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PubMedDate not supplied

Pharmacogenetic associations of CYP2C19 genotype with in vivo metabolisms and pharmacological effects of thalidomide.

Thalidomide requires cytochrome P450 (CYP)-catalyzed biotransformation for its antiangiogenic property, and CYP2C19 is responsible for 5-hydroxylation and 5'-hydroxylation of thalidomide in human. This study explored a hypothesis that patients with poor metabolizing phenotype of CYP2C19 receive little benefit from thalidomide treatment and that the poor metabolizer genotype is associated with lower ability to form the metabolites. A case-control study was conducted with 63 patients with prostate cancer who had been enrolled in a randomized phase II trial of thalidomide monotherapy (200 to 1,200 mg/day). CYP2C19 polymorphism (CYP2C19(*)2, CYP2C19(*)3, CYP2C19(*)4) was compared with clinical events (prostate-specific antigen (PSA) decline) and formations of the hydroxylated metabolites. Two patients were homozygous for the variant CYP2C19(*)2 allele (poor metabolizing phenotype). Both of these were included in the 25 patients whose PSA failed to demonstrate a decline. While 32% and 48% of the patients had quantifiable levels of 5-hydroxythalidomide and cis-5'-hydroxythalidomide, respectively, these metabolite were below quantification in both poor metabolizing patients. None had CYP2C19(*)3 or CYP2C19(*)4 alleles. Although this study had no power to detect the statistical significance of the CYP2C19 genotype, the findings were consistent with our hypothesis. The role of CYP2C19 polymorphism in thalidomide treatments remains to be elucidated.

Alleles↗
PubMed1997

Formed by thalidomide: mass torts as a false cure for toxic exposure.

Professor Bernstein considers a theme of Judge Weinstein's judicial and academic writings--that tort law works imperfectly to effect justice in mass disaster cases--through the vehicle of thalidomide, the paradigmatic toxic substance. Thirty-five years ago, thalidomide poisoned thousands of children, inflicting limb-reduction birth defects. Professor Bernstein argues that the drug has also had a malforming effect on mass tort law. Courts and scholars have used the precedent of thalidomide to build stringent legal standards of proof and causation, without enough attention to the functions and consistency of these standards. Thalidomide has also prompted commentators to celebrate American drug regulation and the American liability system; Professor Bernstein argues that these paeans are exaggerated. She concludes that the United States must confront its thalidomide history, as other nations in the world have done, and build social institutions--strong regulation and social insurance--to guard against toxic disasters of the future.

Abnormalities, Drug-Induced↗
PubMed2000

Thalidomide for treatment of patients with chronic graft-versus-host disease.

In a randomized, placebo-controlled, double-blind trial, thalidomide or placebo together with glucocorticoids and either cyclosporine or tacrolimus was administered as initial therapy for clinical extensive chronic graft-versus-host disease (cGVHD). All patients had thrombocytopenia or cGVHD that evolved directly from acute GVHD as an indicator of a poor prognosis. The study drug (thalidomide or placebo) was administered initially at a dose of 200 mg orally per day, followed by a gradual increase to 800 mg/d if side effects were tolerable. Treatment with the study drug was discontinued before resolution of cGVHD in 23 (92%) of the 25 patients who received thalidomide and in 17 (65%) of the 26 patients who received placebo (P =.02). Neutropenia and neurologic symptoms were the most frequent reasons for early discontinuation of treatment with thalidomide. The duration of treatment with thalidomide was too short to assess its efficacy in controlling cGVHD. (Blood. 2000;96:3995-3996)

Actuarial Analysis↗
PubMed2001

A randomized phase II trial of thalidomide, an angiogenesis inhibitor, in patients with androgen-independent prostate cancer.

