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PubMed2006

Maintenance therapy with thalidomide improves overall survival after autologous hematopoietic progenitor cell transplantation for multiple myeloma.

BACKGROUND: High-dose chemotherapy with autologous hematopoietic progenitor cell (HPC) transplantation improves survival for patients with multiple myeloma (MM); however, most patients develop recurrent disease after undergoing transplantation, and new treatment approaches are needed. The objective of this retrospective review of autologous HPC transplantation for patients with MM was to evaluate the impact of conditioning regimens and posttransplantation therapy on survival. METHODS: The authors reviewed 112 patients with MM who received autologous HPC grafts at their institution. Between June 1992 and August 2001, 54 patients received busulfan, cyclophosphamide, and etoposide (Bu/Cy/VP-16), and 58 patients received high-dose melphalan (MEL-200) followed by autologous HPC transplantation. After transplantation, 36 patients received thalidomide for maintenance or salvage therapy, and 76 patients received no posttransplantation thalidomide. RESULTS: At a median follow-up of 58 months, the median survival was 54 months. There was no statistically significant difference noted with regard to response to conditioning regimen, progression-free survival, or overall survival between the Bu/Cy/VP-16 and MEL-200 cohorts. Patients who received thalidomide after transplantation had improved median survival (65.5 months) compared with patients who did not receive thalidomide (44.5 months; P = .09). When they were separated according to reasons for thalidomide use, patients who received thalidomide as maintenance had improved overall survival compared with patients who received thalidomide as salvage (65 months vs. 54 months; P = .05). CONCLUSIONS: Combination chemotherapy provided no advantage over high-dose melphalan in patients with MM who underwent autologous HPC transplantation. The posttransplantation use of thalidomide seemed to improve the survival of patients compared with historical controls from the prethalidomide era. Further prospective trials are underway to confirm the benefit of thalidomide in the posttransplantation setting.

Adult↗
PubMed2005

Thalidomide in combination with dexamethasone for pretreated patients with multiple myeloma: serum level of soluble interleukin-2 receptor as a predictive factor for response rate and for survival.

The aim of this study was to assess the side effects and the efficacy of thalidomide alone or in combination with dexamethasone in relapsed multiple myeloma (MM) and to evaluate possible predictive factors for response rate and survival. Twenty-nine pretreated patients were enrolled, including 13 patients with a relapse after high-dose chemotherapy. The median number of relapses was 3 (range: 1-7). Twenty-two patients received thalidomide in combination with dexamethasone and seven patients thalidomide alone. The dosage of thalidomide was 400 mg/day and the dosage of dexamethasone 20 mg/m2 daily for 4 consecutive days every 3 weeks. Cycles of dexamethasone were given until maximal decline of myeloma protein was achieved, whereas therapy with thalidomide was maintained until disease progression. Responses occurred in 62% of patients, including 5 (17%) complete remissions and 13 (45%) partial remissions. The median event-free survival (EFS) was 7.2 months and the median overall survival (OS) 26.1 months. In multivariate analysis, pretreatment serum levels of soluble interleukin-2 receptor (sIL-2R) were a significant prognostic factor for EFS, and those of beta2-microglobulin (beta2M) and sIL-2R for OS. Serum levels of sIL-2R significantly increased after 3 weeks of treatment in 89% of patients, possibly representing lymphocyte activation induced by thalidomide. Two patients died of septic complications within 3 months after starting treatment with thalidomide and dexamethasone and one patient of herpes encephalitis after 26 months of treatment with thalidomide alone. Also, one case of pneumonia and one case of deep venous thrombosis of the lower limb occurred. Other side effects were somnolence, peripheral neuropathy, and bradycardia occurring in 35, 55, 38 and 55% of patients, respectively. The combination of thalidomide and dexamethasone is an effective therapy in heavily pretreated myeloma patients with a high response rate and acceptable toxicities. A powerful predictive factor both for EFS and OS was the pretreatment serum level of sIL-2R.

