isotretinoin and Lymphoma--T-Cell--Cutaneous

In a pilot study the therapeutic effect and side effect profile of low-dose interferon alfa-2b in combination with a retinoid for the treatment of cutaneous T cell lymphoma were evaluated. Seven patients (four women, three men) with histologically confirmed cutaneous T cell lymphoma were included. Four patients had received therapy previously. The treatment schedule consisted of 2 million U of interferon alfa-2b administered subcutaneously three times per week and oral 13-cis-retinoic acid, 1 mg/kg/day, with subsequent dose reduction in case of response. The combination therapy produced two complete and two partial remissions. Responses were maintained by continuous therapy for up to 15 months even after dose reduction of both agents by 50%. Side effects were negligible and did not result in discontinuation of treatment in any patient.

Topics: Administration, Oral; Adult; Aged; Drug Therapy, Combination; Female; Humans; Injections, Subcutaneous; Interferon alpha-2; Interferon-alpha; Isotretinoin; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Pilot Projects; Recombinant Proteins; Skin Neoplasms

The treatment of Cutaneous T-cell lymphoma (CTCL) met huge challenges because of the heterogeneity and the scarcity of targeted drugs. ECPIRM derived from isotretinoin exhibited strong anti-proliferation effects in Hut78 and MJ cells rather than Myla cells. However, there was no data regarding the potential target of ECPIRM for its selective activity.. To investigate the potential target of ECPIRM for its selective anti-proliferation activity.. We evaluated the cell viability of CTCL cells after ECPIRM treatment, and detected the effects of ECPIRM on the biomarker genes of CTCL. Subsequently, the mRNA and protein level of Interleukin-2-inducible T-cell kinase (ITK) was determined. Then the induction of apoptosis triggered by ITK inhibitor BMS-509744 and ITK siRNAs were detected, and the docking of ECPIRM interacted with ITK and the effects of ECPIRM on ITK-mediated signaling pathway were analyzed. Finally, we evaluated the anti-growth activity of ECPIRM in Hut78-xenografted nude mice, and the relative expression of cleaved caspase-3, ITK, p-ERK and p-Akt were determined.. ITK was highly expressed in Hut78 and MJ cells rather than Myla cells, and targeted inhibition of ITK triggered cell apoptosis. ECPIRM efficiently bound the hydrophobic active pocket of ITK, and significantly inhibited ITK-mediated signaling pathway. In addition, ECPIRM suppressed tumor growth in Hut78-xenografted model, and upregulated the expression of cleaved caspase 3 and inhibited the expression of ITK, p-ERK and p-Akt in tumor tissues, which was consistent with in vitro study.. ECPIRM might provide a novel strategy for CTCL by inhibiting ITK-mediated signaling pathway.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Female; Humans; Isotretinoin; Lymphoma, T-Cell, Cutaneous; Mice; Protein-Tyrosine Kinases; Signal Transduction; Skin Neoplasms; Xenograft Model Antitumor Assays

Retinoids are important agents for the treatment of cutaneous T-cell lymphomas (CTCL). But side effects and drug resistance caused by activation of RAR/RXR limited their clinical application. Therefore, it is urgent to develop new agents to fight against CTCL. ECPIRM, a 13-cis retinoic acid derivative, was reported that it inhibited proliferation and induced apoptosis of SCL-1 cells.. The aim of this study was to evaluate the biological activities and mechanisms of ECPIEM.. The effect of ECPIRM on cell proliferation was determined by MTT assay and Trypan blue exclusion assay while FACS analysis was used to detect changes in cell cycle and apoptosis in HUT78 cells. The influence of ECPIRM on RAR/RXR and JAK/STAT signaling was evaluated by western blot analysis.. ECPIRM, better than other agents (all-trans retinoic acid,13-cis-retinoic acid or bexarotene), inhibited proliferation and induced apoptosis significantly in HUT78 cells, but with little cytotoxicity on normal lymphocytes. Then ECPIRM induced G0/G1 phase arrest by decreasing the expression of cyclinD1, cyclinE, CDK2 and CDK4 while increasing p21. Furthermore, the unaffected expression of RAR and RXR members suggested that ECPIRM acted independently of RAR/RXR pathway in HUT78 cells. But decreased phosphorylation of JAK1, STAT3, STAT5 and downregulated Bcl-xL, Cyclin D1 and c-Myc indicated that ECPIRM inhibited the activation of JAK/STAT signaling.. ECPIRM inhibited proliferation, induced apoptosis and G0/G1 phase arrest in HUT78 cells through inhibiting JAK/STAT pathway but not RAR/RXR pathway, which presented ECPIRM as a promising candidate for the treatment of CTCL patients.

Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Isotretinoin; Janus Kinase 1; Janus Kinase 3; Lymphoma, T-Cell, Cutaneous; Molecular Structure; Signal Transduction; Skin Neoplasms; STAT3 Transcription Factor; STAT5 Transcription Factor; Structure-Activity Relationship

There is no specific therapy for cutaneous epitheliotropic T-cell lymphoma (CETL). The administration of retinoids in conjunction with interferon-α (IFN-α) in CETL has not been reported in dogs.. Two dogs (Shih tzu and Miniature pinscher) presented with multiple nodular skin lesions. Histopathological examination revealed diffuse infiltrations of lymphocytes in the epidermis and dermis, with a CD3-positive immunophenotypic profile. Based on the clinical and histopathological examination, CETL was diagnosed. Both dogs were treated with isotretinoin in combination with IFN-α and showed clinical improvement with complete or partial remission. The disease in these dogs was well-controlled for more than 264 days of overall median survival time without any additional clinical signs after initiation of the treatment. In both the cases, the dogs were followed up for 27 months, and 10 months without any evidence of recurrence or metastasis, respectively.. We describe the clinical efficacy of isotretinoin combined with IFN-α in 2 dogs with CETL. Long-term management with isotretinoin combined with IFN-α was effective in treating CETL in these cases.

Topics: Animals; Antineoplastic Agents; Dog Diseases; Dogs; Female; Interferon-alpha; Isotretinoin; Lymphoma, T-Cell, Cutaneous; Male; Treatment Outcome

Although cutaneous T-cell lymphoma (CTCL), including mycosis fungoides (MF) and Sézary syndrome, is often responsive to treatment, few current therapies increase survival or consistently induce durable remissions, especially in advanced disease.. In an effort to improve treatment efficacy and outcome in CTCL, a combined modality protocol using 3 to 4 consecutive phases of therapy was initiated in 1987 at M.D. Anderson Cancer Center, Houston, Tex.. During a period of 15 years between 1987 and 2001, 95 patients with early-stage (Ia-IIa, n = 50) and late-stage (IIb-IVb, n = 45) MF were treated with subcutaneous interferon-alpha and oral isotretinoin, followed by total-skin electron beam therapy, and long-term maintenance therapy with topical nitrogen mustard and interferon-alpha. Patients with late-stage (IIb-IVb) disease also received 6 cycles of combination chemotherapy before electron beam therapy.. Combined modality therapy yielded a response rate of 85% with a 60% complete response rate. Among 38 patients with early-stage disease and 18 patients with late-stage disease achieving complete response, 9 (24%) patients with early-stage MF and 3 (17%) patients with late-stage MF achieved sustained remissions lasting more than 5 years. The median disease-free survival (DFS) for early and late stages of disease was 62 and 7 months, with 5-year Kaplan-Meier estimated rates of 50% and 27%, respectively. Current median overall survival times on combined modality are 145 months for patients with early-stage disease and 36 months for those with late-stage disease. Death was attributable to CTCL disease in 17 (55%) of 31 cases. The Kaplan-Meier estimates for 5-year survival are 94% for early-stage and 35% for late-stage disease. Univariate survival analysis in this patient population reveals statistically significant associations of clinical stage with overall response rates (P =.02), DFS (P =.03), and overall survival (P <.0001); age with DFS (P =.001) and overall survival (P =.04); and T stage (P <.0001) and lactate dehydrogenase (P =.007) with overall survival. By multivariate analysis using a Cox proportional hazards model, only age was significantly associated with DFS (hazard ratio 2.9), and only stage with overall survival (hazard ratio 18.2).. This nonrandomized and uncontrolled CTCL study gives supportive evidence that this multiphased combined modality regimen is well tolerated and may yield higher response rates and DFS than total-skin electron beam therapy alone, but provides no evidence for a change in survival.

Topics: Adult; Aged; Combined Modality Therapy; Drug Therapy, Combination; Female; Humans; Interferon-alpha; Isotretinoin; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Mycosis Fungoides; Neoplasm Staging; Prognosis; Proportional Hazards Models; Survival Analysis; Treatment Outcome

Topics: Acitretin; Antineoplastic Combined Chemotherapy Protocols; Calcitriol; Female; Humans; Isotretinoin; Lymphoma, T-Cell, Cutaneous; Mycosis Fungoides; Remission Induction; Skin Neoplasms

Topics: Aged; Calcitriol; Female; Humans; Isotretinoin; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Skin Neoplasms

The virus-associated T cell leukaemias/lymphomas are characterized by a poor prognosis primarily because of the rapid emergence of drug resistance which may lead to failure of subsequent chemotherapy. We report here a case of Epstein-Barr virus-associated T cell lymphoma which relapsed soon after chemotherapy and radiotherapy. The neoplastic cells of the relapsed tumour expressed high levels of multi-drug resistance gene (mdr1)-related P-glycoprotein and glutathione-S-transferase-pi, both of which were absent in the pre-chemotherapy tumour tissues. Empirical treatment with oral 13-cis-retinoic acid (RA) was then given with subsequent complete disappearance of the tumour. The therapeutic effect of RA appears to act through an apoptotic process. In accordance with our previous report of a successful salvage of a refractory Ki-1 large cell lymphoma. RA appears to be a potentially useful drug for some specific type T-cell lymphomas.

Topics: Aged; Apoptosis; Blotting, Southern; Drug Resistance, Multiple; Female; Herpesvirus 4, Human; Humans; Isotretinoin; Lymphoma, T-Cell, Cutaneous; Phenotype; Skin Neoplasms; Tumor Virus Infections