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PubMed1994

Effects of oral thalidomide on rat liver and skin microsomal P450 isozyme activities and on urinary porphyrin excretion: interaction with oral hexachlorobenzene.

Adult female Wistar rats (n = 48) divided into four groups of 12 were treated orally with 3 mg/kg per day thalidomide, a 0.05% hexachlorobenzene (HCB)--containing diet, with both drugs together and with the vehicles (controls) over periods of 10 and 60 days. The protein and P450 contents and the activities of aminopyrine-N-demethylase (ADM) and 7-ethoxyresorufin-O-deethylase (7-ERO-D) were determined in the liver microsomes. The activity of 7-ERO-D was also determined in the skin microsomes and total porphyrins were measured in the urine of the animals. Thalidomide increased the hepatic P450 content, caused distinct changes in the activities of the hepatic and cutaneous microsomal isozymes, modified their induction by HCB and inhibited the porphyrogenic activity of HCB. These findings indicate an interaction between thalidomide and HCB with regard to their effects on the P450 isozymes and the metabolism of porphyrins.

Administration, Oral↗
PubMed1986

Treatment of Behçet's disease with thalidomide.

The clinical response to thalidomide in 30 male patients with Behçet's disease was reviewed. Twenty-six patients with orogenital ulcerations responded (20 completely and 6 partially). Cutaneous lesions including erythema nodosum or necrotic pseudofolliculitis were controlled by treatment in the majority of cases. All patients with arthritis responded (13 completely and 1 partially). Uveitis was improved in 3 patients, stabilizated in 4 and aggravated in 4. Patients with thalidomide purposely discontinued experienced a flare; the reintroduction of therapy controlled the flare. Side effects were uncommon and included skin rash and somnolence. These results suggest that thalidomide may be useful in the therapy of the various manifestations of Behçet's disease and that a controlled study is indicated.

Adolescent↗
PubMedDate not supplied

Thalidomide reduces lipopolysaccharide/zymosan-induced acute lung injury in rats.

Pharmacological therapies targeting fulminant lung inflammation in acute lung injury (ALI) need to be improved. We evaluated the effect of thalidomide, a chemical modulating both acute and chronic inflammation, on ALI induced by intravenous administration of lipopolysaccharide (LPS) and zymosan in male Sprague-Dawley rats. Injection of LPS and zymosan induced significant lung inflammation, as evidenced by increased neutrophil sequestration in lung tissue as well as enhanced nitric oxide metabolite (NO(x)(-)) production in the serum and bronchoalveolar lavage (BAL) fluid. Lactate dehydrogenase (LDH) activity and protein concentration in BAL fluid were significantly increased after administration of LPS and zymosan. Pulmonary microvascular permeability was determined using the Evans blue retention method, which showed a significant increase in microvascular permeability after LPS and zymosan administration, indicating the development of ALI. Animals that received thalidomide (100 mg/kg) 2 h prior to LPS injection had significantly reduced pulmonary NO(x)(-) production, pulmonary microvascular permeability, and LDH activity and protein concentration in BAL fluid. We therefore conclude that thalidomide ameliorates lung inflammation and reduces ALI induced by combined LPS and zymosan administration in rats.

Acute Disease↗
PubMed2006

A North American brain tumor consortium (NABTC 99-04) phase II trial of temozolomide plus thalidomide for recurrent glioblastoma multiforme.

BACKGROUND: Laboratory and clinical data suggest that the anti-angiogenic agent, thalidomide, if combined with cytotoxic agents, may be effective against recurrent glioblastoma multiforme (GBM). OBJECTIVES: To determine 6-month progression-free survival (6PFS) and toxicity of temozolomide plus thalidomide in adults with recurrent GBM. PATIENTS AND METHODS: Eligible patients had recurrent GBM after surgery, radiotherapy, and/or adjuvant chemotherapy. Temozolomide was given at 150-200 mg/m(2)/day on days 1-5 of each 28-day cycle. Thalidomide was given orally at 400 mg at bedtime (days 1-28) and increased to 1,200 mg as tolerated. Patients were evaluated with magnetic resonance imaging scans every 56 days. The study was designed to detect an increase of the historical 6PFS for GBM from 10 to 30%. RESULTS: Forty-four patients were enrolled, 43 were evaluable for efficacy and safety. The study population included 15 women, 29 men; median age was 53 years (range 32-84); median Karnofsky performance status was 80% (range 60-100%). Thirty-six (82%) patients were chemotherapy-naïve. There were 57 reports of toxicity of grade 3 or greater. Non-fatal grade 3-4 granulocytopenia occurred in 15 patients (34%). The objective response rate was 7%. The estimated probability of being progression-free at 6 months with this therapy is 24% [95% confidence interval (C.I.) 12-38%]. The median time to progression is 15 weeks (95% C.I. 10-20 weeks). There was no observed correlation between serum levels of vascular endothelial growth factor, basic fibroblast growth factor, and IL-8 and the 6PFS outcome. CONCLUSION: This drug combination was reasonably safe, but with little indication of improvement compared to temozolomide alone.

