Citations

After decades of disuse because of its teratogenic effects, thalidomide has had a resurgence of use as a promising therapeutic agent for multiple myeloma. Its mechanism of action involves activation of the immune system, antiangiogenic effects, and inhibition of cytokines. Thalidomide does not interact with the cytochrome oxidase system. It is not significantly metabolized, but it does undergo nonenzymatic hydrolysis in plasma. The resulting products are inactive. Despite the potential adverse effects of peripheral neuropathy, constipation, deep vein thrombosis, somnolence, rash, and orthostatic hypotension, thalidomide is an effective first-line agent for multiple myeloma in combination with dexamethasone or melphalan and prednisone. It has also been studied in the palliative care of patients with cytokine-based syndromes such as anorexia-cachexia syndrome. This review describes its use in oncology, hematology, and palliative care.

Abstract The Sleeping Beauty (SB) transposon system has been used as a somatic mutagen to identify candidate cancer genes. In previous studies, efficient leukemia/lymphoma formation on an otherwise wild-type genetic background occurred in mice undergoing whole-body mobilization of transposons, but was accompanied by high levels of embryonic lethality. To explore the utility of SB for large-scale cancer gene discovery projects, we have generated mice that carry combinations of different transposon and transposase transgenes. We have identified a transposon/transposase combination that promotes highly penetrant leukemia/lymphoma formation on an otherwise wild-type genetic background, yet does not cause embryonic lethality. Infiltrating gliomas also occurred at lower penetrance in these mice. SB-induced or accelerated tumors do not harbor large numbers of chromosomal amplifications or deletions, indicating that transposon mobilization likely promotes tumor formation by insertional mutagenesis of cancer genes, and not by promoting wide-scale genomic instability. Cloning of transposon insertions from lymphomas/leukemias identified common insertion sites at known and candidate novel cancer genes. These data indicate that a high mutagenesis rate can be achieved using SB without high levels of embryonic lethality or genomic instability. Furthermore, the SB system could be used to identify new genes involved in lymphomagenesis/leukemogenesis. [Cancer Res 2009;69(21):8429–37]