Aged↗
PubMed2000

Modulation of the pharmacokinetics of the antitumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in mice by thalidomide.

BACKGROUND: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), an investigative drug currently in clinical trial, acts on tumour vasculature through the induction of cytokines. Coadministration of thalidomide, a modulator of cytokine production, potentiates the antitumour activity of DMXAA against the murine Colon 38 carcinoma in mice. We wished to determine whether alteration of the pharmacokinetics of DMXAA by thalidomide could provide an explanation for this potentiation. RESULTS: Coadministration of thalidomide to Colon 38 tumour-bearing mice significantly (P < 0.05) increased the elimination half-life (t1/2) of DMXAA in plasma (413 micromol/l), liver (132 micromol/l), and spleen (77 micromol/l), and significantly (P < 0.05) increased DMXAA concentrations in Colon 38 tumour tissue (0.25-4.5 h). L-Thalidomide had a greater effect on DMXAA elimination (P < 0.01) than did D-thalidomide or the racemate. Coadministration of thalidomide increased the area under the concentration-time curve (AUC) of DMXAA by 1.8-fold in plasma, liver and spleen, and by 3.0-fold in tumour. Bile from mice given thalidomide and DMXAA contained substantially lower amounts of the glucuronide metabolite of DMXAA (DMXAA-G) than did bile from mice given DMXAA alone. CONCLUSION: Glucuronidation is a major excretory pathway for DMXAA in the mouse. Thalidomide, probably as the L-form, decreases the rate of elimination of DMXAA from plasma, spleen, liver and tumour by altering the rate of glucuronidation. The reduction in the elimination of DMXAA by thalidomide may lead to a selective increase in exposure of tumour tissue to drug, providing a basis for its potentiation of antitumour activity.

Animals↗
PubMed2002

Thalidomide: an antineoplastic agent.

It has been more than three decades since the withdrawal of thalidomide from the marketplace. Thalidomide is attracting growing interest because of its reported immunomodulatory and anti-inflammatory properties. Current evidence indicates that thalidomide reduces the activity of the inflammatory cytokine tumor necrosis factor-alpha by accelerating the degradation of its messenger RNA. Thalidomide inhibits angiogenesis. Recently, thalidomide was approved for sale in the United States for the treatment of erythema nodosum leprosum, an inflammatory complication of Hansen's disease. Thalidomide has been used successfully in several other dermatologic disorders, including aphthous stomatitis, Behcet's syndrome, chronic cutaneous systemic lupus erythematosus, and graft-versus-host disease, the apparent shared characteristic of which is immune dysregulation. Many recent studies have evaluated thalidomide in patients with HIV infection, in which this drug is an efficacious agent against oral aphthous ulcers, HIV-associated wasting syndrome, HIV-related diarrhea, and Kaposi's sarcoma. Only in the last several years has thalidomide been aggressively investigated for its antiangiogenic potential and immunomodulatory properties in various tumor types. Current research on thalidomide in oncology covers investigation in a wide range of both solid tumors and hematologic malignancies.

Angiogenesis Inhibitors↗
PubMed2004

Thalidomide salvages lethal hepatic necroinflammation and accelerates recovery from cirrhosis in rats.

BACKGROUND/AIMS: The authors investigated the feasibility of thalidomide employed to treat liver fibrosis. METHODS: A cirrhotic model was established using Sprague-Dawley rats fed thioacetamide. Thalidomide-treated group was given thalidomide (10mg/kg/day) intraperitoneally for 10 consecutive days. Mortality, histopathological changes, TNFalpha, TGFbeta1, TIMP-1 and TIMP-2 were determined. Expression of TNFalpha and TGFbeta1 mRNA of Kupffer's cells derived from the experimental rats were determined. RESULTS: The mortality rates of thalidomide-treated group and vehicle-treated group were 8 and 32%, respectively. The total Knodell score of thalidomide-treated rats was lower than those of vehicle-treated rats. Micro-nodular cirrhosis resolved grossly in thalidomide-treated rats on day 28; while vehicle-treated rats continued to display uneven liver surface on day 28. Expression of TNFalpha, TGFbeta1, TIMP-1, and TIMP-2 was decreased in thalidomide-treated rats compared to those treated with vehicles. Finally, the expression of TNFalpha and TGFbeta1 mRNA of Kupffer's cells derived from rats treated with thalidomide were much lower than those treated with vehicle. CONCLUSIONS: Thalidomide salvages lethal hepatic necroinflammation, accelerates recovery from cirrhosis in rats, and works by suppressing of TNFalpha and TGFbeta1 production of Kupffer's cells.

