Pomalidomide is nonteratogenic in chicken and zebrafish embryos and nonneurotoxic in vitro

Abstract

Thalidomide and its analog, Lenalidomide, are in current use clinically for treatment of multiple myeloma, complications of leprosy and cancers. An additional analog, Pomalidomide, has recently been licensed for treatment of multiple myeloma, and is purported to be clinically more potent than either Thalidomide or Lenalidomide. Using a combination of zebrafish and chicken embryos together with in vitro assays we have determined the relative anti-inflammatory activity of each compound. We demonstrate that in vivo embryonic assays Pomalidomide is a significantly more potent anti-inflammatory agent than either Thalidomide or Lenalidomide. We tested the effect of Pomalidomide and Lenalidomide on angiogenesis, teratogenesis, and neurite outgrowth, known detrimental effects of Thalidomide. We found that Pomalidomide, displays a high degree of cell specificity, and has no detectable teratogenic, antiangiogenic or neurotoxic effects at potent anti-inflammatory concentrations. This is in marked contrast to Thalidomide and Lenalidomide, which had detrimental effects on blood vessels, nerves, and embryonic development at anti-inflammatory concentrations. This work has implications for Pomalidomide as a treatment for conditions Thalidomide and Lenalidomide treat currently.

Immunomodulatory drugs disrupt the cereblon–CD147–MCT1 axis to exert antitumor activity and teratogenicity

“…6d,e). This finding corresponds to a previous report in which lenalidomide and pomalidomide treatment of zebrafish did not result in a reduction in the length of pectoral fins 34 . In agreement with these observations, CD147 was destabilized after only thalidomide treatment, whereas lenalidomide and pomalidomide did not have this effect in zebrafish ( Fig.…”

Anticancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogues

“…Embryos were exposed to either a vehicle control at 24 hpf, or a Gu compound (5-100 μg/mL) for 24 hours. Embryos were anaesthetized in 0.1% tricaine and the length and number of intersegmental vessels were quantified as previously described (28). …”

“…Adult fish were crossed, embryos were obtained and incubated until 72 hpf, whereupon they were sedated in 0.1% tricaine then given a small cut in the dorsal third of the tail fin. They were then incubated with a vehicle control (0.1% DMSO) or a compound of interest (5-100 μg/mL) in aquarium water for 24 h. The number of fluorescent neutrophils migrating to the wound site was quantified as described previously (28). …”

“…Embryos at HH St 18 (E3) were retained for experimentation as at this stage the embryo is undergoing organogenesis and rapid growth. Drug administration was carried out as previously described (5, 28). Briefly, embryonic membranes were removed and the compound of interest was applied over the embryo.…”

Advancing host-directed therapy for tuberculosis

“…Thalidomide analogues have since been developed that reduce expression of TNF and certain other pro-inflammatory cytokines by inhibiting phosphodiesterase isozyme 4 (PDE4) activity, thereby increasing levels of cyclic AMP (cAMP). These PDE4 inhibitors do not bind to cereblon and have not been found to have thalidomidelike teratogenicity 89 . Thalidomide analogues have been studied as adjuncts to isoniazid monotherapy in mouse and rabbit models of tuberculosis, in which they reduce necrosis, fibrosis, granuloma number and size, and mycobacterial burden 90,91 .…”