PURPOSE: Thalidomide is a potent teratogen that causes dysmelia in humans. Recently, in vitro data suggested that it inhibits angiogenesis. Prostate cancer is dependent on the recruitment of new blood vessels to grow and metastasize. Based on those data, we initiated a Phase II trial of thalidomide in patients with metastatic androgen-independent prostate cancer. EXPERIMENTAL DESIGN: This was an open-label, randomized Phase II study. Thalidomide was administered either at a dose of 200 mg/day (low-dose arm) or at an initial dose of 200 mg/day that escalated to 1200 mg/day (high-dose arm). RESULTS: A total of 63 patients were enrolled onto the study (50 patients on the low-dose arm and 13 patients on the high-dose arm). Serum prostate-specific antigen (PSA) decline of > or = 50% was noted in 18% of patients on the low-dose arm and in none of the patients on the high-dose arm. Four patients were maintained for > 150 days. The most prevalent complications were constipation, fatigue, neurocortical, and neurosensory. CONCLUSION: Thalidomide, an antiangiogenesis agent, has some activity in patients with metastatic prostate cancer who have failed multiple therapies. A total of 27% of all patients had a decline in PSA of > or = 40%, often associated with an improvement of clinical symptoms. Because our preclinical studies had shown that thalidomide increases PSA secretion, we believe that the magnitude of PSA decline seen in our trial justifies further study.

Aged↗
PubMed2001

Thalidomide is distributed into human semen after oral dosing.

As part of a double-blind placebo-controlled study of the effect of thalidomide on body weight and the viral load of human immunodeficiency virus-seropositive patients, plasma and semen samples were analyzed for the presence of thalidomide. Patients were orally dosed with 100 mg of thalidomide/day for 8 weeks. Blood samples were obtained at baseline and weeks 4, 8, and 12, and semen was obtained at baseline and weeks 4 and 8. Samples were extracted with solid-phase cartridges and analyzed by liquid chromatography/tandem mass spectrometry using atmospheric pressure chemical ionization in the negative ion mode. Two of four patients taking thalidomide were able to provide semen samples. Both had detectable levels of thalidomide in their plasma (10-350 ng/ml) and semen (10-250 ng/g) at weeks 4 and 8. There was an apparent correlation between plasma and semen levels. Semen levels could be significantly greater for therapeutic doses of more than 100 mg/day. Since the threshold dose for birth defects and thalidomide exposure is not known, male patients are advised to use barrier contraception.

Administration, Oral↗
PubMed2001

Amelioration of experimental colitis by thalidomide.

BACKGROUND: Rectal administration of iodoacetamide induces colitis by blocking sulphhydryl groups and generating inflammatory mediators. Thalidomide, a non-barbiturate hypnotic, also has an anti-inflammatory effect, presumably by suppressing the production of tumor necrosis factor alpha. In patients with Crohn's disease, neutralization or suppression of TNF alpha reduces inflammation. OBJECTIVES: To evaluate the effects of thalidomide in a model of experimental colitis. METHODS: Colitis was induced in rats by intracolonic administration of 3% iodoacetamide. In the treatment group, thalidomide 50 mg/kg was given daily by gavage and continued for 7 days until the rats were sacrificed. Their colons were then processed for wet weight, lesion area, weight of mucosal scraping, myeloperoxidase activity and histology. Serum levels of TNF were determined. RESULTS: Colonic wet weight, lesion area, myeloperoxidase activity and serum levels of TNF alpha were significantly lower (P < 0.05) in the treatment group (iodoacetamide + thalidomide) than the control group (iodoacetamide only). Histologically, colonic inflammation in the treated group was markedly decreased. CONCLUSIONS: Thalidomide effectively decreases colitis induced by iodoacetamide. The mechanism is probably associated with inhibition of TNF alpha, and should be further studied.

Alkylating Agents↗
PubMed2002

Thalidomide metabolism by the CYP2C subfamily.

PURPOSE: This research investigated the biotransformation of thalidomide by cytochrome P-450 (CYP). EXPERIMENTAL DESIGN: We used liver microsomes from humans and/or animals and the recombinant specific CYP isozymes to investigate CYP-mediated metabolism of thalidomide. RESULTS: Thalidomide was biotransformed into 5-hydroxythalidomide (5-OH) and diastereomeric 5'-hydroxythalidomide (5'-OH) by liver microsomes. The human liver microsomes with higher CYP2C19 activity formed more metabolites than those with lower CYP2C19 activity and had less activity in metabolite formations than those from rats. Recombinant human CYP2C19 and rat CYP2C6 isozymes were primarily responsible for forming these metabolites, and the male rat-specific CYP2C11 formed only 5'-OH. 5-OH was subsequently hydroxylated to 5,6-dihydroxythalidomide by CYP2C19, CYP2C9, and CYP1A1 in humans and by CYP2C11, CYP1A1, CYP2C6, and CYP2C12 in rats. Incubations with S-mephenytoin and omeprazole, substrates of CYP2C19, inhibited metabolism by human liver microsomes, supporting the involvement of CYP2C19. alpha-Naphthoflavone, an inhibitor of CYP1A, simultaneously stimulated the 5-OH formation and inhibited cis-5'-OH formation catalyzed by human liver microsomes. The contribution of the CYP2C subfamily was supported by the immunoinhibition study using human liver microsomes. When we used the microsomes from treated rats, the metabolite formations did not increase by inducers for CYP1A, CYP2B, CYP2E, CYP3A, or CYP4A, suggesting that these could not be involved in the main metabolic pathway in rats. CONCLUSIONS: We discovered that the polymorphic enzyme CYP2C19 is responsible for 5- and 5'-hydroxylation of thalidomide in humans. In rats, thalidomide was hydroxylated extensively by CYP2C6 as well as the sex-specific enzyme CYP2C11.

