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PubMed2001

Thalidomide: 40 years on.

Thalidomide was marketed in the late-1950s as a sedative and tranquilliser of exceptionally low general toxicity, but in 1961 it was implicated separately by Lenz and MacBride as the cause of the epidemic of congenital malformations that had been puzzling the world for some years. It is a very potent teratogen in humans, but in few other mammalian species; damage to the embryo is produced at specific stages of gestation, but the mechanism of embryopathic action is still not understood. Following the withdrawal of the drug worldwide, it was consigned to the history of medical tragedies. In 1965, however, Sheskin discovered that it was effective in treating erythema nodosum leprosum, a distressing complication of leprosy. As the drug is neither an antibiotic nor an analgesic, its action was assumed to be immunosuppressive. In Brazil the drug was used widely with few regulatory controls, since when more than 100 cases of congenital malformation have appeared. Sheskin's discovery led to the experimental use of thalidomide in many other indications thought to possess some immunological component. In some cases, e.g. Behçet's syndrome, graft-versus-host disease and aphthous ulceration in HIV-positive patients, the drug has been shown to possess some efficacy. And there is some evidence that it inhibits the replication of one of the immunodeficiency viruses. The AIDS community in the US has exerted much pressure on the FDA to allow the drug on to the market, although the use of a potent immunosuppressive drug of unknown mechanism in an immunodeficiency condition raises further questions. Thalidomide is not always beneficial; its use is associated with an increased mortality in epidermal necrolysis. In 1991, D'Amato confirmed it possessed antiangiogenic properties and this led to further trials in malignant conditions. Results were mixed, but those in multiple myeloma gave some grounds for optimism. In 1998, the FDA announced its extraordinary decision to grant marketing approval for thalidomide.

Anti-HIV Agents↗

PubMedDate not supplied

Thalidomide: when everything old is new again.

Thalidomide is an anti-angiogenesis agent that currently is being evaluated in the treatment of various types of cancer. The teratogenic effects of thalidomide are well-known, and patients who are prescribed this drug often are fearful of its effects. Because of the potential for teratogenicity, patients must adhere to the System for Thalidomide Education and Prescribing Safety (STEPS). Side effects of thalidomide include sedation, dose-related peripheral neuropathy, constipation, thrombiotic events, and skin rash. Nurses have a major role in educating patients about this drug, its effects, and necessary precautions.

Angiogenesis Inhibitors↗

PubMed1975

The action of thalidomide on the peripheral nervous system of the embryo.

The mode of teratogenic action of thalidomide is unknown. A new radiological interpretation of thalidomide-induced limb malformations suggested that pathological changes should be sought in the sensory ganglia. Newborn rabbits with thalidomide-induced limb defects were examined histologically, and failure of maturation of dorsal root ganglion cells was demonstrated. This neuronal immaturity supports the radiological hypothesis of embryonic neuropathy, which is proposed as the underlying pathology of the limb deformities due to thalidomide.

Abnormalities, Drug-Induced↗

PubMedDate not supplied

Thalidomide: focus on its employment in rheumatologic diseases.

Thalidomide is an immunomodulatory agent; although its mechanisms of action are not fully understood, many authors have described its anti-inflammatory and immunosuppressive properties. More interestingly, thalidomide has shown the ability to suppress tumor necrosis factor alpha (TNF alpha) production and to modify the expression of TNF alpha induced adhesion molecules on endothelial cells and on human leukocytes. Thalidomide has been used in several diseases (i.e. dermatological, autoimmune, gastrointestinal). In this review we focus specifically on the use of this drug in disorders with rheumatological features such as lupus erythematosus, rheumatoid arthritis and Still's disease, ankylosing spondylitis, and Behçet's disease. Despite its well known side effects, first of all peripheral nerve involvement and teratogenesis, which can be avoided by following strict guidelines, thalidomide could represent an alternative drug in some rheumatological conditions, particularly in patients who show resistance, contraindication or toxicity with other conventional treatments.

Abnormalities, Drug-Induced↗

PubMed2002

[Thalidomide inhibits the angiogenic activity of culture supernatants of multiple myeloma cell line].