Animals↗
PubMed2006

Thalidomide alters c-MYB and PIM-1 signaling in K-562 cells.

Despite causing birth defects thalidomide is being used therapeutically to treat a number of diseases. While thalidomide's mechanism of action still remains unknown, exposure to thalidomide leads to increased reactive oxygen species (ROS), which can interfere with cell signaling. We hypothesize that thalidomide acts by interfering with the c-Myb signaling pathway. To investigate this hypothesis, human K-562 cells were transfected with plasmids expressing a Myb-responsive luciferase reporter and c-Myb. Cells were then exposed to thalidomide (0 or 40 microg/ml) for 1h and luciferase activities were measured. Cells exposed to thalidomide (40 microg/ml) had significantly decreased c-Myb activity. Pre-incubation of cells with the anti-oxidative enzyme catalase (1600 units/ml), prevented thalidomide-induced decreased c-Myb activity, suggesting a role for ROS in the c-Myb signaling pathway. This result was further substantiated by the dichlorofluorescein assay. Western blot analysis on thalidomide exposed cells showed a decrease in both Pim-1 protein expression and phosphorylated c-Myb protein expression, suggesting that the decrease in Pim-1 and the amount of phosphorylated c-Myb protein may be responsible for the observed decreases in c-Myb activity. Together these results demonstrate that thalidomide affects c-Myb signaling, in part, through increased ROS production.

Fluoresceins↗
PubMed2000

Mechanism of action in thalidomide teratogenesis.

In this commentary, we describe a model to explain the mechanism of the embryopathy of thalidomide. We propose that thalidomide affects the following pathway during development: insulin-like growth factor I (IGF-I) and fibroblast growth factor 2 (FGF-2) stimulation of the transcription of alphav and beta3 integrin subunit genes. The resulting alphavbeta3 integrin dimer stimulates angiogenesis in the developing limb bud, which promotes outgrowth of the bud. The promoters of the IGF-I and FGF-2 genes, the genes for their binding proteins and receptors, as well as the alphav and beta3 genes, lack typical TATA boxes, but instead contain multiple GC boxes (GGGCGG). Thalidomide, or a breakdown product of thalidomide, specifically binds to these GC promoter sites, decreasing transcription efficiency of the associated genes. A cumulative decrease interferes with normal angiogenesis, which results in truncation of the limb. Intercalation into G-rich promoter regions of DNA may explain why certain thalidomide analogs are not teratogenic while retaining their anti-tumor necrosis factor-alpha (TNF-alpha) activity, and suggests that we look elsewhere to explain the action of thalidomide on TNF-alpha. On the other hand, the anti-cancer action of thalidomide may be based on its antiangiogenic action, resulting from specific DNA intercalation. The tissue specificity of thalidomide and its effect against only certain neoplasias may be explained by the fact that various developing tissues and neoplasias depend on different angiogenesis or vasculogenesis pathways, only some of which are thalidomide-sensitive.

Animals↗
PubMed2005

[Thalidomide in the treatment of chronic discoid lupus erythematosus].