Animals↗
PubMed2003

New insights into the pharmacological and toxicological effects of thalidomide.

The molecular activity of thalidomide comprises a wide range of mechanisms. Alteration of cytokine synthesis and release may be as important as changes in lymphocyte trafficking and leukocyte migration. Since endothelial cells play an important role in leukocyte extravasation and maintenance of inflammatory processes in the affected tissue, thalidomide-induced alterations of cellular adhesion molecules, and consequently changes of interaction of leukocytes with the endothelial cell layer, will result in modulation of the response in inflammation and immunity. Thalidomide mainly reduces tumor necrosis factor (TNF)-alpha production by macrophages, and its TNF alpha antagonist properties explain the beneficial effects in several TNF alpha-associated complications of severe diseases. Pathophysiologically relevant alterations most likely include gene regulatory effects, with interference in growth factor-dependent pathways known to be involved in teratogenesis, and effects on the transcriptional control of the inflammatory response via nuclear factor (NF)-kappa B. The effects of thalidomide, its enantiomers and analogs, on a broad range of diseases, and their differential pharmacokinetic and pharmacodynamic properties, give the scope for ongoing investigations in the search for analogs with better selectivity but without thalidomide-related side effects and teratogenicity.

Animals↗
PubMedDate not supplied

[Thalidomide with or without dexamethasone for refractory multiple myeloma].

It was shown in 1999 thalidomide could induce a therapeutic response in patients with refractory multiple myeloma. Between March 2000 and January 2002, we treated 21 patients with refractory multiple myeloma with thalidomide (Thalidomide) at initial dose of 400 mg a day. Response rate (Intergroupe Francophone du Myélome criteria) was 33 percent and median progression-free survival estimated to 15 months. All patients suffered from drowsiness and constipation requiring lowest doses. Five patients developed a sensitive neuropathy. Eight refractory patients were treated by a combination of their prior maximally tolerated dose of thalidomide and monthly dexamethasone (Soludécadron) alone (n = 4) or associated to cyclophosphamide (Endoxan) and étoposide (Etopophos) (n = 4). Six patients on 8 were responders. Our results suggest that the combination thalidomide/dexamethasone should be compared to thalidomide alone in a prospective, randomized study in patients with refractory multiple myeloma.

Adult↗
PubMedDate not supplied

Thalidomide down-regulates the expression of VEGF and bFGF in cisplatin-resistant human lung carcinoma cells.

Anti-angiogenic therapy represents one of the most promising treatment modalities for human cancer. Thalidomide (alpha-N-phthalimidoglutarimide) is a potent inhibitor of angiogenesis, and it is reported to overcome classical drug resistance in human multiple myeloma cells. However, the effect of this agent on the expression of angiogenic growth factors in cisplatin-resistant tumors is largely unknown. In the current study, we showed that thalidomide suppressed the expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in cisplatin-resistant human A549DDP lung carcinoma cells. The mRNA levels of VEGF and bFGF were markedly decreased in the A549DDP cells treated with the therapeutic concentrations of thalidomide (0.6-6 micrograms/ml), as determined by RT-PCR analysis. Consistent with these results, thalidomide also significantly reduced the protein levels of VEGF and bFGF in these cells in a dose- and time-dependent manner. This study provided evidence to support the potential therapeutic applications of thalidomide in cisplatin-resistant human lung cancer and other tumors.

