Inhibition of experimental U-118MG glioblastoma by targeted cytotoxic analogs of bombesin and somatostatin is associated with a suppression of angiogenic and antiapoptotic mechanisms.
Human gliomas express receptors for bombesin and somatostatin that can be used for targeted chemotherapy. In the present study, the efficacy and the mechanism of action of cytotoxic bombesin analog AN-215, and cytotoxic somatostatin analog AN-238 were investigated in U-118MG human glioblastomas xenografted into nude mice. The expression of vascular endothelial growth factor (VEGF) and the apoptotic markers Bcl-2 and Bax was analyzed by Western blotting. The toxicity was evaluated by measuring leukocyte levels and body weights. Treatment with AN-215 or AN-238 reduced tumor growth by approximately 50%, and diminished the levels of VEGF by 45 and 75%, respectively. The relative ratio of Bcl-2 to Bax proteins was decreased by approximately 90%, indicating a net apoptotic gain and efficacy of treatment. Specific receptors for bombesin and somatostatin were found in U-118MG tumors. Our results suggest that targeted cytotoxic analogs, AN-215 and AN-238, could be useful for the treatment of human glioblastomas.
Kanashiro
Celia A
CA
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, LA 70112, USA.
Schally
Andrew V
AV
Nagy
Attila
A
Halmos
Gabor
G
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001835:Body Weight; D001839:Bombesin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006728:Hormones / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018004:Receptors, Bombesin / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000378:metabolism; D013004:Somatostatin / Q000494:pharmacology*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C494827:Bax protein, mouse; D006728:Hormones; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D018004:Receptors, Bombesin; D017481:Receptors, Somatostatin; D042461:Vascular Endothelial Growth Factor A; D051028:bcl-2-Associated X Protein; D013004:Somatostatin; D001839:Bombesin