Evidence for the Intercalation of Thalidomide into DNA: Clue to the Molecular Mechanism of Thalidomide Teratogenicity?

Abstract

The intercalation of thalidomide (a-phthalimidoglutarimide) into nucleic acids was studied by spectrophotometric titrations, displacement of known intercalators, viscosity changes of DNA solutions, and by phase partition analysis. Specific binding of thalidomide was found to DNA of various specimens (human placenta, calf thymus, salmon sperm), but not to RNA (from bakers yeast, torula yeast).

Sea urchin embryos exposed to thalidomide during early cleavage exhibit abnormal morphogenesis later in development

“…Forty years after the thalidomide tragedy, the teratogenic mechanism of this drug remains an enigma. Although numerous theories have been proposed, no one has yet completely unraveled the puzzle of thalidomide's teratogenic effects, particularly in humans (Argiles et al, 1998;Finnell et al, 2002;Knobloch and Ruther, 2008;Knobloch et al, 2007;Koch and Czejka, 1986;Neubert et al, 1999;Stephens and Strecker, 1983;Therapontos et al, 2009;Wells et al, 2009). Our studies on the effects of thalidomide during early sea urchin embryo cleavage approach this puzzle from a different perspective.…”

IVIC syndrome Is caused by a c.2607delA mutation in the SALL4 locus

“…FGF signaling forms a positive feedback loop that is essential for outgrowth of the developing limbs [Wilkie et al, 2002]. Genes like IGF1 and FGF2 also act during embryonic development in tissues involved in the IVIC syndrome [Chen and von Bartheld, 2004;Varela-Nieto et al, 2004;Kashiwakura and Takahashi, 2005;Rosenblatt-Velin et al, 2005;Cediel et al, 2006] and could be targets of SALL4; its promoter regions are possible targets for the intercalating activity of thalidomide [Jönsson, 1972;Koch and Czejka, 1986;Stephens and Fillmore, 2000], a fact which with some speculation could explain the phenotypic resemblance of the thalidomide embryopathy and the IVIC syndrome [Arias et al, 1980], if those genes are also regulated by SALL4. Finally SALL4 expression could be modified by the WNT signaling pathway, as has been recently reported [Bohm et al, 2006;Ma et al, 2006].…”

Synthesis, radioiodination and biological evaluation of a novel phthalimide derivative

“…Compounds containing the phthalimide nucleus have been reported to possess diverse biological activities including antitumor [22], anti-inflammatory [23], antimicrobial [24], antitubercular [25], antivirus [26], liver X receptor antagonistic [27] and angiogenesis inhibitor properties [28]. Special attention has been devoted to the anticancer activity of phthalimides, which is due to their interactions with DNA by intercalation [29]. Despite the molecular mechanism of the antitumor effect of phthalimide derivatives still being unclear, tumor cell proliferation inhibitions by such analogues has being reported against several tumor cell types, probably due to an enhanced susceptibility to apoptosis via DNA damage and G0/G1 cell cycle arrest.…”