OBJECTIVE: To investigate the pro-angiogenic effects of several multiple myeloma (MM) cell line culture supernatants on human bone marrow endothelial cell (HBMEC) proliferation, migration, and capillary formation, and the anti-angiogenic effects of thalidomide. METHODS: HBMEC was cultured in the presence of MM cell lines (IM9, XG1, U266 and MOLP-5) supernatants. Proliferation and migration of HBMEC were determined, capillary-like tubule formation of HBMEC was examined in fibrin and Matrigel. The inhibiting effect of thalidomide was investigated by adding it into myeloma cell line culture supernatants. Vascular endothelial growth factor (VEGF) was measured by ELISA. RESULTS: (1) MM cell lines culture supernatants promoted HBMEC proliferation and migration. (2) In fibrin and Matrigel, capillary-like tubule network formation promoted by the supernatants. (3) All of these effects could be inhibited by thalidomide. (4) This effect was not related to VEGF in the supernatants. CONCLUSIONS: MM cell line promote proliferation, migration and tubule formation by secreting VEGF or other several cytokines. Thalidomide can inhibit these effects.

Angiogenesis Inhibitors↗

PubMed2003

A novel subclass of thalidomide analogue with anti-solid tumor activity in which caspase-dependent apoptosis is associated with altered expression of bcl-2 family proteins.

Thalidomide is clinically useful in a number of cancers. Antitumor activity may be related to a number of known properties, including anti-tumor necrosis factor (TNF)-alpha and T-cell costimulatory and antiangiogenic activities. However, it may also involve direct antitumor effects. A series of second generation thalidomide analogues have been separated into two distinct groups of compounds, each with enhanced therapeutic potential, i.e., SelCIDs, which are phosphodiesterase (PDE) type IV inhibitors, and IMiDs, which have unknown mechanism(s) of action. We report here our efforts to determine direct antitumor effects of thalidomide and compounds from both groups. We found that one of the SelCID analogues (SelCID-3) was consistently effective at reducing tumor cell viability in a variety of solid tumor lines but had no effect on non-neoplastic cells. The antitumor activity was independent of known PDE4 inhibitory activity and did not involve cAMP elevation. Growth arrest was preceded by the early induction of G(2)-M cell cycle arrest, which led to caspase 3 mediated apoptosis. This was associated with increased expression of pro-apoptotic proteins and decreased expression of antiapoptotic bcl-2. Furthermore, extensive apoptosis in vivo was detected during SelCID-3-mediated inhibition of tumor growth in a murine xenotransplantation cancer model. Our results suggest that SelCID-3 represents a novel antitumor agent distinct from thalidomide and from previously characterized analogues with therapeutic potential against a range of solid tumors. This effect appears to be mediated via alterations in the expression of bcl-2 family proteins.

Animals↗

PubMed2002

Immunological effects of thalidomide and its chemical and functional analogs.

Thalidomide has recently shown considerable promise in the treatment of a number of conditions, such as leprosy and cancer. Its effectiveness in the clinic has been ascribed to wide-ranging properties, including anti-TNF-alpha, T-cell costimulatory and antiangiogenic activity. Novel compounds with improved immunomodulatory activity and side effect profiles are also being evaluated. These include selective cytokine inhibitory drugs (SelCIDs), with greatly improved TNF-alpha inhibitory activity, and immunomodulatory drugs (IMiDs) that are structural analogs of thalidomide, with improved properties. A third group recently identified within the SelCID group, with phosphodiesterase type 4-independent activity, is in the process of being characterized in laboratory studies. This review describes the emerging immunological properties of thalidomide, from a historical context to present-day clinical applications, most notably in multiple myeloma but also in other cancers, inflammatory disease, and HIV. We also describe the laboratory studies that have led to the characterization and development of SelCIDs and IMiDs into potentially clinically relevant drugs. Early trial data suggest that these novel immunomodulatory compounds may supercede thalidomide to become established therapies, particularly in certain cancers. Further evidence is required, however, to correlate the clinical efficacy of these compounds with their known immunomodulatory, antiangiogenic, and antitumor properties.

Adjuvants, Immunologic↗

PubMed2003

[The changes of gene expression in multiple myeloma treated with thalidomide].