INTRODUCTION: Thalidomide is the second line treatment of chronic lupus erythematosus. The efficacy of this treatment, the minimal effective doses and tolerance are poorly documented in the literature. PATIENTS AND METHODS: We present the data of a single-center retrospective studied among 18 patients with chronic lupus erythematosus, treated with thalidomide from 1998 to 2003. Inclusion criteria were: the presence of clinical lesions evoking the disease, confirmed by histological examination and direct immunofluorescence and treatment with thalidomide for more than 2 months. RESULTS: Mean age on diagnosis was of 35.8 years. Thalidomide had been initiated a mean of 10.6 years after diagnosis of chronic lupus erythematosus. In 13 out of 18 patients, thalidomide had been prescribed because of failure with prior treatments. Fifteen patients were improved by thalidomide (83.3 p. 100), with 11 (61 p. 100) complete and 4 (22 p. 100) partial remissions. Two (11 p. 100) patients were stabilized and treatment failed in one. The mean initial dose was of 100 mg/d (50-150), and maintenance dose was of around 50 mg/d (56 mg/d). The mean follow-up with thalidomide was of 19.4 months. Only one withdrawal due to side effects was reported. The most frequent side effects were: asthenia (33 p. 100), paresthesia (22 p. 100) and weight gain (16.6 p. 100). No side effects were reported in 10 out of 18 patients. DISCUSSION: This study confirms the efficacy of low dose thalidomide in the treatment of chronic lupus erythematosus. In our experience, tolerance to this treatment is good, the most frequent side effect was asthenia, but usually mild. No significant peripheral neuropathy was noted. The fear of side effects, notably neurological, should not delay initiation of thalidomide in the case of failure with current treatments.

Adolescent↗
PubMedDate not supplied

Neurobehavioral teratogenic effects of thalidomide in rats.

Thalidomide-induced embryopathy has been known for four decades, however, the drug has been reintroduced for human use in a number of countries, including the United States. In utero thalidomide exposure in humans is associated with central nervous system (CNS) effects in addition to the well-known limb, ear and other malformations. Despite knowledge of these CNS effects, not a single experimental study could be found that examined thalidomide for possible developmental neurobehavioral effects. In the present experiment, gravid Sprague-Dawley rats were treated with either thalidomide (100 mg/kg by gavage) or vehicle (propylene glycol) on embryonic days E7-18 and allowed to deliver and raise their own offspring. The offspring were evaluated in a series of neurobehavioral tests (reflexes, locomotor activity, startle reactivity and learning in the Morris and Cincinnati water mazes). There was a small reduction in maternal weight among thalidomide-treated dams during midgestation. Thalidomide offspring showed increased preweaning mortality and male-specific, late onset reduction in growth that persisted until the end of the study. Male thalidomide offspring showed significant increases in errors and latency in the multiple-T Cincinnati water maze. Although rats are refractory to thalidomide-induced teratogenesis, the present results suggest that thalidomide selectively impairs offspring survival and growth and at least one type of learning among male offspring.

Animals↗
PubMed1996

Moderate additive immunosuppressive effect of thalidomide combined with cyclosporin A in rat cardiac transplantation.

Thalidomide is an immunomodulating agent shown to prolong graft survival in experimental skin, renal, cardiac and bone marrow transplantation. The main purpose of the present study was to investigate the possible additive effect of combining thalidomide with cyclosporin A (CyA). Members of our group have previously created a basis for such studies by demonstrating the ability of Linomide to abolish the effect of CyA. The additional effect of combined treatment with a second drug is thereby more readily evaluated, compared with using subtherapeutic dose levels to induce early rejection. Cardiac grafting was performed in three rat strain combinations (BN to WF, DA to Lew, and BN to Lew). Rats were given no treatment, or thalidomide, CyA and/or Linomide in single, double or triple drug therapy. Except for a consistent beneficial effect of CyA as single drug treatment, graft survival varied depending on the rat strain combination used. In the DA to Lew combination, the expected effects of Linomide were seen, and thalidomide was shown to prolong graft survival significantly (P = 0.004) when added to CyA and Linomide. However, there was no effect of thalidomide when given alone. In WF recipients of BN hearts, thalidomide tended to prolong graft survival (P = 0.07), and surprisingly Linomide manifested a marked immunosuppressive effect (P = 0.0002) and did not counteract the effect of CyA. When transplanting BN grafts to Lew recipients, Linomide reduced significantly but did not abolish completely the effect of CyA. Neither Linomide nor thalidomide had any beneficial impact on graft survival on their own. To sum up, thalidomide was shown to have a minimal or moderate immunosuppressive effect additive to that of CyA. The effects of the two immunomodulating drugs, thalidomide and Linomide, varied depending on the rat strain combination used, and were similar with respect to prolongation of graft survival when used as single drug treatment in BN to WF grafting, a fact which may indicate them to have a similar mechanism of action, both having been shown to exert similar effects on levels of tumour necrosis factor alpha.

