Activity of thalidomide in AIDS-related Kaposi's sarcoma
ABSTRACT To assess the toxicity and activity of oral thalidomide in Kaposi's sarcoma (KS) in a phase II dose-escalation study.
Human immunodeficiency virus (HIV)-seropositive patients with biopsy-confirmed KS that progressed over the 2 months before enrollment received an initial dose of 200 mg/d of oral thalidomide in a phase II study. The dose was increased to a maximum of 1,000 mg/d for up to 1 year. Anti-HIV therapy was maintained during the study period. Toxicity, tumor response, immunologic and angiogenic factors, and virologic parameters were assessed.
Twenty patients aged 29 to 49 years with a median CD4 count of 246 cells/mm(3) (range, 14 to 646 cells/mm(3)) were enrolled. All patients were assessable for toxicity, and 17 for response. Drowsiness in nine and depression in seven patients were the most frequent toxicities observed. Eight (47%; 95% confidence interval [CI], 23% to 72%) of the 17 assessable patients achieved a partial response, and an additional two patients had stable disease. Based on all 20 patients treated, the response rate was 40% (95% CI, 19% to 64%). The median thalidomide dose at the time of response was 500 mg/d (range, 400 to 1,000 mg/d). The median duration of drug treatment was 6.3 months, and the median time to progression was 7.3 months.
Oral thalidomide was tolerated in this population at doses up to 1,000 mg/d for as long as 12 months and was found to induce clinically meaningful anti-KS responses in a sizable subset of the patients. Additional studies of this agent in KS are warranted.
- SourceAvailable from: Shreyans Gandhi
British Journal of Haematology 05/2012; 158(3):421-3. DOI:10.1111/j.1365-2141.2012.09157.x · 4.96 Impact Factor
- "In our cohort, complete regression of lymph nodes and symptoms was observed in 91% of patients and was maintained after discontinuation of treatment with a 2-year PFS of 60% after a median followup of almost 2 years, comparing favourably with rituximab alone (Gerard et al, 2007; Bower et al, 2011). Despite small numbers, the low risk of KS reactivation could be thalidomide-related , as has been previously reported (Little et al, 2000). The duration of maintenance with thalidomide in MCD patients following rituximab-thalidomide combination therapy should be explored in a prospective trial. "
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- ". Furthering the clinical revival of this agent, thalidomide emerged as an effective drug to treat complications of HIV disease such as the HIV wasting syndrome, Kaposi's sarcoma, and aphthous ulcers [Little et al. 2000; Jacobson et al. 1997; Reyes-Teran et al. 1996]. "
ABSTRACT: Perhaps no other drug in modern medicine rivals the dramatic revitalization of thalidomide. Originally marketed as a sedative, thalidomide gained immense popularity worldwide among pregnant women because of its effective anti-emetic properties in morning sickness. Mounting evidence of human teratogenicity marked a dramatic fall from grace and led to widespread social, legal and economic ramifications. Despite its tragic past thalidomide emerged several decades later as a novel and highly effective agent in the treatment of various inflammatory and malignant diseases. In 2006 thalidomide completed its remarkable renaissance becoming the first new agent in over a decade to gain approval for the treatment of plasma cell myeloma. The catastrophic collapse yet subsequent revival of thalidomide provides important lessons in drug development. Never entirely abandoned by the medical community, thalidomide resurfaced as an important drug once the mechanisms of action were further studied and better understood. Ongoing research and development of related drugs such as lenalidomide now represent a class of irreplaceable drugs in hematological malignancies. Further, the tragedies associated with this agent stimulated the legislation which revamped the FDA regulatory process, expanded patient informed consent procedures and mandated more transparency from drug manufacturers. Finally, we review recent clinical trials summarizing selected medical indications for thalidomide with an emphasis on hematologic malignancies. Herein, we provide a historic perspective regarding the up-and-down development of thalidomide. Using PubMed databases we conducted searches using thalidomide and associated keywords highlighting pharmacology, mechanisms of action, and clinical uses.10/2011; 2(5):291-308. DOI:10.1177/2040620711413165
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- "Diseases including inflammatory bowel disease, erythema nodosum leprosum, rheumatoid arthritis, multiple myeloma, and cancer are currently being treated with thalidomide, although its mechanism of action remains unclear. The anti-angiogenic properties (D'Amato et al., 1994; Kenyon et al., 1997) and T-cell co-stimulatory activity (Barlett et al., 2004) of thalidomide have both been demonstrated as anti-cancer mechanisms of the drug, which has been reported to inhibit basic fibroblast growth factor (bFGF)induced angiogenesis (D'Amato et al., 1994) and tumor growth in animals (Verheul et al., 1999) and human cancer patients (Little et al., 2000; Singhal et al., 1999). The potent antiinflammatory activity of thalidomide has been shown to suppress lipopolysaccharide-induced production of tumor necrosis factor-α (TNF-α) (Sampaio et al., 1991; Tavares et al., 1997) and interleukin-12 (IL-12) (Corral et al., 1999; Moller et al., 1997). "
ABSTRACT: We investigated the effect of thalidomide on transcriptional and post-transcriptional cyclooxygenase-2 (COX-2) expression, including a pathway leading to COX-2 mRNA destabilization. We found that thalidomide inhibited the interleukin-1beta (IL-1beta)-mediated induction of COX-2 protein and mRNA in Caco-2 cells. Transient transfection with a COX-2 promoter construct demonstrated that thalidomide did not affect IL-1beta-induced transcriptional activation of COX-2, although it did decrease the stability of COX-2 mRNA and suppress IL-1beta-induced cytoplasmic shuttling of an mRNA stabilizing protein, HuR. Thalidomide also suppressed IL-1beta-induced p38 mitogen-activated protein kinase (MAPK) activation, while a p38 MAPK inhibitor destabilized COX-2 mRNA and the cytoplasmic shuttling of HuR induced by IL-1beta. These data suggest that one of the molecular mechanisms of thalidomide may be destabilization of COX-2 mRNA through inhibition of cytoplasmic shuttling of HuR and p38 MAPK.European Journal of Pharmacology 04/2007; 558(1-3):14-20. DOI:10.1016/j.ejphar.2006.11.060 · 2.68 Impact Factor