OBJECTIVE: To investigate the effect of thalidomide on bone marrow cells gene expression in multiple myeloma (MM) patients with suppression subtractive hybridization (SSH) and explore the molecular mechanism of thalidomide therapy for MM. METHODS: In a MM patient receiving thalidomide therapy and bone marrow cell from himself, total RNA extraction, mRNA isolation and cDNA synthesis were carried out respectively with routine procedures. SSH were performed in A and B group respectively. The subtracted cDNA was selectively amplified by suppression PCR. The product was inserted into T vector, and then transfected into the competent host JM109. So two subtractive libraries were constructed. After blue-white screening, colonies were selected and plasmids extracted. Homologous comparation was conducted in GenBank. RESULTS: In group A, seven clones were isolated, including ribosomal protein L19 (HUMAN), IgG lambda chain v-v region (HUMAN), contains Alu repetitive element, NADH-ubiquinone oxidoreductase chain 2, elongation factor 1-gamma, human beta globin region, and 40S ribosomal protein S4 (HUMAN). In group B, six clones were isolated, including cytochrome B, up-regulated by 1,25-dihydroxyvitamin D(3) (VDUP1), NADH- ubiquinone oxidoreductase 20 Kd subunit, mu-calpain large subunit, tumor protein, translationally-controlled 1 (TPT1) and COATOMER alpha subunit. CONCLUSION: Thalidomide induces apoptosis and antiangiogenesis by down-regulating some genes and up-regulating some others genes.

Angiogenesis Inhibitors↗

PubMed2003

[Single-agent thalidomide for advanced and refractory multiple myeloma].

Thalidomide as a single agent (200-400 mg/day) was administered in fourteen cases of refractory myeloma, from March 2001 till February 2002. The median age was 71 years (range 58 to 85 years), and the efficacy of thalidomide was observed in cases receiving treatment for at least three consecutive months. Response was evaluated in February 2002, according to the criteria for assessment of response described by Kakimoto et al. At the time of evaluation, two cases were in the PR2 state, one in PR3, two were stable, and three were PD. Evaluation of the response was not possible in six cases in whom treatment had to be discontinued due to intolerable side effects. The response to thalidomide was variable, with some cases responding well even to a low dose (200 mg/day) while a few others showed an early relapse due to the refractory nature of the disease in its response to the drug. The efficacy of treatment seemed to be correlated with the maturation pattern of myeloma cells. Side effects included neurological complications like somnolence, physiological symptoms such as constipation and so on, etc but all were relieved with symptomatic treatment. The drug was well tolerated in geriatric patients. Neutropenia was a dose limiting factor with half of the cases (7/14) presenting with severe neutropenia (grade 3-4), but a response was observed in all of them on administration of G-CSF. Thromboembolism occurred in two cases, the cause of which is not clear. These results suggest that thalidomide is a well tolerated drug and can be considered as a mainstay in the therapy of refractory myeloma.

Aged↗

PubMedDate not supplied

Combination therapy with paclitaxel and thalidomide inhibits angiogenesis and growth of human colon cancer xenograft in mice.

BACKGROUND: Combination chemotherapy is increasingly practiced for treating malignancies with greater sensitivity and less toxicity. Paclitaxel is a potent anti-tumor agent but has dose-limiting side-effects, whereas thalidomide is an orally active anti-angiogenic drug but less than sufficient to exert anti-tumor effect as a single agent. MATERIALS AND METHODS: Nude mice bearing hypervascular (LS174T) and less vascular (HT29) colon carcinomas were challenged with either a non-cytotoxic dose of paclitaxel, thalidomide or a combination of paclitaxel and thalidomide. RESULTS: Significant growth retardation was noticed only in the combination treatment group of LS174T tumors. Microvessel density data indicated a significantly low count in the combination treatment group compared to the others. Trends of decreased expression of angiogenic growth factors and increased apoptotic index were noticed in the combination treatment group. CONCLUSION: The results of this study underscore the therapeutic efficacy of concomitant use of paclitaxel and thalidomide in the treatment of highly vascular colorectal tumors in a xenograft model.

Adenocarcinoma↗

PubMed2003

A review of thalidomide's history and current dermatological applications.

