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PubMed1997

Peripheral blood progenitor cell collection during hematopoietic recovery following autologous blood progenitor cell transplantation.

BACKGROUND AND OBJECTIVES: Peripheral blood progenitor cells (PBPC) are increasingly used for autologous transplantation after high-dose radio/chemotherapy in patients suffering from cancer. PBPC are usually collected after mobilization with conventional-dose chemotherapy plus growth factor. However, it is conceivable to perform leukapheresis for the second autograft during recovery of hematopoiesis after the first course of HDCT/ABPCT. MATERIALS AND METHODS: We treated two patients this way. In the first, with germ cell cancer, six 12-liter leukaphereses yielded 1.8 x 10(6) CD34+ cells/kg after mobilization with cis-platinum, etoposide and ifosfamide (PEI) plus granulocyte colony-stimulating factor (G-CSF). The second patient, with relapsed Hodgkin's disease, underwent PBPC collection after treatment with dexamethasone, carmustine, etoposide, cytarabine and melphalan (DexaBEAM) plus G-CSF. Due to excellent mobilization, 8.5 x 10(6) CD34+ cells/kg were collected by one 12-liter leukapheresis. Both patients then underwent PBPC collection during hematopoietic recovery following HDCT and ABPCT. RESULTS: In patient 1, following HDCT and ABPCT, three 12-liter aphereses resulted in 0.7 x 10(6) CD34+ cells/kg. In patient 2, also after HDCT and ABPCT, a second autograft with 3.2 x 10(6) CD34+ cells/kg was harvested by a single 10-liter apheresis. No adverse effects were seen in either patient during apheresis following ABPCT. To our knowledge this is the first report dealing with PBCT collection during hematopoietic recovery following HDCT and ABPCT. CONCLUSIONS: (1) PBPC harvesting is feasible and well tolerated in this setting. (2) In appropriate patients with efficient PBPC mobilization after conventional-dose chemotherapy, a further PBPC autograft can be collected during recovery of hematopoiesis after ABPCT, serving as a rescue for a second course of HDCT.

Adult↗
PubMed2000

Thioredoxin reductase as a pathophysiological factor and drug target.

Human cytosolic thioredoxin reductase (TrxR), a homodimeric protein containing 1 selenocysteine and 1 FAD per subunit of 55 kDa, catalyses the NADPH-dependent reduction of thioredoxin disulfide and of numerous other oxidized cell constituents. As a general reducing enzyme with little substrate specificity, it also contributes to redox homeostasis and is involved in prevention, intervention and repair of damage caused by H2O2-based oxidative stress. Being a selenite-reducing enzyme as well as a selenol-containing enzyme, human TrxR plays a central role in selenium (patho)physiology. Both dietary selenium deficiency and selenium oversupplementation, a lifestyle phenomenon of our time, appear to interfere with the activity of TrxR. Selenocysteine 496 of human TrxR is a major target of the anti-rheumatic gold-containing drug auranofin, the formal Ki for the stoichiometric inhibition being 4 nM. The hypothesis that TrxR and extracellular thioredoxin play a pathophysiologic role in chronic diseases such as rheumatoid arthritis, Sjögren's syndrom, AIDS, and certain malignancies, is substantiated by biochemical, virological, and clinical evidence. Reduced thioredoxin acts as an autocrine growth factor in various tumour diseases, as a chemoattractant, and it synergises with interleukins 1 and 2. The effects of anti-tumour drugs such as carmustine and cisplatin can be explained in part by the inhibition of TrxR. Consistently, high levels of the enzyme can support drug resistance. TrxRs from different organisms such as Escherichia coli, Mycobacterium leprae, Plasmodium falciparum, Drosophila melanogaster, and man show a surprising diversity in their chemical mechanism of thioredoxin reduction. This is the basis for attempts to develop specific TrxR inhibitors as drugs against bacterial infections like leprosy and parasitic diseases like amebiasis and malaria.

Chronic Disease↗
PubMed1998

Effect of CD34+ peripheral blood progenitor cell dose on hematopoietic recovery.

