Negligible clinical effects of thalidomide in patients with myelofibrosis with myeloid metaplasia.

We conducted a nonrandomized prospective phase II study of thalidomide in anemic patients with myelofibrosis with myeloid metaplasia (MMM), with or without preceding polycythemia vera or essential thrombocythemia, with a primary aim to improve anemia. Thalidomide was given in escalating doses with a target dose of 800 mg daily, but the median dose of thalidomide that was actually tolerated was 400 mg daily. Fifteen patients were entered into the study and 14 were evaluable for response. Five of 14 (36%) patients discontinued thalidomide before 3 mo because of side effects, and none of these five patients had a response at the time when thalidomide was stopped. When evaluated after 3 mo of therapy, none of the remaining nine patients exhibited a discernible clinical response. Three patients showed progressive disease defined as > 50% increase in the need for red cell transfusions. Treatment was poorly tolerated, with all patients reporting side effects of thalidomide, the most prominent being fatigue documented in 80% of patients. Two patients died while on study, one from acute myelogenous leukemia and one from pneumonia. We conclude that thalidomide given in doses employed in the treatment of multiple myeloma gives no clinically relevant hematological effects in advanced MMM and is hampered by a very high incidence of side effects.

[Role of thalidomide in the treatment of multiple myeloma]. / A thalidomid szerepe a myeloma multiplex gyógykezelésében.

Multiple myeloma is a relatively common hematologic malignancy with no definitive treatment available. Although, therapy may include allogenic bone marrow transplantation, high-dose ablative chemotherapy followed by bone marrow or peripheral stem cell transplantation, melphalan/corticosteroid therapy, alpha-interferon treatment, and combined cytostatic chemotherapy, currently none of these alternatives offers cure for the disease. Thalidomide is an infamous molecule for its teratogenicity, yet it possesses potent immunomodulatory, anti-angiogeneic and, in higher concentrations, direct anti-myeloma-cell properties. At present, the drug is only approved for the treatment of erythema nodosum of leprosy, however, there are several preliminary results that show clinical efficacy in multiple myeloma. This drug has especially potent anti-myeloma effects in combinations with dexamethasone and certain cytostatic chemotherapeutic agents. The effects are evident both in polyresistant, and relapsing myeloma, a form with no accepted effective treatment options. In this paper, the fundamental molecular and cellular effects of thalidomide are summarized then the most important clinical studies with thalidomide are reviewed. It is the authors' hope that thalidomide will soon be a full member of the medical arsenal in the fight against multiple myeloma.

Reduction of clastogenic effect of clofazimine, an antileprosy drug, by vitamin A and vitamin C in bone marrow cells of mice.

Clofazimine (CLF), an antileprosy drug, has earlier been proved to be clastogenic in mice in vivo. It is an important constituent of the triple-drug regimen recommended by WHO for the treatment of leprosy. In this study the protective role of vitamins A and C (vit A and vit C) against the clastogenic effect of CLF in mouse bone marrow cells has been evaluated. Two doses (20 and 40 mg/kg) of vit C and two doses (2500 and 5000 IU/kg) of vit A were tested against a dose of 40 mg CLF/kg. The drug alone induced chromosomal aberrations of about 8 times the control value. Neither of the doses of vit C exhibited any clastogenic effect and, when administered simultaneously with CLF, both reduced the effect of CLF very significantly, the higher dose reducing chromosomal aberrations almost to the control value. Conversely, both doses of vit A, when administered alone, brought about significant increases in chromosome aberrations over the control value; the higher, but not the lower dose, given simultaneously with CLF, minimized the effect of CLF significantly but not as greatly as vit C. A scavenging effect of the vitamins, removing free radicals produced by CLF, is assumed to be responsible for modulation of the clastogenic effect of CLF.

Evaluation of genotoxicity of clofazimine, an antileprosy drug, in mice in vivo. III. Sister chromatid exchange analysis in bone marrow cells.

The potential genotoxicity of an antileprosy drug, clofazimine, was evaluated in mice in an in vivo model by sister chromatid exchange (SCE) analysis. Three different dose levels (4, 20 and 40 mg/kg) were tested, and the animals were treated once daily for 15 days. Sister chromatid differential staining was done by BrdU-tablet implantation and FPG technique. All the doses tested here elevated the SCE frequencies significantly and the increases showed a significant positive correlation with the doses. The results confirm our earlier findings based on metaphase analysis and micronucleus test in the same species.

Cytogenetic effect of dapsone, an antileprotic drug, in the mouse in vivo system.

Potential genotoxicity of dapsone was evaluated in mice following in vivo cytogenetic assays. Adult male mice treated with different doses (20 mg, 40 mg, or 80 mg/kg/day for 4 weeks) and for different periods (40 mg/kg/day for 2, 4, or 8 weeks) provided bone marrow and testes for mitotic and meiotic chromosome analyses, respectively. A dose-response (20 mg, 40 mg, or 80 mg/kg/day for 2 weeks) analysis was done with a separate set of mice using a micronucleus test (MNT). Untreated mice served as controls. Both the metaphase analysis and MNT in bone-marrow cells revealed significantly higher incidences of clastogenicity for all of the dose levels and treatment periods. Chromosome aberrations, with and without gaps, in bone-marrow metaphases showed a positive correlation with the doses, but not with the treatment periods. Correlation was also lacking in the MNT. In the meiotic cells, the incidences of chromosome aberrations increased significantly with the highest dose and with the longest period of treatment.