Once abandoned because of devastating teratogenic effects, thalidomide has reemerged as an alternative treatment in many dermatologic diseases. In 1998, thalidomide became FDA approved for the acute treatment and suppression of the cutaneous manifestations of erythema nodosum leprosum (ENL). ENL is a systemic disorder that typically occurs after several years of antileprosy treatments, usually for lepromatous leprosy. Off-label uses for thalidomide include: aphthous stomatitis, Behçet disease, pyoderma gangrenosum, chronic discoid lupus erythematosus, systemic lupus erythematosus, lichen planus, prurigo nodularis and sarcoidosis. This review examines the background, pharmacokinetics, mechanism of action, side-effects, and indications of thalidomide.

Dermatologic Agents↗

PubMed2003

Successful treatment of muscle sarcoidosis with thalidomide.

A 36-year-old male patient suffered from therapy resistant sarcoidosis with long-standing contractures, myopathy, skin lesions and pulmonary changes. Low-dose therapy with thalidomide (50 mg/day) was well tolerated, and the patient rapidly improved. Thalidomide was effective for muscular, cutaneous, and pulmonary involvement in our patient. This is the first report on the efficacy of thalidomide in muscle sarcoidosis. Therefore, thalidomide may become a second-line agent in patients with severe muscle and skin involvement, but further studies are warranted.

Adult↗

PubMed2004

Thalidomide prolongs disease stabilization after conventional therapy in patients with recurrent glioblastoma.

Thalidomide shows antiangiogenic activity and it has been successfully employed in various tumors. Considering the poor therapeutic options for glioblastoma and the role of angiogenesis in malignant glioma cells growth, we investigated the therapeutic activity of thalidomide in patients affected by recurrent glioblastoma. Inclusion criteria were: recurrent glioblastoma pretreated with surgery and radiotherapy, age >/=18 years, adequate performance status, hematological, renal, and hepatic functions. Exclusion criteria included severe underlying diseases, neuropathy or concurrent radiotherapy. Eighteen patients entered the study, 17 of whom were assessable for toxicity and response. Most of patients were pretreated with chemotherapy (77.8%). Thalidomide was well tolerated: the most common side effects were constipation (76.5% of patients), somnolence (47%), and peripheral neuropathy (11.8%). One minimal response (MR) and 8 stable disease (SD) were observed, with an overall clinical benefit of 52.9%. Median time to progression and median overall survival (OS) for responders was 25 weeks (range 12-40) and 36 weeks (range 16-64), respectively. In conclusion, thalidomide induces modest side effects and it may be considered a valid therapeutic option for patients with recurrent glioblastoma.

Adult↗

PubMed2003

[Desirable and undesirable effects of thalidomide in patients with multiple myeloma].

Thalidomide, an antiemetic administered in 60th of the 20th century to pregnant women, has become notorious for a range of adverse effects which led to its taking off market. In recent years, its antimyeloma effect was discovered. The aim of the work was to evaluate the incidence of adverse reactions to thalidomide. Its therapeutic effect has not been assessed because of a short period of monitoring and diversity of a sample. The assessed sample consisted of 17 patients with diagnosis of multiple myeloma (10 men and 7 women). An average age of patients was 62.9 +/- 9.4. An average time elapsed from making the diagnosis to starting the treatment with thalidomide was 51.0 +/- 23.7 months. An average length of therapy was 20.1 +/- 9.6 weeks. An average daily maximum therapeutic dose was 138.3 +/- 83.2 mg. Data were collected from outpatient physicians reports, regular laboratory tests, and direct interviews with patients. To classify severity of adverse drug effects (grades 0-4) we used WHO criteria, Cancer and Leukemia Group B criteria, and in cases where certain adverse effects were not included in the above mentioned criteria, we defined our own criteria. The most frequent adverse effects included: leucopenia or neutropenia in 12 (70.6%) patients, altered state of consciousness in 11 (64.7%) patients, obstipation in 10 (58.8%) patients, skin alterations in 9 (52.9%) patients, dizziness in 8 (47.1%) patients, peripheral neuropathy in 7 (41.2%) patients, spasms and spasmodic convulsions in 7 (41.2%) patients, and altered liver tests in 6 (35.3%) patients. From the perspective of necessity to interrupt treatment or reduce the dose the most severe disorders included: peripheral neuropathy in 2 patients (inability to control lower extremities), altered consciousness in 1 patient (protracted somnolence during a day), skin alteration in 1 patient (generalized toxoalergic reaction), leucopenia or neutropenia in 1 patient (1.0 resp < 0.5 x 10(9)/l), altered vision in 1 patient (blurred vision), hypothyroidism in 1 patient, and altered mood in 1 patient (subjective feeling of depression). This work proved thalidomide to be beneficial for the patients with multiple myeloma but it also shoved necessity to intensively monitor its adverse effects and to adjust its doses.