The CD34+ cell surface antigen is expressed on progenitor cells required for blood stem cell transplantation. The number of cells expressing CD34+ can be used to assess the peripheral blood progenitor cell (PBPC) graft quality and predict hematopoietic recovery after engraftment. Because there is considerable variability among centers in the determination of CD34+ cell counts, standardizing flow cytometry methodology is essential. It is necessary to define a minimum safety threshold CD34+ cell dose for hematopoietic cell transplantation. This minimum dose would define a cell number in the graft, below which a proportion of patients would be expected to have delayed hematopoietic recovery or failure to engraft. We reviewed data from numerous studies. Although 1-2 x 10(6) CD34+ cells/kg can be considered an adequate graft, available data suggested that doses >5 x 10(6) CD34+ cells/kg were associated with more rapid engraftment and a lower probability of graft failure. The risk of delayed recovery was inversely related to CD34+ cell dose. Delayed recovery may result in greater transfusion requirements, longer hospitalization, increased antibiotic use and growth factor support, and higher health care costs. The extent of prior chemotherapy and radiation treatment are major risk factors for poor PBPC collection. To achieve an optimal CD34+ cell yield, PBPC collection should be initiated early during therapy. PBPC collection should be coordinated with the anticipated number of chemotherapy cycles, duration of chemotherapy, interval between chemotherapy and apheresis, need for radiotherapy, and exposure to the more progenitor cell-toxic drugs such as carmustine or busulfan.

Antigens, CD34↗
PubMed1998

A randomized trial of recombinant human interleukin-11 following autologous bone marrow transplantation with peripheral blood progenitor cell support in patients with breast cancer.

This study assessed the safety and efficacy of recombinant human interleukin (rhIL)-11 in decreasing platelet transfusion requirements in patients with breast cancer who were undergoing autologous bone marrow transplantation (ABMT) with peripheral blood progenitor cell (PBPC) support. After high-dose therapy with cyclophosphamide, cisplatin, and carmustine, 80 patients were randomized to one of three treatment groups: placebo (26), 25 microg/kg of rhIL-11 (28), and 50 microg/kg of rhIL-11 (26). Of those randomized, 75 (94%) received at least one dose of the masked study drug and the remaining 5 (6%) withdrew consent before study drug administration. In the placebo group, each patient received an average 12.4 (+/-10.2) platelet transfusions vs. 9.2 (+/-5.0) in the 25-microg/kg rhIL-11 group (p = 0.17) and 9.9 (+/-3.5) in the 50-microg/kg rhIL-11 group (p = 0.34). There was no statistically significant difference between the rhIL-11 groups and the placebo group in the median number of days to platelet recovery. Neutrophil and red blood cell recovery were similar for all treatment groups. The imbalance in the number of patients already alloimmunized at study entry in the rhIL-11 groups (12) and in the placebo group (1) may have confounded the primary efficacy assessment. Most adverse events were related to the high-dose chemotherapy. Generally mild edema and minor conjunctival bleeding (grades 1 or 2) were statistically associated with rhIL-11 administration (p < 0.04). There was no association between rhIL-11 and the occurrence of atrial arrhythmias, although there was a suggestion of an association with rhIL-11, 5 of 50 cases vs. 1 of 25 in the placebo group. Two cardiovascular events, tachycardia and hypotension (grade 1 or 2), occurred in the 50-microg/kg rhIL-11 group. The number of patients who discontinued study drug dosing because of an adverse event was distributed across all treatment groups. In summary, rhIL-11 was safe and well tolerated in this study. The results did not demonstrate that rhIL-11 treatment significantly decreased platelet transfusion requirements after high-dose chemotherapy with ABMT and PBPC support.

Adult↗
PubMed2001

High-dose therapy and autologous hematopoietic cell transplantation in children with primary refractory and relapsed Hodgkin's disease: atopy predicts idiopathic diffuse lung injury syndromes.