Adjuvants, Immunologic↗
PubMed1999

Pharmacokinetics of thalidomide in an elderly prostate cancer population.

Thalidomide, a glutamic acid derivative, has recently been shown to inhibit in vitro angiogenesis, the process of formation of new blood vessels. This Phase II study examined the pharmacokinetics of thalidomide in patients with clinically progressive hormone-refractory prostate cancer. Patients (aged 55 to 80 years) were randomized to two different arms, low dose versus high dose. Patients in the low-dose group were given 200 mg of thalidomide and patients in the high-dose group received 200 mg of thalidomide, with subsequent dose escalations to 1200 mg. Serial serum or blood samples were obtained for pharmacokinetic assessment after administration of a single oral dose or multiple daily dosing of thalidomide and were assayed by reversed-phase HPLC. Pharmacokinetic parameters for both the single and multiple dosing were calculated with ADAPT II. A one-compartment model best fit the data. After single dosing, the oral clearance and apparent volume of distribution for the low-dose regimen (n = 13) were 7.41 +/- 2.05 L/h and 66.93 +/- 34.27 L, respectively, whereas for the high-dose regimen (n = 11), these values were 7.21 +/- 2.89 L/h and 165.81 +/- 84.18 L, respectively. The elimination half-lives for the low and high dose were 6.52 +/- 3.81 and 18.25 +/- 14.08 h, respectively. After the multiple dosing of thalidomide, the oral clearance and apparent volume of distribution for the low-dose group (n = 10) were 6.35 +/- 1.64 L/h and 64.63 +/- 23.20 L, respectively, whereas for the high-dose group (n = 11), these values were 7.73 +/- 2.27 L/h and 167.85 +/- 82.08 L, respectively. The elimination half-lives for the low and high dose were 7.08 +/- 1.87 and 16.19 +/- 9.57 h, respectively. For both the single and multiple dosing of thalidomide, the apparent volume of distribution and half-life were significantly higher for the high-dose group than those for the low-dose group. The higher apparent volume of distribution may be attributable to several factors, such as change in absorption, protein binding, etc. A dose-proportional increase in thalidomide steady-state concentrations was seen after multiple daily dosing of thalidomide.

Aged↗
PubMedDate not supplied

Combined thalidomide and temozolomide treatment in patients with glioblastoma multiforme.

