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PubMed2000

A possible role of N-cadherin in thalidomide teratogenicity.

Several experimental findings indicate that the adhesion molecule N-cadherin participates in distinct processes of embryogenesis that spatiotemporarily correlate with high sensitivity to thalidomide. Therefore, we suppose that thalidomide might interfere with N-cadherin-mediated interactions. This hypothesis is supported by protein-ligand docking studies simulating and characterizing the binding of thalidomide to N-cadherin molecules. Thalidomide was found to bind at the N-terminal domain of N-cadherin mimicking a tryptophan residue which is critical for the homodimerization of the adhesion molecule. Based on these results, we suggest that thalidomide might disturb cellular recognition and migration processes in morphogenesis by interaction with N-cadherin.

Abnormalities, Drug-Induced↗
PubMed1999

Thalidomide and metabolites: indications of the absence of 'genotoxic' carcinogenic potentials.

Because of the reintroduction into human therapeutics of thalidomide, a recognized developmental toxicant in humans, there has been concern about its potential for inducing other health effects as well. The present study is concerned with the possible mutagenicity and carcinogenicity of this chemical. Using the expert system, META, a series of putative metabolites of thalidomide was generated. In addition to the known or hypothesized metabolites of thalidomide (N=12), a number of additional putative metabolites (N=131) were identified by META. The structures of these chemicals were subjected to structure-activity analyses using predictive CASE/MULTICASE models of developmental toxicity, rodent carcinogenicity and mutagenicity in Salmonella. While thalidomide and some of its putative metabolites were predicted to be developmental toxicants, none of them were predicted to be rodent carcinogens. Putative metabolites containing the hydroxamic acid or hydroxylamine moieties were predicted to be mutagens. None of the 'known' metabolites of thalidomide contained these reactive moieties. Whether such intermediates are indeed generated or whether they are generated and are either unstable in the presence of oxygen or react rapidly with nucleophiles is unknown.

Algorithms↗
PubMed2001

Thalidomide in the management of multiple myeloma.

A phase II trial of thalidomide in refractory multiple myeloma was initiated using a dose schedule that escalated from 200 mg/d to 800 mg/d. More than two thirds of patients had cytogenetic abnormalities and more than half had received at least two cycles of high-dose therapy. A paraprotein reduction of at least 25% was noted in 37% of patients and 14% had either a complete remission (CR) or a near CR. No treatment-related mortality was observed. With a median follow-up of almost 2 years, the 2-year event-free survival (EFS) and overall survival (OS) estimates were 15% and 60%, respectively. A reduction of paraprotein levels by greater than 50% was associated with a significant reduction in bone marrow plasmacytosis and beta(2)-microglobulin levels (beta2M), and greater recovery of hemoglobin and IgM levels compared to patients whose paraprotein was reduced by a lesser degree. Responses occurred more frequently among patients with a lower plasma cell labeling index (PCLI) and normal cytogenetics. Comparing response and survival by thalidomide dose for low- and high-risk groups revealed a thalidomide dose-response effect in the high-risk group of patients. The virtual absence of myelosuppressive toxicity, except in heavily pretreated patients with compromised bone marrow function, suggests that thalidomide is an ideal agent to be used in combination with cytotoxic agents and dexamethasone. Several trials are currently underway at the Arkansas Myeloma and Transplantation Research Center to determine the clinical benefit of adding thalidomide to post-transplant salvage therapy and in the upfront management of patients.

Angiogenesis Inhibitors↗
PubMed2001

Thalidomide: a novel template for anticancer drugs.

Thalidomide is an immunomodulatory agent that is approved for use in patients with cutaneous manifestations of erythema nodosum leprosum (ENL). It is currently under clinical investigation in a wide range of malignancies and immunologic-based disorders. Structural analogs of thalidomide have been synthesized in order to explore potential molecular targets of thalidomide, as well as to identify new therapeutics. Members of one class of analogs, termed immunomodulatory drugs (IMiD), are 100 to 1,000 times more potent than thalidomide in regulating cytokine production by peripheral blood mononuclear cells and providing a costimulatory signal for T-cell proliferation. Notably, the nature of the stimulus and the cell type are important determinants as to whether the IMiDs or thalidomide cause an inhibitory or stimulatory effect. The IMiD CDC-501 has been selected for clinical development; it had been safely administered to volunteers in single doses of 50 to 400 mg and in multiple doses of 100 mg for 7 days. Phase I/II studies of CDC-501 in multiple myeloma are in progress.

