Maternal administration of anti-angiogenic agents, TNP-470 and Angiostatin4.5, induces fetal microphthalmia.
OBJECTIVE
Agents specifically targeting the vasculature as a mode of therapy are finding increasing use in the clinic, primarily in the treatment of colon cancer (Avastin) and age-related macular degeneration (Lucentis). We have previously shown that maternal administration of angiogenic inhibitors (TNP-470 [O-[chloroacetyl-carbamoyl]fumagillol, initially called AGM-1470], the first angiogenic inhibitor to undergo clinical trials, and Angiostatin(4.5), currently in phase I-III clinical trials) cause fetal growth restriction and/or placental abnormalities. During a rapid growth phase of ocular development in the mouse (embryonic days 12 to 19 [E12-E19]), the placenta mediates the metabolic requirements of the fetus and consequently may impact upon the growth of the highly oxygen sensitive fetal eye.


METHODS
We injected pregnant dams (between E10.5 - E18.5) with anti-angiogenic agents, which caused either a placental insufficiency type of IUGR (intrauterine growth restriction; i.e., TNP-470) or frank placental pathology (Angiostatin(4.5) [AS(4.5)]), and assessed changes in absolute ocular dimensions, tissue types, and vascular profiles using stereological techniques.


RESULTS
The experiments showed that ocular volumes were significantly reduced in fetal mice where dams were treated with either TNP-470 or AS(4.5). Furthermore, TNP-470 specifically caused a reduction in hyaloid blood vessel length and volume, the only intraocular vascular circulation in fetal mice.


CONCLUSIONS
These experiments support the hypothesis that the angiogenic inhibitors (specifically TNP-470 and AS(4.5)) induce microphthalmia either indirectly by their known effects on placental morphology (and/or function) or directly via altering microvascular growth in the fetus. These results also warrant further investigation of a new experimental paradigm linking placental pathology-related fetal growth restriction and microphthalmia.
Rutland
Catrin S
CS
Academic Division of Obstetrics and Gynaecology, Nottingham City Hospital, University of Nottingham, Nottingham, UK.
Jiang
Keyi
K
Soff
Gerald A
GA
Mitchell
Christopher A
CA
D020533:Angiogenesis Inhibitors / Q000633:toxicity*; D043168:Angiostatins / Q000633:toxicity*; D000818:Animals; D003510:Cyclohexanes / Q000633:toxicity*; D005123:Eye / Q000098:blood supply / Q000473:pathology; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D005315:Fetal Diseases / Q000139:chemically induced* / Q000473:pathology; D005317:Fetal Growth Retardation / Q000139:chemically induced; D006651:Histocytochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008850:Microphthalmos / Q000139:chemically induced* / Q000473:pathology; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D009929:Organ Size; D010920:Placenta / Q000473:pathology; D011247:Pregnancy; D011897:Random Allocation; D012717:Sesquiterpenes / Q000633:toxicity*; D013723:Teratogens / Q000633:toxicity*
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D012717:Sesquiterpenes; D013723:Teratogens; C483085:angiostatin4.5, human; D043168:Angiostatins; D000077609:O-(Chloroacetylcarbamoyl)fumagillol