OBJECTIVES: Glioblastoma multiforme (GBM) may potentially be responsive to antiangiogenic therapies as these tumors are highly vascularized and overexpress angiogenic factors. Thalidomide exhibits antiangiogenic activity and may provide additive or synergistic antitumor effects when given concurrently with temozolomide, an alkylating agent. To further evaluate this new concept of combining an antiangiogenic with an alkylating agent, efficacy and tolerability of thalidomide alone and in combination with temozolomide were explored in a single-institution, nonrandomized open-label phase II study. PATIENTS AND METHODS: Forty-four patients with GBMs, who received thalidomide for a period of at least three months, were evaluated for survival, time to tumor progression (TTP), and side effects. Microsurgical tumor extirpation and radiotherapy preceded chemotherapy. Nineteen patients (43%) received thalidomide only (T), and 25 patients (57%) had a combined chemotherapy of thalidomide and temozolomide (TT). Median thalidomide dosage was 200 mg/day. Median temozolomide dosage was 200 mg/m2/day for five days, in monthly cycles. Neuroradiological outcomes were assessed by a semiquantitative grading system. RESULTS: Median survival was 103 weeks (95% CI, 65-141 weeks) for TT-patients and 63 weeks (95% CI, 49-77 weeks) for T-patients (p < 0.01). Median TTP for the TT-group was 36 weeks (95% CI, 20-52 weeks) and 17 weeks (95% CI, 13-21 weeks) for the T-group (p < 0.06). Neuroradiologically, 14 patients (56%) of the TT-group and six (32%) of the T-group had evidence of stable disease on at least two successive neuroradiological follow-ups. Progressive disease was found in nine patients (36%) of the TT-group and in 13 (68%) of the T-group. In two patients (8%) of the TT-group, a response with tumor regression was found. Thalidomide and concurrent temozolomide were safe and well tolerated with mild to moderate toxicities. CONCLUSIONS: The combination of thalidomide and temozolomide in the treatment of GBM appears to be more effective than that of thalidomide alone with respect to survival, TTP, and neuroradiological documentation of progression, stable disease or response. Further concurrent prospective studies of these agents in a larger group of patients with GBM will be required to establish the soundness of these intriguing observations.

Adult↗
PubMed1999

Thalidomide analogue CC1069 inhibits development of rat adjuvant arthritis.

The cytokine tumour necrosis factor-alpha (TNF-alpha) has been implicated in the aetiology of rheumatoid arthritis in humans as well as of experimental arthritis in rodents. Thalidomide, and to a greater extent the new thalidomide analogue CC1069, inhibit monocyte TNF-alpha production both in vitro and in vivo. The aim of the present study is to establish whether these drugs block production of TNF-alpha as well as IL-2 by rat leucocytes and whether this inhibition affects the development of rat adjuvant arthritis (AA). Cultured splenocytes were stimulated with either lipopolysaccharide (LPS) or concanavalin A (Con A) in the presence of thalidomide, CC1069, or solvent, and the production of TNF-alpha and IL-2 were compared. Next, adjuvant was injected into the base of the tail of rats without or with daily intraperitoneal injections with 100-200 mg/kg per day thalidomide or 50-200 mg/kg per day CC1069. Disease activity, including ankle swelling, hind limb radiographic and histological changes, weight gain, and ankle joint cytokine mRNA levels, were monitored. CC1069, but not the parent drug thalidomide, inhibited in vitro production of TNF-alpha and IL-2 by stimulated splenocytes in a dose-dependent manner. In vivo, a dose-dependent suppression of AA disease activity occurred in the CC1069-treated animals. In contrast, thalidomide-treated rats experienced comparable arthritis severity to placebo-treated animals. There was also a reduction in TNF-alpha and IL-2 mRNA levels in the ankle joints of CC1069-treated rats compared with thalidomide- and placebo-treated arthritic rats. Early initiation of CC1069 treatment suppressed AA inflammation more efficiently than delayed treatment. We conclude that thalidomide, which did not suppress TNF-alpha or IL-2 production in vitro by Lewis rat cells, did not suppress development of rat AA. However, the development of rat AA can be blocked by the thalidomide analogue CC1069, which is an efficient inhibitor of TNF-alpha production and IL-2 in vitro.

Animals↗
PubMed2000

Clinical and immunologic parameters during thalidomide treatment of lupus erythematosus.

