Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects

Abstract

The anti-tumour effects of thalidomide have been associated with its anti-angiogenic properties. Second generation thalidomide analogues are distinct compounds with enhanced therapeutic potential. Although these compounds are beginning to enter trials for the treatment of cancer there is very little information regarding the anti-angiogenic activity of these clinically relevant compounds. Furthermore, it is not known how the various immunomodulatory activities of these compounds relate to anti-angiogenic activity. In this study we assessed the anti-angiogenic activity of compounds from both IMiD and SelCID classes of analogues using a novel in vitro multicellular human assay system and the established rat aorta assay. Our results show that both the IMiDs and SelCIDs tested are significantly more potent than thalidomide. The anti-angiogenic potency of the analogues was not related to inhibition of endothelial cell proliferation, nor their TNF-alpha/PDE type 4 inhibitory properties. However, anti-migratory effects in vitro and inhibition of tumour growth in vivo was observed with the analogue IMiD-1 (clinically known as REVIMID). Our results show that anti-angiogenic activity spans both currently defined classes of thalidomide analogue and is not related to their previously described immunomodulatory properties. Identification of the differential effects of these compounds will enable targeting of such compounds into the appropriate clinical setting.

Figure 1

Illustrates the effect of a thalidomide analogue, IMiD-1 (C,F) and suramin (B,E) in comparison to their relative controls (A,D) on microvessel outgrowths in the rat aorta assay (top row) and on tubule development in the human angiogenesis model (bottom row).

Figure 2

Inhibition of angiogenesis as demonstrated by the reduction of tubule development following co-culture for 11 days with SelCIDs (A) or with thalidomide or IMiDs (B) in the human angiogenesis model. The effect of suramin or VEGF on tubule development is also shown. . *=P<0.05 vs control (Dunnett's test).

Figure 3

Inhibition of angiogenesis as demonstrated by the reduction in the number of microvessels observed following co-culture with SelCIDs (A) or with IMiDs (B) in the rat aorta angiogenesis model. The effect of suramin on microvessel development is also shown. *=P<0.05 vs control (Dunnett's test).

Figure 4

The effect of Thd, IMiDs and SelCIDs on bFGF and VEGF-induced HUVEC proliferative responses. The data is representative of three independent experiments.

Figure 5

The effect of suramin and IMiD-1 on the migratory properties of EA.hy926 cells in an in vitro wound healing assay. Results are expressed as mean number of cells migrating per field. *=P<0.05 versus control (Dunnett's test).

Figure 6

The effect of IMiD-1 on the growth rate of CMT93 colorectal tumour in nude mice (A). Data is representative of at least two independent experiments. *=P<0.05 vs control (Dunnett's test). Histological examination revealed that treatment with IMiD-1 (bottom picture) increased necrosis within the tumour (B). Magnification ×400.