Iodine-125-Chlorambucil as Possible Radio Anticancer for Diagnosis and Therapy of Cancer: Preparation and Tissue Distribution.

Chlorambucil (CLB) is an aromatic nitrogen mustard and an alkylating agent. It has been mainly used in the chemotherapy. A method for radiopharmaceutical preparation of [125I]- iodo-Chlorambucil a potential cancer therapeutic agent is described. The method is based on direct electrophilic radioiodination of Chlorambucil with [125I] in the presence of chloramine-T (CAT) as oxidizing agent. The reaction conditions were optimized in order to obtain a radiochemical yield higher than 98% of [125I]-iodo chlorambucil. Different chromatographic techniques (electrophoresis, and high pressure liquid chromatography (HPLC)) were used to evaluate the radiochemical yield and purity of the labeled product. Biodistribution studies of 125I- chlorambucil were carried out in both normal and tumor bearing Albino Swiss mice. The results revealed that this new tracer, 125I-chlorambucil, has a high affinity to be localized in the tumor site for a long period which indicates the specificity of this tracer to the tumor cells. The results indicate the possibility of using [125I]- iodo chlorambucil for imaging and treatment of cancer.

Chlorambucil and ascorbic acid-mediated anticancer activity and hematological toxicity in Dalton's ascites lymphoma-bearing mice.

Chlorambucil is an anticancer drug with alkylating and immunosuppressive activities. Considering various reports on the possible antioxidant/protective functions of ascorbic acid (vitamin C), it was aimed at to explore the modulatory effect of ascorbic acid on therapeutic efficacy and toxicity induced by chlorambucil. Dalton’s ascites lymphoma tumor serially maintained in Swiss albino mice were used for the present experiments. The result of antitumor activity showed that combination treatment with ascorbic acid and chlorambucil exhibited enhanced antitumor activity with 170% increase in life span (ILS), which is significantly higher as compared to chlorambucil alone (ILS 140%). Analysis of apoptosis in Dalton’s lymphoma tumor cells revealed a significantly higher apoptotic index after combination treatment as compared to chlorambucil alone. Blood hemoglobin content, erythrocytes and leukocytes counts were decreased after chlorambucil treatment, however, overall recovery in these hematological values was noted after combination treatment. Chlorambucil treatment also caused morphological abnormalities in red blood cells, majority of which include acanthocytes, burr and microcystis. Combination treatment of mice with ascorbic acid plus chlorambucil showed less histopathological changes in kidney as compared to chlorambucil treatment alone, thus, ascorbic acid is effective in reducing chlorambucil-induced renal toxicity in the hosts. Based on the results, for further devel­opment, hopefully into the clinical usage, the administration of ascorbic acid in combination with chlorambucil may be recommended.

Effects of hydroxychloroquine on the apoptosis of peripheral blood mononuclear cells and Th17 in systemic lupus erythematosus / 中华风湿病学杂志

Objective To observe the effect of Hydroxychloroquine (HCQ) on the apoptosis of peripheral blood mononuclear cells (PBMCs) of Systemic lupus erythematosus (SLE) patients and on the level of Th17 cells and IL-17.Methods The peripheral blood of 20 incipient SLE patients in active stage were taken,and PBMC were separated for cell culture.Using HCQ and Chlorambucil (CLB) as an intervention,and after cultured for 24 h and 48 h,the apoptosis of PBMC and the level of Th17 were tested using Flow cytometry (FCM),the supernatants were collected to test for the level of cytokine IL-17 by ELISA.One-way ANOVA was used and SNK-q was used in the comparison between every two groups.Results There was significant difference in the apoptosis rate of mononuclear cells between the HCQ and CLB group at 24 h [HCQ:(10.3±0.7)％,CLB:(8.5±1.1)％] and48 h [HCQ:(13.9±0.6)％,CLB:(11.8±0.8)％] (P＜0.05).There was significant difference between HCQ [24 h:(0.81±0.13)％,48 h:(0.73±0.45)％] and CLB group [24 h:(0.78±0.26)％,48 h:(0.68±0.20)％] in Th17 percentage (P＜0.05).The levels of IL-17 in the supematants of the HCQ group [24 h:(26.3±0.97)％,48 h:(24.2±0).91)％] and CLB group [24 h:(24.6±0.7)％,48 h:(22.6±1.1)％] were significandy different between the two groups(P＜0.05).Conclusion HCQ has apoptosis-induction effect on PBMC,and it can decrease the number of Th17 and IL-17 level in the PBMCs.