Adjuvants, Immunologic↗
PubMed2001

A randomized phase II trial of docetaxel (taxotere) plus thalidomide in androgen-independent prostate cancer.

New therapeutic alternatives are needed to improve outcomes in patients with androgen-independent prostate cancer (AIPC). For several years, researchers at the National Cancer Institute have been interested in elucidating the importance of angiogenesis in the pathogenesis of prostate cancer and in identifying inhibitors of this process. Thalidomide has been shown to inhibit the ability of tumors to recruit new blood vessels. In a recent phase II trial of thalidomide in AIPC, 28% of patients achieved a prostate-specific antigen (PSA) decrease of >40%. The taxane docetaxel also produces PSA and measurable disease responses when used as monotherapy or as a component of combination chemotherapy for AIPC. Thus, based on the single-agent activity of thalidomide and docetaxel, we initiated a randomized phase II study of weekly docetaxel with or without thalidomide, 200 mg at bedtime, in patients with chemotherapy-naive metastatic AIPC. Docetaxel, 30 mg/m(2) intravenously, was administered every 7 days for 3 weeks, followed by a 1-week rest period. Both regimens have been well tolerated among the first 59 treated patients, with a near absence of grade (3/4) myelosuppression. Fatigue, hyperglycemia, and pulmonary toxicity were seen in both groups. Thrombotic events have been seen in the combination arm. Thirty-five percent (6 of 17) of the patients receiving docetaxel alone and 53% (19 of 36) of those receiving docetaxel and thalidomide have had a PSA decrease of at least 50%. Combining a cytotoxic agent with an angiogenesis inhibitor is a promising area of investigation for prostate cancer management.

Adenocarcinoma↗
PubMed1999

S.T.E.P.S.: a comprehensive program for controlling and monitoring access to thalidomide.

In July 1998, the US Food and Drug Administration approved the marketing of thalidomide for the treatment of cutaneous manifestations of erythema nodosum leprosum. To ensure that fetal exposure to this teratogenic agent does not occur, the manufacturer has instituted a comprehensive program to control prescribing, dispensing, and use of the drug. This program, known as the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S. [Celgene Corporation, Warren, New Jersey]), is based in part on experience gained with other drugs--specifically isotretinoin and clozapine--that offer important clinical benefits but carry the potential for serious harm. To achieve its goal of the lowest possible incidence of drug-associated teratogenicity, the S.T.E.P.S. program uses a three-pronged approach: (1) controlling access to the drug; (2) educating prescribers, pharmacists, and patients; and (3) monitoring compliance. Clinicians who wish to prescribe thalidomide must be registered in the S.T.E.P.S. Prescriber Registry and agree to prescribe the drug in accordance with S.T.E.P.S. patient eligibility criteria and monitoring procedures. Pharmacies must also register and agree to comply with patient identification and monitoring criteria. Finally, patients receive visual aids, including a videotape, written material, and verbal counseling about the benefits and risks of thalidomide therapy, the importance of not becoming pregnant during therapy, and the types of contraception required (including emergency contraception) and their availability. Women of childbearing potential must agree to undergo pregnancy testing before starting therapy and on a regular schedule during therapy. All patients must agree to complete a confidential survey about their compliance with contraception, testing, and drug therapy. The manufacturer is monitoring survey results and outcome data and is prepared to make whatever modifications to the S.T.E.P.S. program are necessary to ensure its effectiveness. In addition to minimizing the potential risk for fetal harm associated with thalidomide therapy, the S.T.E.P.S. program may provide a model for future cases in which a drug offers compelling benefits but poses profound risks unless its distribution is carefully controlled.

Dermatologic Agents↗
PubMed1997

Thalidomide reduces MPTP-induced decrease in striatal dopamine levels in mice.