Adult↗
PubMed1990

The potential use of thalidomide in the therapy of graft-versus-host disease--a review of clinical and laboratory information.

This article reviews the historical development of thalidomide as an immunosuppressive agent and the current state of knowledge of thalidomide as an anti-graft-versus-host disease (GVHD) agent. The evidence suggests that metabolites of thalidomide act at an early stage in the antigen recognition-activation pathway of graft T lymphocytes and down regulate normal lymphocyte responses. This effect seems to have beneficial effects in both acute and chronic GVHD, but the optimal mode of use in the clinical setting remains to be determined.

Acute Disease↗
PubMed1996

Thalidomide promotes metastasis of prostate adenocarcinoma cells (PA-III) in L-W rats.

Two contradictory actions have been ascribed to thalidomide relative to tumor metastasis: immunosuppression and anti-angiogenesis. The latter effect was determined with basic fibroblast growth factor in a rabbit cornea micropocket assay system. The prostate adenocarcinoma (PA-III) transplanted tumor line in Lobund-Wistar (L-W) rats produces a tumor at the subcutaneous implant site from which tumor cells metastasize uniformly only through lymphatic channels through the heart to the lungs in which secondary tumors develop. L-W rats were implanted with PA-III cells and administered, by gavage, thalidomide (50 mg/kg body wt per day) in corn oil. Control rats with PA-III cells were administered corn oil. Autopsy examinations on day 30 revealed that the thalidomide-treated rats developed more metastatic tumor foci in the lungs than in the controls.

Adenocarcinoma↗
PubMed1992

Determination of thalidomide in plasma and blood by high-performance liquid chromatography: avoiding hydrolytic degradation.

Thalidomide was determined in plasma and blood by reversed-phase high-performance liquid chromatography with ultraviolet detection. The coefficient of variation of the assay was 1-2% over the 0.25-4.0 micrograms/ml concentration range. Hydrolysis of thalidomide during storage and work-up of the samples was avoided by the addition of an equal volume of citrate buffer, pH 1.5. The assay could be applied to the determination of blood concentrations of thalidomide in rats for at least 28 h after a single oral dose, with multiple blood sampling from the same animal.

Animals↗
PubMed1989

Thalidomide for the therapy of graft-versus-host disease following allogeneic bone marrow transplantation.

The immunosuppressive effects of the sedative drug thalidomide have been utilised in a variety of immune disorders. In the present study, 6 patients were treated who developed graft-versus-host disease (GvHD) following allogeneic bone marrow transplantation (BMT) with thalidomide and in a dose range of 200-600 mg daily. Two of 3 patients with chronic GvHD showed clear improvement, whereas none of the 3 patients with acute GvHD derived unequivocal benefit. Although based on a small number of patients, these data suggest that thalidomide may find a useful place in the therapy of GvHD, perhaps specifically in the chronic form of this disorder.

Adolescent↗
PubMed2004

Thalidomide analogues demonstrate dual inhibition of both angiogenesis and prostate cancer.

