Maternal administration of anti-angiogenic agents, TNP-470 and Angiostatin(4.5), induces fetal microphthalmia

PURPOSE: 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.