Adenocarcinoma↗
PubMed2003

[Effect of thalidomide on tumor growth in mouse hepatoma H22 model].

BACKGROUND & OBJECTIVE: Thalidomide may have curative effect on tumor because of its function of anti-angiogenesis. The aim of this research was to observe the effect of thalidomide on tumor homograft growth in mouse H22 model and to investigate the mechanisms involved and its curative possibility to hepatoma. METHODS: BALB/c mice were inoculated subcutaneously with H22 cells. The first treatment group was injected intraperitoneal everyday with thalidomide 50 mg/kg from the day of inoculation and the second treatment group was injected from the fourth day of inoculation. The diameters of the tumors were measured everyday. On the twelfth day, the mice were sacrificed and the tumors were weighed. The microvessel densities of the tumors were measured by immunohistochemical staining with anti-CD31 monoclonal antibody; CD31 expression, apoptosis, and proliferation were analyzed by flow cytometry. Expression of vascular endothelial growth factor (VEGF) mRNA was examined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The tumor weight of the first treatment group (2.27+/-0.33 g) was decreased compared with that of control group (2.70+/-0.61 g) (P >0.05); the ratio of inhibition was 15.93%. The tumor weight of the second treatment group (3.32+/-0.47 g) was decreased compared with that of control group (3.42+/-0.60 g) (P >0.05); the ratio of inhibition was 2.92%. The microvessel count (48.40+/-12.90) and CD31 expression (5.59+/-0.75) of the first treatment group were significantly decreased (P< 0.05) in comparison with those of control groups (81.20+/-26.91,7.04+/-0.50) (P< 0.05). The microvessel count (46.4+/-9.71) and CD31 expression (7.29+/-0.48) of the second treatment group were not statistically significant (P >0.05) compared with those of control groups (74.0+/-32.69, 6.80+/-0.68) (P >0.05). The apoptosis indices of the two treatment groups (17.20+/-7.80,15.33+/-4.10) were significantly increased, compared with control groups (4.37+/-1.98,4.87+/-1.91) (P< 0.05), while there was no significant difference of VEGF mRNA expression between the two treatment groups and control groups (P >0.05). The relative quantities of VEGF mRNA of the two treatment groups were 0.50+/-0.13 and 0.51+/-0.06 (control groups:0.48+/-0.11 and 0.64+/-0.11) (P >0.05), respectively. CONCLUSION: Thalidomide can significantly induce apoptosis and inhibit angiogenesis in mouse H22 model when it is used at the beginning of carcinogenesis, but it has no obvious anti-angiogenic efficacy on the grown tumor. Thalidomide cannot inhibit VEGF mRNA expression of grafted H22 tumor in mouse.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Venous thrombosis occurring after initiation of thalidomide for the treatment of cicatricial pemphigoid.

Thalidomide is increasingly being used for the treatment of a variety of dermatologic conditions. Some of the risks associated with thalidomide use, however, are still being uncovered. Increased incidence of venous thrombosis following thalidomide use has recently been reported in the treatment of diseases with disease-related thrombotic risks, such as malignancy and lupus with antiphospholipid antibody syndrome. We report a case of venous thrombosis resulting from thalidomide use in a patient with cicatricial pemphigoid, illustrating the potential concern for increased thrombosis following thalidomide use in the dermatology setting.

Axilla↗
PubMed2004

A low serum level of soluble tumor necrosis factor receptor p55 predicts response to thalidomide in advanced multiple myeloma.

BACKGROUND AND OBJECTIVES: Thalidomide modulates the production of tumor necrosis factor (TNF-alpha). Soluble TNF receptors, TNFR p55 and TNFR p75, modify TNF-alpha activity. In this study, we explored the relation between soluble TNF receptors and outcome in patients with advanced multiple myeloma treated with thalidomide. DESIGN AND METHODS: The levels of soluble TNF receptor p55 and p75 were assessed in serum from 34 myeloma patients with relapsed or refractory disease before starting thalidomide treatment. Serial measurements were performed for 16 patients in serum collected during treatment. RESULTS: The pre-treatment serum level of soluble TNFR p55 in thalidomide responders was significantly lower than that in non-responders (median 1.75 ng/mL (range 1.19-2.84) vs. 2.79 ng/mL (1.36-5.51), p=0.004). The levels of p55 declined significantly during treatment. The levels of p75 showed the same pattern as p55, but the differences were not significant. The median survival of myeloma patients with pre-treatment levels of p55 < 2.79 ng/mL was 404 days; the median survival of patients with pre-treatment levels >or= 2.79 ng/mL was shorter (65 days, log-rank test p=0.02). INTERPRETATION AND CONCLUSIONS: We conclude that soluble TNFR p55 is an adverse prognostic factor in myeloma patients with relapsed or refractory disease treated with thalidomide. Patients with a low pre-treatment level of this receptor have a better response rate and a longer overall survival.