The use of high-dose therapy (HDT) and autologous hematopoietic cell transplantation (AHCT) for children and adolescents with primary refractory and relapsed Hodgkin's disease is increasing. The purpose of this retrospective analysis was to: (1) evaluate the outcome of HDT and AHCT in pediatric patients with Hodgkin's disease, and (2) identify factors that predispose patients to the development of transplantation-related complications. We describe the experiences of 34 pediatric patients from a single institution with primary refractory or relapsed Hodgkin's disease. HDT regimens consisted of cyclophosphamide and etoposide combined with either carmustine, chloroethylcyclohexylnitrosurea, or fractionated total body irradiation. Kaplan-Meier survival predicts that 67% (95% confidence interval [CI] 47%-87%) of patients will be alive and disease-free at 5 years. Nine patients had disease recurrence, of whom 5 relapsed after 1 year (1.5-6.3 years). Five patients succumbed to treatment-related toxicities, of whom 4 died of pulmonary failure. Fifteen patients (44%) developed post-AHCT idiopathic diffuse lung injury syndrome: acute alveolitis (n = 2); diffuse alveolar hemorrhage (n = 2); acute respiratory distress syndrome (n = 2); delayed interstitial pneumonitis (n = 8); and bronchiolitis obliterans (n = 1). The following factors did not predict for the development of a diffuse lung injury syndrome in univariate analysis: prior treatment with bleomycin, pre-HDT pulmonary function tests, and prior thoracic irradiation. Of the patients in our cohort, 44% had a history of atopy (allergic rhinitis and/or asthma). Multivariate logistic analysis revealed that a preexisting history of atopy was highly predictive of idiopathic pulmonary complications (P = .0001, odds ratio = 21, CI 3.6-125). Our experience shows that HDT followed by AHCT results in durable remissions in two thirds of pediatric patients with refractory and relapsed Hodgkin's disease, and a history of atopy is associated with post-AHCT pulmonary complications.

Adolescent↗
PubMed2001

Inhaled steroids as prophylaxis for delayed pulmonary toxicity syndrome in breast cancer patients undergoing high-dose chemotherapy and autologous stem cell transplantation.

PURPOSE: To evaluate the efficacy of inhaled fluticasone propionate (Flovent) as prophylaxis against delayed pulmonary toxicity syndrome (DPTS) and decline in pulmonary function in breast cancer patients undergoing high-dose chemotherapy with the conditioning regimen of cyclophosphamide, cisplatin, and carmustine (CPB) followed by autologous stem cell transplantation (ASCT). PATIENTS AND METHODS: Sixty-three consecutive patients with multinode-positive or metastatic breast cancer undergoing high-dose chemotherapy with CPB and ASCT who were treated at the Duke University Adult Bone Marrow Transplant Program. All patients were started on inhaled fluticasone propionate, 880 microg every 12 hours, for 12 weeks from the start date of their CPB conditioning regimen. Pulmonary function tests (PFTs) with a single-breath diffusing capacity of carbon monoxide (DLCO) were performed pre-ASCT as well as approximately 6 and 12 weeks post-ASCT. DPTS was defined as follows: (1) development of a nonproductive cough and dyspnea with or without fever, plus a fall in DLCO to less than 60% predicted; or (2) decline in DLCO to less than 50% predicted with or without symptoms. RESULTS: Pulmonary function tests were done on all patients pre-ASCT, on 56 of the 63 patients at a median of 44 days (range, 25 to 73 days) post-ASCT, and on 51 of the 63 patients at a median of 96 days (range, 50 to 190 days) post-ASCT. The PFTs showed an average of an 8% (+/-26%) and 21% (+/-22%) decline in DLCO. These declines compare favorably with our historical control group of 45 consecutive breast cancer patients undergoing ASCT with CPB as a conditioning regimen, who experienced average declines in DLCO of 29% (+/-18%) (P < .001) and 33% (+/-18%) (P < .001) at comparable time periods post-ASCT. Delayed pulmonary toxicity syndrome occurred in 35% of treated patients compared to 73% of the historical controls (P = .0003). No patients died of DPTS or pulmonary problems, and there were no fungal pneumonias. CONCLUSION: Inhaled fluticasone propionate may decrease the incidence of DPTS in patients treated with CPB as a conditioning regimen for ASCT, as well as help to preserve pulmonary function as measured by DLCO. These results are worthy of further study in a randomized clinical trial.

Administration, Inhalation↗
PubMed2001

Transplantation of highly purified CD34+Thy-1+ hematopoietic stem cells in patients with recurrent indolent non-Hodgkin's lymphoma.