The identification of agents with antiproliferative activity against endothelial cells has significant value for the treatment of many angiogenesis-dependent pathologies. Herein, we describe the discovery of a series of thalidomide analogues possessing inhibitory effects against both endothelial and prostate cancer cells. More specifically, several analogues exhibited low micromolar to mid-nanomolar potency in the inhibition of human microvascular endothelial cell (HMEC) proliferation, both in the presence and absence of vascular endothelial growth factor (VEGF), with the tetrafluorophthalimido class of compounds demonstrating the greatest potency. Additionally, all the compounds were screened against two different androgen independent prostate cancer cell lines (PC-3 and DU-145). Again, the tetrafluorophthalimido analogues exhibited the greatest effect with GI(50) values in the low micromolar range. Thalidomide was found to demonstrate selective inhibition of androgen receptor positive LNCaP prostate cancer cells. Furthermore, we showed that, as an example, tetrafluorophthalimido analogue 19 was able to completely inhibit the prostate specific antigen (PSA) secretion by the LNCaP cell line, while thalidomide demonstrated a 70% inhibition. We have also demonstrated that a correlation exists between HMEC and prostate cancer cell proliferation for this structural class. Altogether, our study suggests that these analogues may serve as promising leads for the development of agents that target both androgen dependent and independent prostate cancer and blood vessel growth.

Androgens↗
PubMed2005

Angiogenesis inhibitors derived from thalidomide.

5-Hydroxy-2-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione (5HPP-33: 10), which was obtained during our previous structural development studies on thalidomide, was revealed to possess potent anti-angiogenic activity in a human umbilical vein endothelial cell (HUVEC) assay. Thalidomide (1) and its metabolite, 5-hydroxythalidomide (5-HT: 2), which possesses a hydroxyl group at the position corresponding to that of 5HPP-33, as well as IMiDs (immunomodulatory derivatives of thalidomide: 3 and 5), also showed weak or moderate activity in the same assay.

Angiogenesis Inhibitors↗
PubMed2004

Apoptosis and nitric oxide release induced by thalidomide, gossypol and dexamethasone in cultured human chronic myelogenous leukemic K-562 cells.

The effects of different dosages of thalidomide, gossypol and dexamethasone on the levels of apoptosis and nitric oxide (NO) production were studied in a human chronic myelogenous leukemic cell line, K-562. Increases in the levels of apoptosis were induced by both 15 and 30 microM of thalidomide but only 15 microM significantly increased NO production. All dosages of gossypol used increased the production of NO and all dosages except 200 microM raised the level of apoptosis. After dexamethasone treatment the level of NO either decreased or stayed constant. Thus, some dosages of thalidomide and gossypol concomitantly raise the levels of apoptosis and NO production, but dexamethasone, though it induced apoptosis, had no significant effect on NO production.

Apoptosis↗
PubMedDate not supplied

Phase II trial of GM-CSF + thalidomide in patients with androgen-independent metastatic prostate cancer.

BACKGROUND: Androgen-independent metastatic prostate cancer is a major therapeutic dilemma. Granulocyte-macrophage colony stimulating factor (GM-CSF) and thalidomide have some biologic activity as single agents in this disease subset. We performed a Phase II trial of this combination to assess its toxicity and potential utility as an immunomodulatory approach to management of advanced prostate cancer. METHODS: Twenty-two patients were treated with GM-CSF 250 microg administered SC on Monday, Wednesday and Friday of each week. Thalidomide was escalated to reach the study dose of 200 mg/day. Patients were assessed every 4 weeks with therapy continuing to a maximum of 6 months. RESULTS: All 22 patients had a decrement in PSA at 2 weeks postinitiation of therapy. Five patients had a > or =50% decline (56, 64,66,66, and 94%, respectively) from baseline verified at 4 weeks post best response. This corresponds to an observed response rate of 23% (95% confidence interval 8-45%). Therapy was well tolerated with the majority of patients experiencing only one event. CONCLUSIONS: The combination of GM-CSF + thalidomide is relatively well tolerated and has the potential to produce antitumor activity in a population of patients with metastatic, androgen independent prostate cancer. This nonchemotherapy combination should be explored in a subset of patients with less advanced disease.

Aged↗
PubMed2005

[Search for new anti-angiogenic agents with structural analogy with thalidomide].

Despite its teratogenic effects, thalidomide has been reintroduced in human anticancer treatment for its anti-angiogenic activity, especially observed in patients with multiple myeloma. Here, we report the synthesis of new analogues designed to increase the thalidomide anti-tumour properties. The anti-angiogenic activity of the compounds was tested on EA.hy 926 endothelial cell lines. In this model, that is easier to manipulate than HUVEC cells, thalidomide is active in a similar dose range as reported on HUVEC cells and one of our compounds is more efficient.

