reduced the total number of radioresistant CD133+ cancer stem cells (CSCs). These results were encouraging, and showed the superiority of combined treatment of mAbs to EGFR and radiation over each single therapy against glioblastoma multiforme (GBM), confirming the role of these drugs as radiosensitisers in human GBM. In addition, we first showed the ability of mAb specifics against EGFR to target radioresistant glioma CSC, supporting the potential use in patients.
Diaz Miqueli
A
A
Department of Experimental Immunotherapy, Centre of Molecular Immunology, PO Box 16040, 214 Street, Havana 11600, Cuba. arlhee@cim.sld.cu
Rolff
J
J
Lemm
M
M
Fichtner
I
I
Perez
R
R
Montero
E
E
D000071916:AC133 Antigen; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000032:analysis; D001932:Brain Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000502:physiology; D005260:Female; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000737:chemistry / Q000187:drug effects; D010455:Peptides / Q000032:analysis; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D000071916:AC133 Antigen; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D011838:Radiation-Sensitizing Agents; C501466:nimotuzumab; D066246:ErbB Receptors; D000068818:Cetuximab