PURPOSE: To evaluate the results of high-dose chemotherapy and transplantation of highly purified "mobilized" peripheral blood CD34+Thy-1+ hematopoietic stem cells (HSCs) in patients with recurrent indolent non-Hodgkin's lymphoma (NHL) or mantle cell lymphoma (MCL). PATIENTS AND METHODS: Twenty-six patients with recurrent indolent NHL or MCL were mobilized witheither granulocyte colony-stimulating factor (G-CSF) alone or cyclophosphamide plus G-CSF. Apheresis was performed, and the product was purified using the Isolex immunomagnetic positive CD34+ cell selection device initially and subsequent high-speed flow-cytometric cell sorting for the final purification of CD34+Thy-1+ HSCs. The patients received high-dose chemotherapy with BEAC (carmustine, etoposide, cytarabine, and cyclophosphamide) followed by transplantation with the purified HSCs in 2 dose cohorts (cohort 1: > or =5 x 10(5) viable and pure HSC/kg; cohort 2: > or =3 x 10(5) HSC/kg). RESULTS: We attempted to mobilize 26 patients with G-CSF alone. Six patients did not collect adequate cells with G-CSF alone; subsequent mobilization with cyclophosphamide plus G-CSF was attempted, but adequate CD34+Thy-1+ HSCs could not be collected on these 6 patients. Twenty patients underwent transplantation with the BEAC transplantation regimen followed by purified HSCs. Patients in cohort 1 engrafted at a median of day 12 to an absolute neutrophil count (ANC) >500/microL, a median of day 19 for platelet transfusion independence, and a median of day 20 for red blood cell transfusion independence. Patients in cohort 2 engrafted at a median of day 12 to an ANC >500/microL, a median of day 12 for platelet transfusion independence, and a median of day 12 for red blood cell transfusion independence. Fourteen of the 20 patients had significant infections reported at some point posttransplantation, including influenza, respiratory syncytial virus, pneumonitis, and Pneumocystis carinii pneumonia. With a median follow-up of 38 months, 8 of the 20 patients have had progressive lymphoma and 5 patients have died. The 3-year event-free survival is 55%, and overall survival is 78%. CONCLUSIONS: CD34+Thy-1+ HSCs can be collected successfully from most lymphoma patients mobilized with G-CSF alone. The engraftment and disease outcomes in the patients in this small pilot study using these cells do not appear to be different from the outcomes of similar patients cited in the literature. However, the short- and long-term risks of infection were a concern in this patient population.

Adult↗
PubMed2002

Effective purging of autologous hematopoietic stem cells using anti-B-cell monoclonal antibody-coated high-density microparticles prior to high-dose therapy for patients with non-Hodgkin's lymphoma.

Contamination of hematopoietic stem cells (HSCs) with tumor cells has been associated with increased incidence of relapse in patients with non-Hodgkin's lymphoma following autologous HSC transplantation. Effective purging of tumor cells may improve the results of HSC transplantation, but current methods of purging are technically difficult to perform with large numbers of cells and do not consistently remove all detectable cells. We report a pilot clinical trial in which 10 patients with relapsed B-cell non-Hodgkin's lymphoma received high-dose chemotherapy followed by infusion of autologous HSCs depleted of B-cells by high-density microparticles (HDM) coated with anti-CD19 and anti-CD20 monoclonal antibodies (BCell-HDM). HSCs were mobilized with cyclophosphamide and granulocyte colony-stimulating factor. In 6 of the 10 patients, B-cells were detectable by immunocytochemical analysis of the apheresis products prior to treatment. Following treatment with the BCell-HDM, no B-cells were detected in the products from 5 of these patients, a result representing a median depletion of >2.2 logs (range, >0.4 to >5.1 logs). The median recovery of nontarget cells postdepletion was 73% for CD34 cells and 78% for CD3+ cells. All patients received high-dose cyclophosphamide, BCNU (carmustine), and etoposide prior to reinfusion of their B-cell-depleted autologous HSCs. The median number of CD34+ cells cryopreserved was 3.6 x 10(6) cells/kg (range, 2.2-10.1 x 10(6) cells/kg). Engraftment was rapid in all cases, with a median time to achieve an absolute neutrophil count of 0.5 x 10(9)/L of 10 days (range, 8-11 days). The median time to achieve a platelet count of 20 x 10(9)/L unsupported by platelet transfusion was 11.5 days (range, 8-17 days). This nonmagnetic negative-depletion technology is simple, rapid, and effective in depleting target cells to undetectable levels, with excellent recovery of nontarget cells.

