Norepinephrine-mediated inhibition of antitumor cytotoxic T lymphocyte generation involves a beta-adrenergic receptor mechanism and decreased TNF-alpha gene expression.
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We have previously shown that norepinephrine (NE) inhibits the in vitro generation of anti-MOPC-315 CTL activity by spleen cells from BALB/c mice rejecting a large MOPC-315 tumor as a consequence of low-dose melphalan (l -phenylalanine mustard (l -PAM)) treatment (l -PAM TuB spleen cells). Since TNF-alpha plays a key role in the generation of antitumor CTL activity in this system, we determined whether NE mediates this inhibition through inhibition of TNF-alpha production. Here, we show that NE inhibits the production of TNF-alpha protein and mRNA by l -PAM TuB spleen cells stimulated in vitro with mitomycin C-treated tumor cells. Flow cytometric analysis of intracellular expression of TNF-alpha revealed substantial NE-mediated decreases in the percentages of TNF-alpha+ cells among CD4+ and CD8+ T cells and F4/80+ activated macrophages. NE inhibition of CTL generation was largely overcome by addition of TNF-alpha to the stimulation cultures. When the beta-adrenergic antagonist propranolol was added to the stimulation cultures of l -PAM TuB spleen cells at a concentration that prevented NE-induced cAMP elevation, the NE-mediated decrease in TNF-alpha mRNA and NE-mediated inhibition of CTL generation were reversed. Collectively, these results suggest that NE inhibits antitumor CTL generation, at least in part, by inhibiting TNF-alpha synthesis through a mechanism(s) involving beta-adrenergic receptor signaling. (+info)
Prospective randomized trial of melphalan and prednisone versus vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of primary systemic amyloidosis.
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PURPOSE: Primary systemic amyloidosis is an immunoglobulin deposition disorder in which insoluble light chains cause organ dysfunction and death. The established conventional therapy is treatment with melphalan and prednisone. We investigated whether treatment with multiple alkylating agents improved the response rate or survival time, compared with melphalan and prednisone therapy. PATIENTS AND METHODS: We treated 101 patients with biopsy-proven primary amyloidosis. The patients were randomly assigned to receive melphalan and prednisone (52 patients) or vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (49 patients). Patients were stratified according to the presence of cardiac involvement, time from diagnosis to randomization, serum beta2-microglobulin level, and whether peripheral neuropathy was the major manifestation of the disease. RESULTS: The median duration of survival after randomization was 29 months, with no differences in survival time between the two groups. There were 29 patients who fulfilled the response criteria: 15 in the vincristine, carmustine, melphalan, cyclophosphamide, and prednisone arm and 14 in the melphalan and prednisone arm. CONCLUSION: Therapy with multiple alkylating agents did not result in a higher response rate or longer survival time, compared with standard melphalan and prednisone treatment in patients with primary systemic amyloidosis. (+info)
Improvement of amyloid-related symptoms after autologous stem cell transplantation in a patient with hepatomegaly, macroglossia and purpura.
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AL amyloidosis was diagnosed in a 56-year-old woman with spontaneous purpura, macroglossia and hepatomegaly, a serum IgGk monoclonal gammopathy and a 25% plasma cell bone marrow infiltration. She was started on high-dose treatment consisting of four monthly cycles of VID chemotherapy, then underwent a stem cell collection after priming with cyclophosphamide + G-CSF. Myeloablative therapy was with melphalan and busulfan. Hematologic recovery was fast and uncomplicated. At follow-up 22 months from ASCT, the patient shows a complete remission of the clonal plasma cell disorder, normalization of liver size and alkaline phosphatase level and a significant improvement in the signs of vascular and soft tissue amyloid infiltration. (+info)
High-dose therapy with autologous hematopoietic cell support as salvage treatment for patients with breast cancer who have relapsed after previous high-dose chemotherapy.
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Twenty-six patients with breast cancer who had relapsed after previously receiving high-dose chemotherapy and autologous hematopoietic cell support received a second course of high-dose cytoreductive therapy and autologous hematopoietic cell support as salvage therapy. Several different high-dose therapy regimens were employed for the second transplant, including a radiolabeled immunoconjugate. Two patients died of treatment-related complications. The remaining 24 patients relapsed a median of 126 (range 22-635) days after salvage transplant. All have since died. The median survival after salvage transplant was 362 (range 31-931) days. We conclude that second courses of high-dose therapy as salvage treatment are generally well-tolerated but their efficacy is modest. Alternative treatment strategies are needed for these patients. (+info)
Patients with multiple myeloma may safely undergo autologous transplantation despite ongoing RSV infection and no ribavirin therapy.
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Respiratory syncytial virus (RSV) has been reported as a cause of death among autologous peripheral blood stem cell (ASCT) and marrow recipients and recommendations for therapy with aerosolized ribavirin plus intravenous immunoglobulin (IVIG) made. This therapy is expensive, may be toxic, and causes a significant disruption of patient care. The purpose of this study was to evaluate the morbidity and mortality of RSV infections in patients with multiple myeloma undergoing ASCT without ribavirin therapy. During the months of February-April 1997, 10 consecutive patients (median age 57 years, seven males) with advanced and heavily pretreated myeloma underwent ASCT while having active RSV upper respiratory tract infection. After melphalan (200 mg/m2), all patients became neutropenic (<1000 cells/mm3) for a median of 7 days. Ribavirin was not given to any patient. No patient developed lower respiratory tract infection, required transfer to intensive care or died at a median follow-up of 8 months. One patient developed tracheobronchitis requiring oxygenation by nasal cannula. No delay in the treatment of the underlying myeloma was incurred. RSV infection may not necessarily be a contraindication for ASCT or an indication for therapy with aerosolized ribavirin. Additional studies are needed to confirm our preliminary findings. (+info)
High-dose BEAM chemotherapy with autologous haemopoietic stem cell transplantation for Hodgkin's disease is unlikely to be associated with a major increased risk of secondary MDS/AML.