Chlorambucil and cyclosporine A in Brazilian patients with Behçet's disease uveitis: a retrospective study / Clorambucil e ciclosporina A em pacientes brasileiros com doença de Behçet e uveíte: estudo retrospectivo

PURPOSE: To assess the efficacy and side effects of immunosuppressive therapy in patients with Behçet's disease uveitis. METHODS: A nonrandomized retrospective case-series study analyzed data from 22 patients with Behçet's disease uveitis, from a single Uveitis Service, São Paulo, Brazil (period 1978-2007), under systemic chlorambucil and/or cyclosporine A, for at least 6 months with a minimum one-year follow-up. Drug efficacy was measured by reduction in relapse rate and reduction of prednisone dose. RESULTS: Patients (10M/12F) mean age was 29 (range 10-43) years-old at the onset of uveitis. The median duration of followup was 11 (range 1-29) years-old. Chlorambucil (2-6 mg/day) was used in 13 patients and cyclosporine A (3-5 mg/kg/day) in 9 patients at initiation. Drugs were switched because of no effectiveness or side-effects. Chlorambucil was effective in 78.5 percent (11/14) and induced disease remission in 43 percent (6/14) of patients, whereas cyclosporine A was effective in 57 percent (8/14) of patients. Chlorambucil and cyclosporine A were discontinued due to side effects in 21 percent (leucopenia) and in 57 percent of patients (nephrotoxicity, 36 percent and gastrointestinal complications, 21 percent), respectively. No case of late malignancy was observed. 36 percent (16/44) of eyes had final visual acuity <0.1, among which 69 percent (11/16) had already this visual acuity at the first visit. CONCLUSION: This study reiterates previous data that chlorambucil can induce long-term remission of Behçet's disease uveitis, whereas cyclosporine is effective but side effects limit its use. Chlorambucil therapy may still be a reasonable option in patients with intractable, sight-threatening Behçet's disease uveitis.

OBJETIVOS: Avaliar a eficácia e efeitos colaterais da terapia imunossupressora em pacientes com uveíte associada à doença de Behçet. MÉTODOS: Estudo retrospectivo não randomizado no qual são analisados dados de 22 pacientes com uveíte associada à doença de Behçet que utilizaram clorambucil e/ou ciclosporina A sistêmica por período mínimo de 6 meses, acompanhados pelo período mínimo de 1 ano, num único Serviço de Uveíte, São Paulo, Brasil (período 1978-2007). A eficácia do tratamento foi avaliada pela redução no número de recidivas da inflamação e pela redução na dose diária de prednisona. RESULTADOS: Vinte e dois pacientes (10 M/12 F), com idade média de 29 (variação 10-43) anos, apresentaram tempo mediano de acompanhamento de 11 (variação 1-29) anos. Clorambucil (2-6 mg/dia) foi utilizado em 13 pacientes e ciclosporina A (3-5 mg/kg/dia) em 9 pacientes como droga de primeira escolha. As drogas foram substituídas quando não eficazes ou não toleradas devido a efeitos colaterais. Clorambucil foi eficaz em 78,5 por cento (11/14) e induziu remissão da doença em 43 por cento (6/14) dos pacientes; ciclosporina foi eficaz em 57 por cento (8/14) dos pacientes. Clorambucil e ciclosporina A foram suspensos devido a efeitos colaterais em 21 por cento (leucopenia) e em 57 por cento (nefrotoxicidade, 36 por cento e complicações gastrointestinais, 21 por cento) dos pacientes, respectivamente. Nenhum caso de malignidade foi observado. 36 por cento (16/44) olhos tiveram acuidade visual final <0,1, sendo que 69 por cento (11/16) já apresentavam esta acuidade na primeira consulta. CONCLUSÃO: Este estudo reforça dados de literatura que o clorambucil induz remissão da doença de Behçet enquanto a ciclosporina A é efetiva, porém efeitos colaterais limitam o seu uso. A terapia com clorambucil pode ser uma opção a ser considerada em pacientes com uveíte refratária associada à doença de Behçet.