Adult↗
PubMed2002

Use of thrombopoietin in combination with chemotherapy and granulocyte colony-stimulating factor for peripheral blood progenitor cell mobilization.

This phase I/II dose-escalation study examined the safety and efficacy of recombinant human thrombopoietin (rhTPO) and granulocyte colony-stimulating factor (G-CSF) for postchemotherapy mobilization of peripheral blood progenitor cells (PBPCs) in patients with advanced breast cancer. Patients received cyclophosphamide, etoposide, and cisplatin (CVP) followed by G-CSF (6 microg/kg twice a day) and rhTPO (0.6, 1.2, 2.4, or 3.6 microg/kg as a single dose on day 5 or as 3 doses on days 5, 7, and 9 after chemotherapy). PBPCs were collected by daily leukapheresis when the postnadir white blood cell count reached > or = 2 x 10(9)/L; leukapheresis was continued until acquisition of a target dose of > or = 5 x 10(6) CD34+ cells/kg. Mobilized PBPCs were transplanted into patients after additional high-dose chemotherapy with cyclophosphamide, carmustine, and thiotepa (CBT). Comparisons were made with contemporaneously treated, nonrandomized, control patients who received the same chemotherapy regimens and G-CSF support but who did not receive rhTPO. Of 32 evaluable patients receiving rhTPO and G-CSF after CVP, 91% required only 1 leukapheresis to achieve a target PBPC graft; by contrast, only 69% of 36 of the control patients achieved the target graft with just 1 leukapheresis (P = .026). A median of 26.7 x 10(6) CD34 cells/kg per leukapheresis was obtained from the rhTPO-treated patients compared with 11.5 x 10(6) cells/kg per leukapheresis from the controls (P = .09). Higher rhTPO doses appeared to yield more CD34+ cells. When PBPCs were infused after high-dose CBT chemotherapy, the median times to return of an absolute neutrophil count of 0.5 x 10(9)/L and a platelet count of 20 x 10(9)/L were 15 and 16 days, respectively; these values did not differ from those in the control group (15 days for both neutrophil and platelets). No patient developed anti-TPO antibodies. These results indicate that rhTPO safely and effectively augments the number of PBPCs mobilized with chemotherapy and G-CSF and can reduce the required number of leukaphereses. Further studies are also warranted in patients who are likely to experience suboptimal PBPC mobilization when treated with currently available techniques.

Adult↗
PubMed2003

State-of-the-art treatment of high-grade brain tumors.

The incidence of primary brain tumors has rapidly increased in recent years. The current standard of care for patients with high-grade malignant glioma is resection followed by radiotherapy. However, the use of adjuvant chemotherapy and the standard of care at first relapse are still under debate for patients with glioblastoma multiforme and anaplastic astrocytoma. Meta-analyses have suggested that adjuvant chemotherapy, specifically with nitrosourea-based regimens, is associated with improved survival. However, no randomized, controlled trial has shown a clear advantage for adjuvant chemotherapy in these patients. Cumulative toxicity associated with both radiotherapy and chemotherapy, as well as resistance to nitrosourea-based regimens related to exposure in the adjuvant setting, prevent the use of radiotherapy and nitrosourea-based regimens at first relapse. The combination of procarbazine, carmustine, and vincristine (PCV) has shown activity at first relapse in patients who have not received adjuvant chemotherapy. Temozolomide (Temodar [US], Temodal [international]; Schering-Plough Corporation, Kenilworth, NJ) has shown activity at both first and second relapse in patients who have received prior nitrosourea-based regimens. The better safety profile of temozolomide suggests that it may be preferred to PCV for treatment of patients with recurrent high-grade malignant glioma. Additional randomized, controlled trials are needed to fully define the best option for first-line chemotherapy in both the adjuvant and recurrent settings in patients with high-grade malignant glioma.