The effects of thalidomide, a sedative, anti-inflammatory and immunosuppressive agent were studied in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) murine model of Parkinson's disease. The striatal levels of dopamine (DA) and of its main metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured both in the MPTP control group (3 x 15 mg/kg intraperitoneally) and in the thalidomide groups (repeated treatments at 25 mg/kg or 50 mg/kg postoperatively). For mice treated with thalidomide, a dose-dependent protection was observed against the MPTP-induced decrease in DA. The decrease in HVA levels was totally antagonized by thalidomide at both doses. That thalidomide has activity in this model suggests that an inflammatory process may be involved in the induction of lesions by MPTP in DAergic neurons.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1997

Thalidomide may impede cell migration in primates by down-regulating integrin beta-chains: potential therapeutic utility in solid malignancies, proliferative retinopathy, inflammatory disorders, neointimal hyperplasia, and osteoporosis.

A growing number of human inflammatory disorders are reported to respond to treatment with thalidomide, and recently this drug has been shown to inhibit angiogenesis in the rabbit, in doses which can elicit teratogenicity in this species. Studies in marmosets and humans indicate that thalidomide, and a teratogenic analogue, decrease the expression of beta integrin subunits, most notably beta 3 and the beta 2 produced by leukocytes. Since integrins are crucial for cell-matrix interactions, and the beta 2 integrins of leukocytes mediate adhesion to endothelium, it is reasonable to postulate that thalidomide inhibits cell migration in susceptible species, and that this accounts for its anti-inflammatory, anti-angiogenic, and teratogenic activity. This perspective suggests that thalidomide will show utility in the prevention or treatment of a wide range of disorders, including solid tumors, proliferative retinopathies, many inflammatory diseases, neointimal hyperplasia, and osteoporosis. It is likely that dietary fish oil-as well as selective inhibitors of urokinase, when and if they become clinically available-will complement the efficacy of thalidomide in most if not all of these applications.

Animals↗
PubMed2002

Stereointegrity of thalidomide: gas-chromatographic determination of the enantiomerization barrier.

Enantioselective chromatographic methods, representing the most commonly used techniques for the determination of enantiomeric ratios, can also be used for the evaluation of stereochemical integrity. In the present study, two chromatographic methods, dynamic gas chromatography (DGC) and stopped-flow gas chromatography (SFGC) were used to determine the enantiomerization barrier of thalidomide. In the presence of a chiral stationary phase (CSP), the enantiomers of thalidomide produced characteristic elution profiles exhibiting plateaus and/or peak broadening which were observed between 190 and 220 degrees C in DGC. To obtain the enantiomerization barrier of thalidomide from experimental data, the fast and efficient simulation program ChromWin was used to simulate the elution profiles and obtain kinetic activation parameters. From temperature-dependent measurements the rate constants k(1) and k(-1) and the kinetic activation parameters DeltaG#, DeltaH# and DeltaS# of the enantiomerization of thalidomide were obtained by DGC. The enantiomerization barrier DeltaG# was determined to be 154+/-2 kJ/mol with DGC and 150+/-3 kJ/mol with the sfGC technique at 200 degrees C, respectively. The concept of the retention increment R' has been applied to separate the enantiomerization barrier of thalidomide in the dissolved and complexed state of the CSP.

Chromatography, Gas↗
PubMed2001

Synthesis and immunological activity of water-soluble thalidomide prodrugs.

A series of new water-soluble thalidomide prodrugs was prepared. All compounds were derivatized on the nitrogen of the glutarimide ring. Esters of natural amino acids and succinic acid derivatives have been introduced by reaction with the hydroxymethyl thalidomide 2. Nicotinic acid derivatives were prepared from halomethyl derivatives. Additionally, a methoxymethyl derivative and a carboxymethyl derivative were prepared directly from thalidomide. Most compounds showed a very large increase in water solubility compared to thalidomide itself (0.012mg/mL). The amorphous hydrochlorides of the N-methylalanine ester 8, valine ester 9, and glycylglycine ester 10, respectively, were the most soluble compounds showing solubility greater than 300mg/mL, which equals an increase greater than 15,000-fold. The lipophilicity of the prodrugs has been determined by their HPLC capacity factors k'. The stability of selected compounds was determined. The hydrolysis rates follow pseudo-first order kinetics. In order to assess the immunological activity, the prodrugs were tested using tumor necrosis factor-alpha and interleukin-2 inhibition assays. Selected compounds were additionally investigated on their abililty to inhibit the local Shwartzman reaction, an assay to determine the vascular permeability. The prodrugs retained high effectiveness in the inhibition of TNF-alpha release. Our results indicated that the more stable prodrugs exhibited higher activity in the immunological assays. Some compounds showed higher activity than thalidomide itself, suggesting a high affine binding to the pharmacophore. In conclusion, the prodrugs exhibited high water solubility and high activity and might therefore be used in therapeutic applications.