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Hodgkin's disease is curable in the majority of patients, although a proportion of patients are resistant to or relapse after initial therapy. High-dose therapy with autologous stem cell support has become the standard salvage therapy for patients failing chemotherapy, but there have been reports of a high incidence of myelodysplasia/acute myeloid leukaemia (MDS/AML) following such treatment. Patients who receive such therapy form a selected group, however, who have already been subjected to other leukaemogenic factors, such as treatment with alkylating agents. In order to ascertain the true risk of MDS/AML, comparison must be made with other patients subjected to the same risks but not undergoing transplantation. We report a retrospective comparative study of 4576 patients with Hodgkin's disease from the BNLI and UCLH Hodgkin's databases, which includes 595 patients who have received a transplant. Statistical analysis including Cox's proportional hazards multivariate regression model with time-dependent covariates was employed. This analysis reveals that the risk of developing MDS/AML was dominated by three factors, namely quantity of prior therapy (relative risk [RR] 2.01, 95% confidence intervals [CI] 1.49-2.71, for each treatment block, P < 0.0001) and whether the patient had been exposed to MOPP (RR 3.61, 95% CI 1.64-7.95, P = 0.0009) or lomustine chemotherapy (RR 4.53, 95% CI 1.96-10.44, P = 0.001). Following adjustment for these factors in the multivariate model the relative risk associated with transplantation was 1.83 (95% CI 0.66-5.11, P = 0.25). This study provides no evidence of a significantly increased risk of MDS/AML associated with BEAM therapy and autologous transplantation in Hodgkin's disease. Concern over MDS/AML should not mitigate against the timely use of this treatment modality. (+info)
Salvage chemotherapy with mini-BEAM for relapsed or refractory Hodgkin's disease prior to autologous peripheral blood stem cell transplantation.
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BACKGROUND AND OBJECTIVE: High-dose chemotherapy and autologous bone marrow transplantation (ABMT) has become the standard approach for most patients with relapsed or refractory Hodgkin's disease. Disease status at transplant has been correlated with outcome following ABMT. In light of this, we employ mini-BEAM (BCNU, etoposide, cytarabine and melphalan) salvage therapy in order to achieve a state of minimal residual disease prior to transplantation. DESIGN AND METHODS: From February 1992 to June 1998 twenty-four patients receiving mini-BEAM therapy for resistance or relapse of their Hodgkin's disease were included. Four patients had obtained no response with initial chemotherapy (refractory), eight had obtained an incomplete response, seven were in first relapse and five in second or subsequent relapse. Fifteen patients received mini-BEAM as first salvage chemotherapy regimen. The remaining nine patients had previously been exposed to a median of one salvage regimen. Patients received a median of three cycles of mini-BEAM. RESULTS: Sixteen patients achieved complete remission and four partial remission, yielding an overall response rate of 83%. No significant differences in response were observed between patients who received mini-BEAM as initial salvage therapy and those who had received a prior salvage regimen. Eighteen out of the twenty responding patients went on to intensive therapy and peripheral blood stem cell transplantation. With a median follow-up of 52 months, the cumulative probability of 7-year overall survival is 71% for the responders and that of the 6-year disease-free survival is 42%. No treatment-related deaths were observed. INTERPRETATION AND CONCLUSIONS: Mini-BEAM is an effective salvage regimen with moderate toxicity that may be useful for cytoreduction prior to stem cell procedures. (+info)
The role of drug transport in resistance to nitrogen mustard and other alkylating agents in L518Y lymphoblsts.
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An investigation was undertaken of the mechanism of resistance to nitrogen mustard (HN2) and other alkylating agents, with particular emphasis on the interaction between cross-resistance and drug transport mechanisms in L5178Y lymphoblasts. Dose-survival curves demonstrated that the D0 for HN2-sensitive cells (L5178Y) treated with HN2 in vitro was 9.79 ng/ml and the D0 for HN2-resistant cells (L5178Y/HN2) was 181.11 ng/ml; thus, sensitive cells were 18.5-fold more responsive than were resistant cells and the difference was highly significant (p less than 0.001). A similar evaluation of 5 additional alkylating agents, including chlorambucil, melphalan, 1,3-bis(2-chloroethyl)-l-nitrosourea, Mitomycin C, and 2,3,5-tris(ethyleneimino)-1,4-benzoquinone, revealed that L5178Y/HN2 cells were also cross-resistant, in part, to each of these compounds. Furthermore, the degree of cross-resistance was remarkably similar; for each drug, dose-survival studies showed that HN2-resistant cells were approximately 2- to 3-fold more resistant to therapy than were sensitive cells. L5178Y/HN2 cells were also cross-resistant to cyclophosphamide in vivo; after treatment with cyclophosphamide, DBA/2 female mice that were given inoculations of L5178Y cells, but not those given transplants of L5178Y/HN2 cells, showed a significant prolongation of survival time (p less than 0.01). Transport of HN2, hydrolyzed derivative of HN2 and choline by L5178Y lymphoblasts in vitro was not competitively inhibited by any of the other alkylating agents, suggesting that transport of these compounds was by an independent mechanism. These findings suggest that the mechanism whereby L5178Y/HN2 cells are cross-resistant to other alkylating agents may involve nontransport factors and that these other drugs may bypass a major portion of HN2 resistance by using independent transport systems. (+info)