Adult↗
PubMed2003

Arguments against the routine use of currently available adjuvant chemotherapy in high-grade gliomas.

The results of adjuvant chemotherapy in high-grade gliomas are disappointing. Carmustine (BCNU) wafers placed in the resection cavity provide a modest increase in median survival. However, the overall benefit of this approach is small, it offers no potential for cure, and the results are not statistically significant in patients with glioblastoma multiforme. During the past three decades, controlled clinical trials of systemically administered adjuvant chemotherapy have consistently failed to show significant benefit in patients with glioblastoma multiforme. Furthermore, as of 2003, no randomized studies convincingly document improved survival from adjuvant chemotherapy in anaplastic astrocytomas or anaplastic oligodendrogliomas, which are the most chemotherapy sensitive gliomas. These findings result from the limited efficacy of available chemotherapy in malignant gliomas and the current design of adjuvant brain tumor trials that allow accrual of patients with bulky residual disease. Until further information becomes available, it is reasonable to use radiation alone as adjuvant therapy and to reserve chemotherapy for the treatment of recurrences. This approach minimizes toxicities and ensures that chemotherapy is administered when its effect can be assessed using measurable disease. Improving outcome in high-grade gliomas requires an emphasis on discovering novel therapies and improving the design of adjuvant trials.

Antineoplastic Agents↗
PubMed2000

The effect of tamoxifen and cisplatin on the disease-free and overall survival of patients with high risk malignant melanoma.

The adjuvant treatment of high-risk malignant melanoma remains problematic. Previously we reported moderate success in the treatment of metastatic disease using tamoxifen, cisplatin, dacarbazine and carmustine. Based upon data that suggested tamoxifen and cisplatin were the active agents in this regimen, we initiated a phase II trial of this combination in the adjuvant setting. We treated 153 patients with 4 cycles of tamoxifen (160 mg day(-1), days 1-7) and cisplatin (100 mg m(-2), day 2) for 28-day intervals. Patients received an anti-nausea regimen of dexamethasone with ondansetron or granisetron. During the first 2 years of follow-up, patients were evaluated every 2 months with a history, physical exam, laboratory work and computed tomography scans of the chest, abdomen and pelvis every 4 months. Thereafter, patients were evaluated every 3 months and radiographic studies were performed if necessary. Currently, with a median follow-up of 36 months, the disease-free survival (DFS) is 68.4% and overall survival (OS) is 84.5%. Kaplan-Meier analysis predicts a 5-year DFS of 62% with an OS of 79%. Relapses after 20 months have been rare. No effect of gender or number of positive lymph nodes was noted, however, stage of disease prior treatment was a factor. The major toxicity proved to be gastrointestinal in nature with nausea the most prevalent symptom. Minimal renal, haematologic and neurologic toxicity occurred. These preliminary results suggest that there is a positive impact of tamoxifen and cisplatin on both the DFS and OS of high-risk malignant melanoma patients. The 5-year projected DFS and OS compare favourably with those reported for the ECOG 1684 trial and warrant confirmation in a prospective randomized trial.

Adult↗
PubMed2001

Nitric oxide and free stable nitroxyl radicals in the mechanism of biological action of the spin-labeled compounds.

A comparison of more important physical, chemical and biological properties of the nitric oxide (NO) and free stable nitroxyl radicals (nitroxides) on the base of their structural similarity is made in the article. The active moiety in the nitroxide molecule represents a sterically hindered nitric oxide. The mechanisms of biological action of the nitroxides and especially of their derivatives with antitumor agents from the groups of nitrogen mustards, nitrosoureas, aziridines and triazenes (spin-labeled compounds) is explained through the biological activities of sterically hindered NO. Similarly to NO, nitroxides also can react with superoxide anion radical (O(2)(-)), they possess superoxide dismutase (SOD) mimetic action. While the interaction of NO with O(2)(-)yields very toxic peroxynitrite (ONOO(-)), its formation is strongly limited in the presence of a nitroxide. It is known that the nitrosourea antitumor drugs, like lomustine (CCNU) and carmustine (BCNU), showed high general toxicity, one of the reasons for that probability is the formation of NO, and subsequently of ONOO(-), during their metabolism. The biological investigations of the nitroxides showed their considerably lower general toxicity that could be explained with the SOD-mimetic action of the nitroxide present in their molecule.