Animals↗
PubMed2002

Effect of thalidomide on the skeletal muscle in experimental heart failure.

BACKGROUND: Tumour Necrosis Factor alpha (TNFalpha) has been shown to contribute to heart failure (CHF) progression. AIMS: We have tried to antagonise the detrimental effects of TNFalpha on skeletal muscle apoptosis, by using thalidomide, a drug that inhibits its biosynthesis. METHODS: CHF was induced in 20 rats by injecting monocrotaline, which determines right ventricle (RV) failure. After 2 weeks, when CHF developed, 12 rats were treated with thalidomide 3.5.mg/kg per day for 2 weeks. Eight had saline and served as CHF controls. RESULTS: Thalidomide failed to decrease TNFalpha and its second messenger sphingosine (SPH), but was able to prevent the shift toward the fast myosin heavy chains. In the Tibialis Anterior muscle of the thalidomide group, the degree of atrophy, the number of apoptotic nuclei and the levels of caspases, were similar to those of the CHF controls. CONCLUSIONS: Thalidomide, at the doses used in this study, which are the same employed for the treatment of tubercolosis, leprosy, AIDS and cancer in humans, did not lower either TNFalpha or SPH and only marginally influenced the apoptosis-induced muscle atrophy. Since other TNFalpha blockers are under investigation for improving the clinical status of patients with CHF, the present data could be relevant in the design of randomised clinical trials in humans.

Animals↗
PubMed2003

Thiothalidomides: novel isosteric analogues of thalidomide with enhanced TNF-alpha inhibitory activity.

Thalidomide is being increasingly used in the clinical management of a wide spectrum of immunologically-mediated and infectious diseases, and cancers. However, the mechanisms underlying its pharmacological action are still under investigation. In this regard, oral thalidomide is clinically valuable in the treatment of erythema nodosum leprosum (ENL) and multiple myeloma and effectively reduces tumor necrosis factor-alpha (TNF-alpha) levels and angiogenesis in vivo. This contrasts with its relatively weak effects on TNF-alpha and angiogenesis in in vitro studies and implies that active metabolites contribute to its in vivo pharmacologic action and that specific analogues would be endowed with potent activity. Our focus in the structural modification of thalidomide is toward the discovery of novel isosteric active analogues. In this regard, a series of thiothalidomides and analogues were synthesized and evaluated for their TNF-alpha inhibitory activity against lipopolysacharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC), This was combined with a PBMC viability assay to differentiate reductions in TNF-alpha secretion from cellular toxicity. Two isosteric analogues of thalidomide, compounds 15 and 16, that mostly reflect the parent compound, together with the simple structure, dithioglutarimide 19, potently inhibited TNF-alpha secretion, compared to thalidomide, 1. The mechanism underpinning this most likely is posttranscriptional, as each of these compounds decreased TNF-alpha mRNA stability via its 3'-UTR. The potency of 19 warrants further study and suggests that replacement of the amide carbonyl with a thiocarbonyl may be beneficial for increased TNF-alpha inhibitory action. In addition, an intact phthalimido moiety appeared to be requisite for TNF-alpha inhibitory activity.

3' Untranslated Regions↗
PubMed2001

Thalidomide and dexamethasone combination for refractory multiple myeloma.

