Preferential susceptibility of brain tumors to the antiangiogenic effects of an alpha(v) integrin antagonist.
OBJECTIVE
Brain tumors are highly angiogenic, and their growth and spread depend on the generation of new blood vessels. We examined the effect of the cyclic peptide antagonist pentapeptide EMD 121974, an antiangiogenic agent, on orthotopic and heterotopic brain tumor growth.


METHODS
The human brain tumor cell lines DAOY (medulloblastoma) and U87 MG (glioblastoma) were injected into either the forebrain (orthotopic) or the subcutis (heterotopic) of nude mice, and daily systemic treatment with the active peptide was initiated after tumors were established.


RESULTS
All control animals with orthotopic brain tumors and that received the inactive peptide EMD 135981 daily died as a result of tumor progression within 4 to 6 weeks; tumors measured 3 to 5 mm in diameter. In contrast, mice with orthotopic tumors that were treated daily with the active peptide survived for more than 16 weeks, and histological examination of the brains after 4, 8, and 12 weeks showed either no tumors or microscopic residual tumors. The growth of these brain tumor cells injected simultaneously or separately into the subcutis of nude mice (heterotopic model) was not affected by the active peptide, suggesting that the brain environment is a critical determinant of brain tumor susceptibility to growth inhibition by this pentapeptide.


CONCLUSIONS
The cyclic pentapeptide EMD 121974 may become a treatment option specific to brain tumors. Because of its antiangiogenic effect, its use may be especially indicated after tumors are removed surgically.
MacDonald
T J
TJ
Department of Pediatrics, Children's Hospital and University of Southern California Keck School of Medicine, Los Angeles 90027, USA.
Taga
T
T
Shimada
H
H
Tabrizi
P
P
Zlokovic
B V
BV
Cheresh
D A
DA
Laug
W E
WE
D000482:Allantois / Q000098:blood supply; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply; D004351:Drug Resistance; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000188:drug therapy; D012910:Snake Venoms; D014183:Transplantation, Heterologous
D020533:Angiogenesis Inhibitors; D016023:Integrins; D010456:Peptides, Cyclic; D012910:Snake Venoms; C422910:Cilengitide