Angiogenesis Inhibitors↗
PubMed2002

New concerns about thalidomide.

Recently, the Food and Drug Administration (FDA) approved thalidomide for the treatment of the painful symptoms of erythema nodosum leprosum. This most recent FDA decision is a marked reversal to its previous rejection of this drug in the 1960s. The initial rejection by the FDA in the 1960s spared countless American children as thalidomide was shown to cause birth defects and miscarriages worldwide. The FDA's reputation as one of the finest consumer safety authorities was strengthened because of this decision. The recent approval of thalidomide by the FDA, with accompanying strict guidelines and monitoring procedures, has not only brought forth potential benefits, but also created new potential problems.

Congenital Abnormalities↗
PubMed2000

Effect of thalidomide on gastrointestinal toxic effects of irinotecan.

Irinotecan is the only accepted second-line treatment for colorectal cancer in the USA. Doses are, however, frequently limited by associated late-onset diarrhoea. Thalidomide has antiangiogenic and immunomodulatory properties and is being investigated as an antineoplastic. We did a pilot study of combination therapy with thalidomide and irinotecan for metastatic colorectal cancer. In an interim analysis of nine patients, thalidomide had almost eliminated the dose-limiting gastrointestinal toxic effects of irinotecan, especially diarrhoea and nausea (each p<0.0001), and eight of nine patients were able to complete the chemotherapy course.

Antineoplastic Agents, Phytogenic↗
PubMed2006

Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial.

BACKGROUND: Since 1960, oral melphalan and prednisone (MP) has been regarded as the standard of care in elderly multiple myeloma patients. This multicentre randomised trial compared oral MP plus thalidomide (MPT) with MP alone in patients aged 60-85 years. METHODS: Patients with newly diagnosed multiple myeloma were randomly assigned to receive oral MP for six 4-week cycles plus thalidomide (n=129; 100 mg per day continuously until any sign of relapse or progressive disease) or MP alone (n=126). Analysis was intention-to-treat. This study is registered at , number NCT00232934. RESULTS: Patients treated with thalidomide had higher response rates and longer event-free survival (primary endpoints) than patients who were not. Combined complete or partial response rates were 76.0% for MPT and 47.6% for MP alone (absolute difference 28.3%, 95% CI 16.5-39.1), and the near-complete or complete response rates were 27.9% and 7.2%, respectively. 2-year event-free survival rates were 54% for MPT and 27% for MP (hazard ratio [HR] for MPT 0.51, 95% CI 0.35-0.75, p=0.0006). 3-year survival rates were 80% for MPT and 64% for MP (HR for MPT 0.68, 95% CI 0.38-1.22, p=0.19). Rates of grade 3 or 4 adverse events were 48% in MPT patients and 25% in MP patients (p=0.0002). Introduction of enoxaparin prophylaxis reduced rate of thromboembolism from 20% to 3% (p=0.005). CONCLUSION: Oral MPT is an effective first-line treatment for elderly patients with multiple myeloma. Anticoagulant prophylaxis reduces frequency of thrombosis. Longer follow-up is needed to assess effect on overall survival.

Aged↗
PubMed1984

Thalidomide in severe orogenital ulceration.

Thalidomide was given to 15 patients with severe orogenital ulceration (OGU). 4 patients underwent a double-blind controlled trial with glutethimide as placebo and 11 were treated openly. Treatment with thalidomide produced complete resolution of ulcers in 14 and significant improvement in the remaining patient. No peripheral neuropathies developed. Patients did not respond to glutethimide. Thalidomide is an effective treatment for severe OGU. Adequate contraceptive measures should be taken during treatment.

Adolescent↗
PubMed2003

An UK myeloma forum phase II study of thalidomide; long term follow-up and recommendations for treatment.

Myeloma remains incurable with conventional treatment in the vast majority of patients. The introduction of thalidomide in 1999 for the treatment of relapsed disease offers the opportunity to treat patients who have developed myelotoxicity or who are refractory to conventional chemotherapy. The optimal schedule remains unresolved and only two studies have reported long term follow-up data. We report a phase II low dose escalation study of thalidomide with long term follow-up showing overall survival (OS) of 19 months and progression free survival (PFS) of 14 months. In addition we report on the side effects and toxicity and give recommendations for the use of thalidomide in the relapsed setting based upon these findings.

Adult↗