Female↗

PubMed2003

[Management of a patient receiving thalidomide].

THE USE OF A DRUG WITH A TEMPORARY MARKETING AUTHORISATION: Thalidomide is currently available in France for nominative or cohort use with a temporary marketing authorisation (TMA). It is only prescribed and delivered in hospital settings. SIX OFFICIAL INDICATIONS: Its current indications are principally lepromatous nodular erythema, severe aphtosis, Jessner-Kanoff's cutaneous lymphocyte infiltration, discoid lupus erythematosis, chronic graft-versus-host reactions, and relapsed and or refractory multiple myeloma (after the failure of standard therapies). In the majority of cases, thalidomide is a last resort treatment of rare pathologies. On withdrawal, it is responsible for more or less long-term recurrences of the disease that require its re-introduction. SURVEILLANCE IS CRUCIAL: The side effects induced by thalidomide must never be forgotten, notably its teratogenic effects and its often irreversible neurotoxicity. The latter limit the long-term use of thalidomide and imply strict rules for its prescription and surveillance (efficient contraception, clinical neurological examinations, electroneurophysiological controls).

Abnormalities, Drug-Induced↗

PubMed2003

[Thalidomide--new prospective therapy in oncology].

Thalidomide was first produced in Germany in the 1950s. The drug was promoted as a safe sedative and was found to be useful as an antiemetic during pregnancy. In late 1960s, reports of teratogenic actions resulted in the withdrawal of thalidomide from world markets. Thalidomide has multiple actions, including anti-inflammatory and anti-angiogenic ones. This article reviews the pharmacology and clinical trials of the drug for the treatment of various cancers including multiple myeloma. Furthermore, in preliminary studies, thalidomide has been found to be effective in several syndromes related to advanced cancer, such as the cancer cachexia, chronic nausea and pain.

Analgesics↗

PubMedDate not supplied

Management of thalidomide toxicity.

Thalidomide has re-emerged as a novel antineoplastic agent with immunomodulatory and antiangiogenic activities. In the early sixties, it was withdrawn from the market after its infamous association with congenital abnormalities that left about 10,000 children affected world-wide. With strict regulations and precautions, thalidomide is now approved by the FDA for the treatment of erythema nodosum leprosum. Its role in cancer therapy is promising, with clinical trials in the past 5 years showing significant activity in multiple myeloma. Several trials are ongoing in other malignancies, such as myelodysplastic syndrome, agnogenic myeloid metaplasia, renal cell carcinoma, and prostate cancer. The major toxicities of thalidomide are birth defects, sensorimotor peripheral neuropathy, somnolence, rash, fatigue, and constipation. Less common side effects include deep venous thrombosis, Stevens-Johnson syndrome, elevated liver enzymes, malaise, and peripheral edema. The incidence and severity of adverse events are related to dose and duration of therapy. Doses of the drug of 200 mg/day or less are usually well tolerated. In this review, we will discuss the incidence and management of the side effects of thalidomide and the precautions and interventions needed to minimize the toxicities of this drug.

Clinical Trials as Topic↗

PubMed2004

[Interstitial pneumonia during treatment with thalidomide in a patient with multiple myeloma].

A 66-year-old man was referred to our hospital for the treatment of refractory multiple myeloma with thalidomide. He had a history of an interstitial pneumonia of unknown etiology two months before admission. Eight days after starting 200 mg/ day of thalidomide, he developed dyspnea and fever, followed by a macropapular rash in the trunk. The dyspnea got worse and a CT scan revealed interstitial pneumonia 16 days after the treatment. He required mechanical ventilatory support. Bronchoalveolar lavage fluid revealed eosinophilia, suggesting a thalidomide-induced interstitial pneumonia. Thalidomide was discontinued and methylprednisolone (1000 mg/d x 3 days) was started, and the pneumonia and rash markedly improved within six days. After that the patient contracted MRSA pneumonia and died of MRSA septicemia.

Aged↗