BACKGROUND: Thalidomide is used as an experimental drug for the treatment of chronic inflammatory diseases with an autoimmune or infectious background. The pharmacologic action involves the downregulation of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and inhibition of basic fibroblast growth factor (bFGF)-induced angiogenesis; however, not much is known about thalidomide's effect on immunologic parameters in lupus erythematosus (LE). Method This is an open study of a group of five consecutive systemic lupus erythematosus (SLE) patients treated with thalidomide (100 mg/day) and five consecutive cutaneous LE patients not responsive to conventional therapy. The clinical and immunologic parameters (C-reactive protein, immunoglobulin, and complement serum levels, lymphocyte counts) were investigated during thalidomide treatment for up to 2 years in both patient groups. RESULTS: An increase in the absolute peripheral lymphocyte count was observed beginning after 2 weeks of systemic thalidomide treatment in nine out of 10 LE patients, and remained stable throughout thalidomide treatment. Elevated serum levels of C-reactive protein and titers of autoantibodies to double-stranded (ds) DNA decreased in SLE patients. No significant changes were detected in the serum levels of the complement components C3 and C4 and immunoglobulins in all LE patients. Regression of inflammatory skin lesions and regrowth of hair were recorded. As a side-effect, polyneuropathy was observed in four out of 10 patients, with the earliest onset at 3 weeks of thalidomide treatment. CONCLUSIONS: Thalidomide is a potent anti-inflammatory drug in patients with SLE and cutaneous LE, possibly interacting with the recruitment of lymphocytes. It leads to the regrowth of hair in LE-related alopecia and effluvium. Early symptoms of polyneuropathy should be registered and the drug should be withdrawn. Thalidomide should be restricted to patients who show no response to standard therapeutic regimens and should only be used under strict precautions with regard to its known teratogenic risk.

Adult↗
PubMed2002

Renal cell carcinoma may adapt to and overcome anti-angiogenic intervention with thalidomide.

OBJECTIVE: To report on the failure of thalidomide to inhibit tumour growth in an animal model of human renal cell carcinoma (RCC). MATERIALS AND METHODS: An orthotopic xenograft model of human RCC was used in which tumour cells were implanted in the left kidney of male 'severe combined immunodeficient' mice. Thalidomide was administered by intraperitoneal injection and after 34 days the mice were killed. The extent of tumour growth was compared in treated and untreated mice. Total RNA was extracted from both tumour-affected and contralateral kidneys, and analysed by reverse transcription-polymerase chain reaction for various genes implicated in angiogenesis and metastasis in RCC. RESULTS: Thalidomide failed to inhibit the growth of xenograft tumours. The expression of angiogenic genes, e.g. vascular endothelial growth factor and fibroblast growth factor type 2 (FGF-2) within normal and tumour-affected kidney tissue was not reduced by thalidomide. Intratumoral transcription of beta3-integrin, a critical component of angiogenesis, was significantly increased in response to thalidomide treatment (P < 0.01). There was also a trend to increased expression of FGF-2 and tumour necrosis factor-alpha in thalidomide-treated tumours. CONCLUSIONS: These findings suggest that RCC is capable of adapting to the inhibitory effects of thalidomide. The current uncertainty surrounding the action of thalidomide in vivo warrants caution about its use in humans. Further studies of thalidomide should be carried out in animal models, particularly to establish its safety and effectiveness as part of a combined therapeutic strategy.

Angiogenesis Inhibitors↗
PubMed2003

Thalidomide inhibits tumor necrosis factor-alpha production and antigen presentation by Langerhans cells.

Thalidomide is an effective treatment for several inflammatory and autoimmune disorders including erythema nodosum leprosum, Behcet's syndrome, discoid lupus erythematosus, and Crohn's disease. Thalidomide is believed to exert its anti-inflammatory effects, at least in part, by inhibiting tumor necrosis factor-alpha (TNF-alpha) production by monocytes. We studied the effects of thalidomide on epidermal Langerhans cells (LC). LCs are epidermal antigen-presenting dendritic cells that play important roles in skin immune responses. Using the murine epidermis-derived dendritic cell lines, XS106A from A/J mice and XS52 from BALB/c mice as surrogates for LC, we found that thalidomide inhibited TNF-alpha production in a concentration-dependent manner. Northern blot analysis revealed that thalidomide significantly decreased the peak-induced mRNA level of TNF-alpha in XS106A cells and XS52 cells. We then examined the effect of thalidomide on fresh LC enriched to approximately 98% using positive selection of Ia+ cells with antibodies conjugated to magnetic microspheres. TNF-alpha production was reduced by 67.7% at a thalidomide concentration of 200 microg per mL. Thalidomide also had a profound inhibitory effect on the ability of LC to present antigen to a responsive TH1 clone. Thalidomide inhibits TNF-alpha production and the antigen-presenting ability of epidermal LCs. These mechanisms may contribute to the therapeutic effects observed with this agent.

