Thalidomide And Analogs In Angiogenesis And Cancer

Thalidomide and related compounds, including PG acid, EM-12, and EM-138 were tested in mice, and each of these related compounds inhibited bFGF- and VEGF-induced corneal neovascularization (20). In these studies, intraperitoneal, but not oral, administration of thalidomide inhibited angiogenesis in mice. The route-dependence of thalidomide as an antiangiogenic agent in mice was similar to the reported susceptibility of rodents to congenital malformations induced by intraperitoneal injections of thalidomide (31,34). Therefore, the route of delivery is again a critical parameter when evaluating the effects of thalidomide on angiogenesis (20) and tumor growth (41).

Gordon et al. provided evidence for the conversion of thalidomide to a toxic arene oxide metabolite by liver microsomes (10), possibly by the action of cytochrome P-450 (42). Since both a 3- and a 4-hydroxy metabolite of thalidomide have been detected, it was hypothesized that a reactive 3,4-epoxy form of thalidomide may mediate its teratogenic action (10). Interestingly, tetrafluorothalidomide, a fluorinated analog of thalidomide that cannot be hydroxylated or converted into an epoxide (43), inhibited angiogenesis comparable to thalidomide at its maximum tolerated dose (unpublished data). This suggests that neither epoxide formation nor hydroxylation of the pthalimide ring is essential for inhibiting angiogenesis. Other metabolites of thalidomide and EM-12, including 3-hydroxyphthalmide, 4-hydroxythalidomide, EM-27, and EM-356, were also tested but did not inhibit corneal neovascularization (20). S ince PG-acid and EM-138 inhibited angiogenesis in both the chick CAM assay and in mice, PG acid and EM-138 may be metabolites of thalidomide and EM-12, respectively, which mediate their antiangiogenic effect.

Experiments examining the effect of thalidomide enantiomers on angiogenesis in mice revealed that the S(-) enantiomer had the strongest antiangiogenic activity in VEGF- and bFGF-induced corneal neovascularization, which further supported a link between thalidomide's antiangiogenic and teratogenic activities (30,32,44). The antiangiogenic activity of thalidomide correlated with the teratogenic but not the sedative or mild immu-nosuppressive properties of thalidomide. Supidimide (Fig. 2), an analog of thalidomide that retains sedative but not teratogenic activity, did not inhibit angiogenesis.

Negative results using thalidomide have been reported in rodent cancer models (41,45). These studies did not, however, take into consideration that thalidomide is neither teratogenic nor antiangiogenic in rodents when administered orally. In contrast, other studies in mice have shown that thalidomide had small antitumor effects, and in combination with 5,6-dimethylxanthenone-4-acetic acid, an analog of flavone acetic acid, resulted in complete cures in mice (46). Mice treated with thalidomide administered by intraperitoneal route in combination with cytoxan and adriamycin

Fig. 3. Hydrolysis of thalidomide (A) and EM-12,

Fig. 3. Hydrolysis of thalidomide (A) and EM-12, showed significantly smaller tumors than those given the two chemotherapeutic agents alone in a model of breast cancer (47). Since the effects of thalidomide may be more accurately reflected in rabbits than rodent models, thalidomide was tested o

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