BACKGROUND: Thalidomide is effective in approximately 30% of patients with refractory multiple myeloma. Dexamethasone is active in 25% of patients with disease resistant to alkylating agents. We investigated the combination of thalidomide with dexamethasone as salvage treatment for heavily pretreated patients with multiple myeloma, in order to assess its efficacy and toxicity. PATIENTS AND METHODS: Forty-four patients with refractory myeloma were treated with thalidomide, 200 mg p.o. daily at bedtime, with dose escalation to 400 mg after 14 days, and dexamethasone, which was administered intermittently at a dose of 20 mg/m2 p.o. daily for four days on day 1-4, 9-12, 17-20, followed by monthly dexamethasone for four days. Patients' median age was 67 years. All patients were resistant to standard chemotherapy, 77% were resistant to dexamethasone-based regimens and 32% had previously received high-dose therapy. RESULTS: On an intention-to-treat basis twenty-four patients (55%) achieved a partial response with a median time to response of 1.3 months. The thalidomide and dexamethasone combination was equally effective in patients with or without prior resistance to dexamethasone-based regimens and in patients with or without prior high-dose therapy. Toxicities were mild or moderate and consisted primarily of constipation, morning somnolence, tremor, xerostomia and peripheral neuropathy. The median time to progression for responding patients is expected to exceed 10 months and the median survival for all patients is 12.6 months. CONCLUSION: The combination of thalidomide with dexamethasone appears active in patients with refractory multiple myeloma. If this activity is confirmed, further studies of this combination as second-line treatment for patients resistant to conventional chemotherapy, and as primary treatment for patients with active myeloma, should be considered.

Adult↗
PubMed2001

Thalidomide in multiple myeloma, myelodysplastic syndromes and histiocytosis. Analysis of clinical results and of surrogate angiogenesis markers.

BACKGROUND: Thalidomide, as a single agent, has been recently found to induce a clinical response in one third of refractory or relapsed myeloma patients. Although it has been reported that thalidomide significantly inhibits angiogenesis. it is still unclear whether its clinical effect is mediated, at least in part, by its anti-angiogenic properties. PATIENTS AND METHODS: We evaluated thalidomide as a single agent in myeloma, myelodysplastic syndromes (MDS) and histiocytosis, i.e. hematological diseases characterized by increased angiogenesis, and measured prospectively a number of surrogate angiogenesis markers. RESULTS: Clinical responses were observed in 7 of 17 myeloma and 2 of 5 MDS patients. The histiocytosis patient had a partial response. At the time of the best clinical response, plasma levels of angiogenic growth factors, vascular endothelial growth factor (VEGF) and basic-fibroblast growth factor (b-FGF), were significantly decreased, and flow cytometry indicated a decrease of activated endothelial cells in the bone marrow of responding MDS patients. CONCLUSIONS: These observations confirm thalidomide efficacy in myeloma, suggest a possible use in MDS and histiocytosis and may contribute to the prediction of clinical response and to understanding the mechanism of thalidomide's action.

Aged↗
PubMed2002

A phase II study of thalidomide in advanced metastatic renal cell carcinoma.

OBJECTIVES: To evaluate the toxicity and activity of thalidomide in patients with advanced metastatic renal cell cancer and to measure changes of one angiogenic factor, vascular endothelial growth factor (VEGF)165, with therapy. PATIENTS AND METHODS: 29 patients were enrolled on a study of thalidomide using an intra-patient dose escalation schedule. Patients began thalidomide at 400 mg/d and escalated as tolerated to 1200 mg/d by day 54. Fifty-nine per cent of patients had had previous therapy with IL-2 and 52% were performance status 2 or 3. Systemic plasma VEGF165 levels were measured by dual monoclonal ELISA in 8 patients. RESULTS: 24 patients were evaluable for response with one partial response of 11 months duration of a patient with hepatic and pulmonary metastases (4%), one minor response, and 2 patients stable for over 6 months. Somnolence and constipation were prominent toxicities and most patients could not tolerate the 1200 mg/day dose level. Systemic plasma VEGF165 levels did not change with therapy. CONCLUSION: These results are consistent with a low level of activity of thalidomide in renal cell carcinoma. Administration of doses over 800 mg/day was difficult to achieve in this patient population, however lower doses were practical. The dose-response relationship, if any, of thalidomide for renal cell carcinoma is unclear.

Adult↗
PubMed2003

Phase II trial and pharmacokinetic study of thalidomide in patients with metastatic colorectal cancer.