Adult↗
PubMed2004

[A case report of metastatic pancreatic cancer that responded remarkably to the combination of thalidomide, celecoxib and irinotecan].

The prognosis of pancreatic cancer with metastases or recurrence is quite poor. Chemotherapy has not resulted in a significant survival benefit; median survival is 3-6 months. Various chemotherapeutic agents have been evaluated and the standard chemotherapy of pancreatic cancer is gemcitabine. The response rate, however, is low at 13%. Thalidomide and celecoxib have different mechanisms of action and activity in various malignant tumors. Both have been evaluated and shown to demonstrate activity against solid tumors. Thalidomide decreased the stability of TNF-mRNA and COX-2 mRNA. COX-2 is a bifunctional enzyme possessing both cyclooxygenase and peroxidase activities. Although celecoxib inhibits PG biosynthesis, most do not affect the peroxidase activity of COX, which can generate proximate carcinogens. Because thalidomide does not completely inhibit COX-2 expression or PG biosynthesis, a therapeutic strategy combining celecoxib with thalidomide might be more effective than using either agent alone. Differences in the mechanism of action of gemcitabine and irinotecan suggest that a change of gemcitabine to irinotecan could provide clinically efficacious outcomes. In order to accomplish new treatment strategies, we have been using thalidomide, celecoxib and irinotecan in low-doses. We believe this combination represents a viable treatment for patients of pancreatic cancer with recurrence or metastases.

Aged↗
PubMed2005

Thalidomide treatment reduces colon injury induced by experimental colitis.

The immunological and genetic pathogeneses of inflammatory bowel disease (IBD) have been well studied but not well elucidated in the recent years. Accordingly, the pharmacological treatment of IBDs is focusing upon the individual pathologic step (targeting therapy). It has been shown recently that new drugs such as biological immunomodulating agents and anti-inflammatory cytokines have better short-term effects in some respects than the conventional drugs, and they might change the treatment strategy of IBDs in the near future. The aim of the present study was to examine the effects of thalidomide treatment in the development of experimental colitis. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). DNBS-treated mice experienced diarrhea and weight loss. At 4 days after administration of DNBS, the mucosa of the colon exhibited large areas of necrosis. The observed mucosa alteration was associated with the colon production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and vascular endothelial growth factor (VEGF). Neutrophil infiltration (determined by histology as well as an increase in myeloperoxidase activity in the mucosa) was associated with an upregulation of intercellular adhesion molecule-1. Immunohistochemistry for nitrotyrosine and poly (ADP ribose) showed an intense staining in the inflamed colon. When compared with DNBS-treated mice, thalidomide-treated (200 mg/kg orally) mice subjected to DNBS-induced colitis experienced a significantly lower rate in the extent and severity of the histological signs of colon injury. Thalidomide also caused a substantial reduction of the rise in myeloperoxidase activity (mucosa), in the increase in the tissue levels of TNF-alpha, IL-1beta, and VEGF, in the increase in staining (immunohistochemistry) for nitrotyrosine and for poly (ADP ribose), as well as in the upregulation of intercellular adhesion molecule-1 caused by DNBS in the colon. Thus, thalidomide treatment reduces the degree of colitis caused by DNBS. We propose that this evidence may help to clarify the therapeutic actions of thalidomide in patients with Crohn's disease.

Animals↗
PubMed2005

[Anti-tumor effect of thalidomide and paclitaxel on hepatocellular carcinoma in nude mice].