Antineoplastic Agents↗
PubMed1997

The mechanism of thioredoxin reductase from human placenta is similar to the mechanisms of lipoamide dehydrogenase and glutathione reductase and is distinct from the mechanism of thioredoxin reductase from Escherichia coli.

Thioredoxin reductase, lipoamide dehydrogenase, and glutathione reductase are members of the pyridine nucleotide-disulfide oxidoreductase family of dimeric flavoenzymes. The mechanisms and structures of lipoamide dehydrogenase and glutathione reductase are alike irrespective of the source (subunit M(r) approximately 55,000). Although the mechanism and structure of thioredoxin reductase from Escherichia coli are distinct (M(r) approximately 35,000), this enzyme must be placed in the same family because there are significant amino acid sequence similarities with the other two enzymes, the presence of a redox-active disulfide, and the substrate specificities. Thioredoxin reductase from higher eukaryotes on the other hand has a M(r) of approximately 55,000 [Luthman, M. & Holmgren, A. (1982) Biochemistry 21, 6628-6633; Gasdaska, P. Y., Gasdaska, J. R., Cochran, S. & Powis, G. (1995) FEBS Lett 373, 5-9; Gladyshev, V. N., Jeang, K. T. & Stadtman, T.C. (1996) Proc. Natl. Acad. Sci. USA 93, 6146-6151]. Thus, the evolution of this family is highly unusual. The mechanism of thioredoxin reductase from higher eukaryotes is not known. As reported here, thioredoxin reductase from human placenta reacts with only a single molecule of NADPH, which leads to a stable intermediate similar to that observed in titrations of lipoamide dehydrogenase or glutathione reductase. Titration of thioredoxin reductase from human placenta with dithionite takes place in two spectral phases: formation of a thiolate-flavin charge transfer complex followed by reduction of the flavin, just as with lipoamide dehydrogenase or glutathione reductase. The first phase requires more than one equivalent of dithionite. This suggests that the penultimate selenocysteine [Tamura, T. & Stadtman, T.C. (1996) Proc. Natl. Acad. Sci. USA 93, 1006-1011] is in redox communication with the active site disulfide/dithiol. Nitrosoureas of the carmustine type inhibit only the NADPH reduced form of human thioredoxin reductase. These compounds are widely used as cytostatic agents, so this enzyme should be studied as a target in cancer chemotherapy. In conclusion, three lines of evidence indicate that the mechanism of human thioredoxin reductase is like the mechanisms of lipoamide dehydrogenase and glutathione reductase and differs fundamentally from the mechanism of E. coli thioredoxin reductase.

Dihydrolipoamide Dehydrogenase↗
PubMed2003

Treatment of relapsing refractory diffuse large cell lymphoma after matched unrelated donor bone marrow transplant with immunosuppression withdrawal and rituximab.

A 31-year-old man with a diffuse large-cell lymphoma in first refractory relapse received a bone marrow transplant (BMT) from a matched unrelated donor using CAMPATH-1H, carmustine, etoposide, cytarabine and melphalan as conditioning regimen, and methotrexate and tacrolimus for graft-versus-host disease (GVHD) prophylaxis. The transplant was complicated by grade II skin acute GVHD. Lymphoma relapse occurred 4 months post-transplant. Immunosuppression withdrawal plus rituximab induced a complete response. He remains in complete remission (CR) 11 months post-immunosuppression withdrawal and 15 months post-transplant.

Adult↗
PubMed2000

High CD34 cell doses do not worsen regimen-related toxicity or early mortality after autologous blood stem cell transplantation for breast cancer.