INTRODUCTION: This study was designed to estimate the percentage of objective tumor responses, toxicity profile, and obtain additional information about the plasma pharmacokinetics of thalidomide in patients with refractory and progressing metastatic colorectal cancer. STUDY DESIGN: This phase II clinical trial was conducted according to the two-stage Simon method with the inclusion of consecutive patients. The study protocol was approved by the Institutional Review Board (IRB) of the Academic Hospital (HCPA) of the Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil. PATIENTS AND METHODS: Seventeen patients with previously treated, refractory progressive metastatic colorectal cancer were eligible. Six patients had prior radiotherapy. The patients had a median of one previous chemotherapy regimen. Patients were initially treated with 200 mg/day of thalidomide with an increase in dose by 200 mg/day every 2 weeks until a final daily dose of 800 mg/day was achieved. Patients were evaluated every 8 weeks for response by radiographic criteria. Plasma pharmacokinetics studies were performed in four patients at 200 mg level and in one patient at 600 mg during the first 24 h. MAIN OUTCOME MEASURES AND RESULTS: A total of 17 patients were accrued, all of them being evaluable for toxicity and 14 for response. Thalidomide was well tolerated, with constipation, somnolence, dizziness, and dry mouth being the major toxicities. There were no objective response or stable disease. The median survival was 3.6 months. Single-agent thalidomide is a generally well-tolerated drug that showed no antitumor activity in patients with advanced pretreated metastatic colorectal cancer. Although thalidomide did not show antitumor activity in this patient population, future studies of this agent in patients at initial stages of the disease (when its antiangiogenic properties may be more relevant to disease progression) could be considered.

Adult↗
PubMed2004

Thalidomide neuropathy: clinical, electrophysiological and neuroradiological features.

OBJECTIVE: Thalidomide is a promising therapy for multiple myeloma. Sensory neuropathy is a side effect of thalidomide and resulted to be partially reversible in 50% of cases, suggesting a sensory ganglionopathy. Spinal cord magnetic resonance imaging (MRI) was found to be useful in the diagnosis of sensory ganglionopathies and we use it to determine if thalidomide neuropathy has features of a ganglionopathy. MATERIAL AND METHODS: Six patients with multiple myeloma developed thalidomide-induced polyneuropathy. Nerve conduction studies, somatosensory-evoked potentials (SEPs) and cervical and dorsal spinal cord MRI were obtained in all. RESULTS: All patients had a sensory neuropathy, with clinical or electrophysiological abnormalities involving all four limbs. Spinal cord MRI showed high signal intensity in the posterior columns in only one patient, with abnormal central conduction time at SEPs. CONCLUSION: Our results suggest that thalidomide can induce either an axonal length-dependent neuropathy or, less frequently, a ganglionopathy.

Adult↗
PubMed1995

Effect of thalidomide on tumour necrosis factor production and anti-tumour activity induced by 5,6-dimethylxanthenone-4-acetic acid.

The investigational anti-tumour agent, 5,6-dimethylxanthenone-4-acetic acid (5,6-MeXAA), an analogue of flavone acetic acid (FAA), has been scheduled for clinical evaluation. Like FAA, 5,6-MeXAA exhibits excellent experimental anti-tumour activity and is an efficient inducer of cytokines in mice. We have examined the effect of pharmacological suppression of tumour necrosis factor (TNF) production on the anti-tumour activity of 5,6-MeXAA, taking advantage of previous observations that TNF production in response to endotoxin in vitro is inhibited by thalidomide. Thalidomide at doses of between 8 and 250 mg kg-1 efficiently suppressed serum TNF activity in response to 5,6-MeXAA at its optimal TNF inducing dose of 55 mg kg-1. Suppression was achieved when thalidomide was administered at the same time as, or up to 4 h before, 5,6-MeXAA. Under conditions in which TNF activity was suppressed, the degree of tumour haemorrhagic necrosis and the proportion of cures in the subcutaneous Colon 38 tumour were increased. In mice administered thalidomide (100 mg kg-1) together with 5,6-MeXAA (30 mg kg-1), complete tumour regression was obtained in 100% of mice, as compared with 67% in mice receiving 5,6-MeXAA alone. The results suggest a possible new application for thalidomide and pose new questions about the action of 5,6-MeXAA and related compounds.

Animals↗