BACKGROUND: Thalidomide is reviving for its antiangiogenic effect on corneal neovascularization models. Recently, it has been employed in tumor research in several types of solid carcinomas. However, its effect on hepatocellular carcinoma (HCC) has not yet been clarified. METHODS: A total of 48 nude mice bearing human HCC with a high metastatic potential were randomly divided into 4 groups. Thalidomide (200 mg/kg), paclitaxel (13 mg/kg), or their combination, which was dissolved in 0.5% sodium carboxyl methyl cellulose (CMC) suspension, was intraperitoneally injected in each group since the second day of the establishment of animal model. The group simply administered with 0.5% CMC was set as placebo-control. The mice were sacrificed on the 30th day, for the measurement of tumor size, weight and metastasis in the lungs. The levels of CD34 and endothelial growth factor (VEGF) mRNA in tumor tissues were detected by immunohistochemistry and semiquantitative RT-PCR, respectively, and microvessel density (MVD) was evaluated. RESULTS: No statistical difference was found in tumor weight and volume between the thalidomide group and control (P>0.05). Paclitaxel showed a growth-inhibiting effect on tumors (P<0.05). The value of MVD and VEGF mRNA and metastases to the lungs in each group were lower than those in the placebo-control group (P<0.05); such difference in the combination group was statistically significant (P<0.05). CONCLUSIONS: Paclitaxel, but not thalidomide, has significant growth inhibitory effect on tumors, but both significantly inhibit angiogenesis and metastasis of human HCC in nude mice, such effects of paclitaxel can be amplified by thalidomide.

Animals↗
PubMed2006

Differentiating effect of thalidomide and FGM-CS combination on HL-60 acute promyelocytic leukemia cells.

AIM: To investigate whether granulocyte-macrophage colony-stimulating factor (GM-CSF) with or without thalidomide can induce apoptosis and differentiation of HL-60 acute promyelocytic leukemia cell line in vitro. METHODS: Effect of GM-CSF and thalidomide on proliferation of HL-60 cells was evaluated by MTT assay, cell cycle analysis was performed by propidium iodide staining approach and flow cytometry, and apoptosis rate was analyzed using FITC-conjugated annexin-V and FACScan flow cytometry. RESULTS: The study revealed that thalidomide alone at high concentrations inhibited HL-60 cell growth and induced apoptosis. Three days treatment of low-dose thalidomide in combination with GM-CSF induced marked terminal differentiation of HL-60 cells, as it was assessed by increased expression of differentiation antigens on cell surface. CONCLUSION: Treatment of HL-60 cells by low concentration of thalidomide combined with GM-CSF induced terminal differentiation of HL60 cells in vitro, which may be advantageous for the elaboration of novel therapeutic regimens in patients with differentiation-inducible leukemias.

Antigens, Differentiation↗
PubMed1989

The significance of genetic factors for thalidomide teratogenicity in the Norway rat.

Thalidomide teratogenicity was tested on a model based on the system of congenic strains of the laboratory rat, including the mutant allele lx, which determines the polydactyly-luxate syndrome. The phenotypic expression of the allele lx changes according to the genetic background of the carrier and also according to factors of the external environment. On a hybrid genetic background LEW/BN the allele lx acts as recessive, and heterozygotes +/lx are unaffected. In a number of experiments it was proved, however, that these hybrids (LEW/BN, +/lx) had an increased sensitivity to the induction of limb malformations (polydactyly, tibial hemimelia, oligodactyly) by various teratogens. Thalidomide was administered on the 12th day of pregnancy by the intraperitoneal route in a mixture of Tween 20 with saline (1:3) in doses of 25, 50 and 200 mg/kg to females with genetic background LEW that were purposely mated with males of the BN or BN.lx strains. The produced progeny had genotypes LEW/BN, +/+ or LEW/BN, +/lx. In offsprings that had in the genotype the mutant allele lx in a heterozygous condition (+/lx) preaxial polydactyly of hind limbs developed after all the thalidomide doses tested. This malformation occurred in 17 out of 18 litters, altogether in 97 out of 162 foetuses +/lx, i.e. in 59.9%. In the progeny without the mutant allele (genotype +/+) polydactyly did not develop in any of the 108 cases. Control foetuses +/+ the mothers of which had been administered only Tween 20 with saline remained unaffected, while in control foetuses +/lx polydactyly developed in 8.1% (3 cases). The result demonstrates thalidomide teratogenicity in the laboratory rat where it has not been proved unambiguously so far. The teratogenic effect is the outcome of the interaction of thalidomide with the mutant allele lx. At the same time there is emphasized the importance of the genotype of the experimental animals in the testing of teratogens.

Animals↗