Thalidomide: lack of mutagenic activity across phyla and genetic endpoints

Ashby, John; Tinwell, H.; Callander, R.D.; Kimber, Ian; Clay, Philip; Galloway, Sheila M.; Hill, Rosina; Greenwood, Susan K.; Gaulden, Mary Esther; Ferguson, Martha J.; Vogel, E.; Nivard, Madeleine J.M.; Parry, James M.; Williamson, J.

doi:10.1016/s0027-5107(97)00174-7

Cited by 32 publications

(12 citation statements)

References 54 publications

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“…Current evidence suggests that the parent molecule is not mutagenic, genotoxic, and clastogenic [16,21]. Current evidence suggests that the parent molecule is not mutagenic, genotoxic, and clastogenic [16,21].…”

Section: Discussionmentioning

confidence: 99%

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Assessment of the in vitro and in vivo genotoxicity of Thalomid� (thalidomide)

Teo¹,

Morgan²,

Stirling³

et al. 2000

Teratog. Carcinog. Mutagen.

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Thalomid is the FDA-approved commercial formulation of thalidomide currently used in the US to treat erythema nodosum leprosum, a complication of leprosy. The genotoxicity of Thalomid thalidomide was assessed in the Ames reverse mutation, AS52/XPRT mammalian cell forward gene mutation, and mouse bone marrow micronucleus assays. The Ames and AS52 assays were performed with and without S9. In the Ames, Salmonella typhimurium strains TA1535, 1537, 98, 100, and 102 and Escherichia coli strain WP2 uvrA were used. Assays were performed by using plate incorporation and liquid pre-incubation systems at thalidomide doses of 50-10,000 microg/plate. In the AS52 assay, Chinese hamster ovary cells were plated with fortified Ham's F12 medium and incubated overnight. The medium was then incubated with 1-1000 microg/ml thalidomide. After a series of aspirations, washings, reconstitutions, and incubations, mutant AS52 cells were fixed and stained. Colonies were then counted and the relative survival frequencies compared to negative controls. In the mouse micronucleus assay, Crl:CD-1 albino mice were dosed with 500, 2,500, and 5,000 mg/kg thalidomide and sacrificed over 72 h. Femurs were flushed with fetal bovine serum and the suspensions centrifuged. The supernatant was aspirated and the cell pellet resuspended and stained. Polychromatic erythrocytes were scored for micronucleated polychromatic and normochromatic erythrocytes. Thalidomide did not increase revertant frequencies in all bacterial strains. It also did not produce any significant increase in the average mutant frequencies of AS52 cells and mouse micronucleated polychromatic erythrocytes. We conclude that Celgene's Thalomid thalidomide is non-genotoxic.

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Section: Discussionmentioning

confidence: 99%

“…Previous genotoxicity studies have however been performed in other formulations of thalidomide in various in vitro and in vivo systems [16]. Rodent oncogenicity assays are currently ongoing and results will not be available for at least 2 years.…”

Section: Introductionmentioning

confidence: 99%

Assessment of the in vitro and in vivo genotoxicity of Thalomid� (thalidomide)

Teo¹,

Morgan²,

Stirling³

et al. 2000

Teratog. Carcinog. Mutagen.

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“…Although not mutagenic, 66 thalidomide intercalates DNA. 67,68 Specifically, S( À ) thalidomide is predicted to intercalate into the major groove of the DNA-double helix structure at purine sites (with greater affinity for guanine over adenine) where its glutarimide moiety oriented in a 3 0 -direction.…”

Section: Evidence For Genetic and Epigenetic Effects Of Imidsmentioning

confidence: 99%

Thalidomide-analogue biology: immunological, molecular and epigenetic targets in cancer therapy

2013

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Thalidomide and its analogues (lenalidomide and pomalidomide) are small molecule glutamic acid derivatives of the immunomodulatory drug (IMiD) class. In addition to the immuno-adjuvant and anti-inflammatory properties that define an IMiD, the thalidomide analogues demonstrate an overlapping and diverse range of biological activities, including anti-angiogenic, teratogenic and epigenetic effects. Importantly, the IMiDs possess anti-cancer activity with selectivity for molecularly defined subgroups of hematological malignancies, specifically mature B-cell neoplasms and myelodysplasia with deletion of chromosome 5q. Emerging insight into the pathophysiological drivers of these IMiD-responsive disease states can now be synthesized using previously disclosed IMiD activities and recently discovered thalidomide targets to build unifying models of IMiD mechanism of action. Attention to mechanisms of IMiD-induced clinical toxicities, in particular the recently identified association of lenalidomide with second primary malignancies, provides an additional tool for determination of drug mechanism. This review seeks to define the molecular IMiD targets and biological outputs that underpin their anti-neoplastic activity. It is anticipated that elucidation of important IMiD targets will allow the rational development of new-generation therapeutics with the potential to separate thalidomide-analogue efficacy from clinical toxicity.

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“…The transgenerational transmission of a defect induced by thalidomide is therefore a reasonable hypothesis. It is very unlikely that this could be due to mutagenic activity, because there is no obvious way that an induced mutation would occur, nor is there any evidence that thalidomide is mutagenic in various test systems [66]. The transgenerational transmission of the phenotype might, however, be explained as heritable epigenetic defect.…”

Section: Pharmaceutical Drugmentioning

confidence: 99%