Animals↗
PubMed2002

Thalidomide prevents alcoholic liver injury in rats through suppression of Kupffer cell sensitization and TNF-alpha production.

BACKGROUND & AIMS: Sensitization of Kupffer cells (KCs) to lipopolysaccharide (LPS) and overproduction of tumor necrosis factor (TNF) alpha are critical for progression of alcoholic liver injury. Thalidomide has been shown to suppress TNF-alpha production from macrophages. Accordingly, the purpose of this study was to determine whether thalidomide could prevent alcohol-induced liver injury. METHODS: Rats were given ethanol (5 g/kg body wt) and thalidomide (5 mg/kg) once every 24 hours intragastrically. To assess the sensitization of Kupffer cells, LPS (5 mg/kg intravenously) was administered and liver histology was evaluated 24 hours later. KCs were isolated after 4 weeks of ethanol treatment and intracellular Ca2+ ([Ca2+]i) was measured using fura-2, whereas TNF-alpha was evaluated by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay. CD14 was determined by Western and fluorescence staining. RESULTS: Treatment with ethanol for 8 weeks caused marked steatosis, necrosis, and inflammation in the liver. These pathologic parameters were diminished markedly by treatment with thalidomide. In the 4-week ethanol group, the LPS-induced liver damage was aggravated and KCs were sensitized to LPS. Coadministration of thalidomide with ethanol prevented the KC sensitization completely. Furthermore, thalidomide abolished the LPS-induced increase in CD14 expression and [Ca2+]i elevation in KCs. Gut permeability was increased about 10-fold after 4 weeks of ethanol exposure, which was not affected by thalidomide. Moreover, thalidomide reduced the LPS-induced TNF-alpha production by KCs by decreasing TNF-alpha messenger RNA. CONCLUSIONS: These results collectively indicate that thalidomide prevents alcoholic liver injury through suppression of TNF-alpha production and abolishment of KC sensitization.

Animals↗
PubMed2003

Thalidomide and CC-5013 in multiple myeloma: the University of Arkansas experience.

Based on the activity of single-agent thalidomide in relapsed/refractory multiple myeloma in a landmark phase II study of 169 patients conducted at the University of Arkansas for Medical Sciences (UAMS), UAMS initiated several trials of thalidomide and the more potent thalidomide analog CC-5013. In an ongoing trial evaluating thalidomide plus the proteasome inhibitor bortezomib and dexamethasone in patients with relapsed/refractory disease following stem cell transplantation, approximately 50% of patients have experienced a paraprotein reduction of 50% or greater. In patients without cytogenetic abnormalities, the estimated 12-month event-free and overall survival rates are 69% and 100%, respectively. In a second ongoing trial building on the UAMS Total Therapy I regimen, newly diagnosed patients are randomized to thalidomide or no thalidomide pretransplantation followed by consolidation therapy with dexamethasone and multiagent chemotherapy post-transplantation (Total Therapy II). Although the Total Therapy II regimen appears to be superior to the original Total Therapy I regimen, assessment of the effect of thalidomide on Total Therapy II is pending accrual completion. Lastly, based on the increased potency and reduced toxicity profile of CC-5013 compared with thalidomide, a study of CC-5013 in patients with relapsed/refractory disease following transplantation was initiated. Patients are randomized to CC-5013 25 mg daily for 20 days versus CC-5013 50 mg every other day for 10 days. Preliminary results indicate the superiority of the 25-mg arm, with 40% of patients randomized to that arm experiencing a paraprotein reduction of 50% or greater. These preliminary results corroborate the role for thalidomide and CC-5013 in relapsed/refractory and newly diagnosed multiple myeloma based on the UAMS phase II study as well as several other studies of these agents outside of UAMS.

Adjuvants, Immunologic↗