A Case of Dermatomyositis Treated with Chlorambucil Combination Therapy

We herein report a case of therapy-resistant dermatomyositis treated with oral prednisolone and chlorambucil combination therapy. Concurrently, she showed cervical carcinoma in situ(CIS). Initially, we started to treat her with combination oral prednisolone, intramuscular methotrexate, hydroxychloroquin, and removal of cervical CIS. However, our patient failed to respond to these regimens. Thus, we had have another combination treatment of oral prednisolone and chlorambucil. After the treatment of this combination regimen, her recalcitrant dermatomyositis improved dramatically without recurrence. There were no significant adverse side effects with chlorambucil therapy.

Therapeutic Effects of Cytotoxic agents (cyclophosphamide and chlorambucil), Cyclosporine and Levamisole in Children with Steroid-dependent Nephrotic Syndrome / 대한신장학회잡지

Prolonged administration of steroid in children with steroid-dependent nephrotic syndrome can cause serious complications including growth failure, and various alternative treatments have been used for these children to alleviate steroid-induced complications and to achieve long-lasting remission. Present study was undertaken to compare the therapeutic efficacy of cytotoxic agents (cyclophosphamide and chlorambucil), cyclosporine and levamisole in 88 children with steroid-dependent mininal-change nephrotic syndrome, who have been followed-up in Pediatric Department, Kyungpook National University Hospital from 1985 to 1995. Cyclophosphamide and chlorambucil were given for 8 weeks (cyclophosphamide in 36 and chlorambucil in 13 cases) or 12 weeks (cyclophosphamide in 34 and chlorambucil in 12 cases), and cyclosporine (3-5mg/kg/day) and levamisole (2-2.5mg/kg alternate day) were given for 6-12 months. And the results were as follows ; Results of cytotoxic therapy ; At the end of the 1st year, remission rate with 12 wks course of cyclophosphamide(53%) was better than with 12 wks course of chlorambucil(33%) or 8 wks course of either drugs. However, at the end of the 2nd year, no difference was noted in remission rate between 12 wk course of cyclophosphamide(19%) and chlorambucil(17%). Results of cyclosporine therapy ; Out of 44 cases, 28(64%) showed sustain-ed remission, 8(18%) relapse with decreased frequency and steroid-sparing effect, and 8 no therapeutic effects. During treatment period, BUN, creatinine and blood pressure were remained in normal ranges. Remission rates with cyclosporine alone therapy without steroid in cyclosporine-responsive children were 83%, 83%, 57% and 43% at 2, 4, 6 and 8 months, respectively. Results of levamisole therapy ; Out of 16 cases, 8 (50%) showed sustained remission, 5(31%) relapse with decreased frequency and steroid-sparing effect, and 3 no therapeutic effects. In one case, transient neutropenia was observed without serious sequelae. Remission rate with levamisole alone therapy without steroid in levamisole-responsive children were 88%, 85%, 67% and 44% at 2, 4, 6 and 8 months, respectively. In conclusion, present study indicates that 12 weeks course of cyclohospha-mide or chlorambucil seems to be the most effective therapy for inducing long-lasting remission in steroid-dependent nephrotic children. And long-term use of cyclosporine or levamisole can also be used quite effectively in achieving prolonged remission and steroid-sparing effects without serious side effects.