BACKGROUND: Some transplant-related complications, such as the engraftment syndrome, are thought to be mediated by cytokines released during expansion of hematopoietic progenitors at the time of neutrophil recovery. Since there is an inverse correlation between CD34(+) cell dose and time to neutrophil recovery, we sought to determine if peritransplant toxicity and early mortality were adversely affected by high CD34(+) cell doses. METHODS: The study group included 186 women with breast cancer who received high-dose cyclophosphamide, carmustine, thiotepa and an autologous PBSC transplant. The median CD34(+) cell dose was 5.9 x 10(6)/kg (1.0-154.7 x 10(6)/kg). Patients were categorized by CD34(+) cell dose (1.0-3.5, 3.6-5.9, 6.0-19.9, and 20.0-154.7 x 10(6)/kg) for assessment of outcomes. RESULTS: Grades 2-4 mucositis occurred in 49%, cardiac toxicity in 7%, pulmonary toxicity in 5%, cystitis in 4%, diarrhea in 3%, renal toxicity in 1%, and central nervous system toxicity in 1%. A Grade 2-4 regimen-related toxicity occurred in 109 patients (59%) and Grade 3-4 in eight patients (4%). Overall survival was 100% at Day 30, 96% at Day 90, and 89% at 1 year. Treatment-related mortality was 3.8%. In multivariate analyses that included prior chemotherapy, disease status, visceral metastases, prior chest radiation and age, CD34(+) cell dose group was not an independent risk factor for Grade 2-4 mucositis, Grade 2-4 maximum toxicity, Grade > or =3 cumulative toxicity, 90 day survival or 1 year survival. DISCUSSION: We conclude that CD34(+) cell doses >20 x 10(6)/kg do not affect transplant outcome in a negative or positive fashion.

Adult↗
PubMed1999

Permeability of nitrile rubber, latex, polyurethane, and neoprene gloves to 18 antineoplastic drugs.

The permeability of four glove materials to various antineoplastic drugs was studied. Eighteen antineoplastic drugs posing potential health hazards to handlers were prepared at the highest concentrations normally encountered by hospital personnel. Four glove materials-nitrile rubber, latex, polyurethane, and neoprene-were exposed to the drugs for 30, 60, 90, and 120 minutes. Glove thickness was measured with an electronic digital caliper. Random samples of material were selected from the glove fingertips, and triplicate samples were tested for each drug at each interval. For a majority of the drugs, a bacterial mutagenicity assay was used to measure the amount of drug (if any) that permeated the material. High-performance liquid chromatography was used for drugs not tested with the bacterial assay. The nitrile gloves were the thinnest (0.12 mm), and the latex gloves were the thickest (0.18 mm). The four materials were generally impermeable to each drug. One sample of the nitrile gloves appeared to have a defect, allowing >5% of the drug solution to pass through at 30 minutes. One sample each of the latex, polyurethane, and neoprene gloves demonstrated minimal permeability (< or =1%): One latex glove sample was permeated by carmustine, and paclitaxel permeated one sample each of the polyurethane and neoprene materials. Nitrile rubber, latex, polyurethane, and neoprene gloves were impermeable to 18 antineoplastic drugs in most, but not all, cases.

Antineoplastic Agents↗
PubMed2003

Permeation of cytotoxic formulations through swatches from selected medical gloves.

The permeability of selected medical glove materials to various cytotoxic agents is described. Fifteen cytotoxic agents were prepared at the highest concentrations normally encountered by hospital personnel. Four single-layer and two double-layer glove systems made of two materials--latex and neoprene--were exposed to the drugs for 30, 60, 90, 120, 150, and 180 minutes. Circular sections of the glove material were cut from the cuff and evaluated without any pretreatment. Permeability tests were conducted in an apparatus consisting of a donor chamber containing the cytotoxic solution and a collection chamber filled with water (the acceptor medium). The two sections were separated by the glove material. Permeating portions, collected in water as the acceptor medium, were analyzed by either ultraviolet-visible light spectrophotometry or high-performance liquid chromatography (HPLC). Permeation rates were calculated on the basis of the concentration of the cytotoxic agent in the acceptor medium. Spectrophotometric measurements were taken every 30 minutes, and HPLC analysis was performed at the end of the three-hour period. Average permeation rates for 14 drugs were low (< 0.2 nmol/[min.cm2]) or no permeation was detected in all glove materials. All glove materials tested were impermeable to most of the cytotoxic agents over a period of three hours. Carmustine was the only agent that substantially permeated single-layer latex glove materials. Permeation of most tested cytotoxic formulations was low through swatches of material from various medical gloves.

Carcinogens↗