Oxidative stress and apoptosis: a new treatment paradigm in cancer.

Redox regulation has been shown to be an important component of malignant cell survival. Tipping the cellular redox balance through pharmacologic regulation in favor of increasing intracellular reactive oxygen species (ROS) and/or depleting protective reducing metabolites (such as glutathione and nicotinamide adenine dinucleotide phosphate) may lead to oxidative stress and resultant induction of apoptosis for the treatment of cancer. We review the biology and importance of ROS with regard to malignant and normal cells.

Long-term outcome of individuals with pure red cell aplasia and antierythropoietin antibodies in patients treated with recombinant epoetin: a follow-up report from the Research on Adverse Drug Events and Reports (RADAR) Project.

Since its introduction in 1988, recombinant human erythropoietin (epoetin) has been standard treatment for patients with anemia due to chronic kidney disease. From 1998 to 2004, nearly 200 epoetin-treated persons with chronic kidney disease developed antibodies to epoetin, resulting in pure red cell aplasia (PRCA). The majority of these patients received Eprex, an epoetin alfa product marketed exclusively outside the United States.

Use of total leukocyte and platelet counts to guide stem cell apheresis in healthy allogeneic donors treated with G-CSF.

Healthy stem cell donors start leukapheresis 4-5 days after starting G-CSF based on the peripheral blood CD34+ cell count (PBCD34). Data from 137 harvests (68 donors) were analyzed to determine correlation between pre-apheresis leukocytes (11.0-94.

Motexafin gadolinium induces oxidative stress and apoptosis in hematologic malignancies.

Redox mechanisms have been shown to be important in malignant cell survival and are a system that may be modified for the treatment of hematologic malignancies. Motexafin gadolinium (MGd) is a synthetic expanded porphyrin that selectively accumulates in tumor cells and oxidizes various intracellular metabolites, including ascorbate, nicotinamide adenine dinucleotide phosphate, glutathione, and protein thiols, to generate reactive oxygen species in a process known as futile redox cycling. The rationale for its use in hematologic malignancies is that, like naturally occurring porphyrins, it tends to concentrate selectively in cancer cells, and it has a novel mechanism of action of inducing redox stress and triggering apoptosis in a broad range of malignancies.

The Research on Adverse Drug Events and Reports (RADAR) project.

Context: In 1998, a multidisciplinary team of investigators initiated RADAR (Research on Adverse Drug events And Reports), a clinically based postmarketing surveillance program that systematically investigates and disseminates information describing serious and previously unrecognized adverse drug and device reactions (ADRs).

Objective: To describe the structure, operations, and preliminary findings from the RADAR project and related dissemination efforts by pharmaceutical suppliers and the US Food and Drug Administration (FDA).

Design: After identifying a serious and unexpected clinical event suitable for further investigation, RADAR collaborators postulated clinical hypotheses and derived case series and incidence estimates from physician queries, published and unpublished clinical trials, published case reports, FDA databases, and manufacturer sales figures.

Epoetin-induced pure red-cell aplasia (PRCA): preliminary results from the research on adverse drug events and reports (RADAR) group.

In 2002, investigators from France reported 13 patients in whom pure red cell aplasia developed during treatment with recombinant human erythropoietin (epoetin). We reviewed 208 cases of this syndrome reported worldwide. Adverse event reports describing suspected and confirmed cases of epoetin-associated PRCA in websites maintained by the manufacturers and distributors of epoetin products and other publicly available sources were reviewed.

Clinical characteristics of erythropoietin-associated pure red cell aplasia.

Recombinant human erythropoietin (epoetin) was first used for the treatment of anemia resulting from renal disease in 1986. During the first 10 years of its use, there were only three cases of epoetin-induced antibodies reported, which resulted in pure red cell aplasia (PRCA). Between 1998 and 2002, 191 chronic kidney disease patients developed PRCA during the course of epoetin treatment.

Motexafin gadolinium: a redox-active tumor selective agent for the treatment of cancer.

Purpose Of Review: Redox regulation has been shown to be an important component of malignant cell survival and is a system that may be pharmacologically manipulated for the treatment of cancer. Motexafin gadolinium is a member of a class of rationally designed porphyrin-like molecules called texaphyrins. The rationale for its use in cancer therapy is that, like naturally occurring porphyrins, it tends to concentrate selectively in cancer cells and it has a novel mechanism of action as it induces redox stress, triggering apoptosis in a broad range of cancers.

Can the stem cell mobilization technique influence CD34+ cell collection efficiency of leukapheresis procedures in patients with hematologic malignancies?

A total of 415 leukaphereses in 201 patients stimulated with growth factor (GF; n = 119) or chemotherapy-GF (n = 296) were studied to determine CD34+ cell collection efficiency (CE). The pre-apheresis leukocyte count was 1-93 x 10(9)/l (median 20), and peripheral blood CD34 count (PBCD34) was 1-1104/microl (median 19). The total number of CD34+ cells collected was 4-6531 x 10(6) (median 151); corresponding to 0.

High-intensity targeted screening for elevated blood lead levels among children in 2 inner-city Chicago communities.

Objectives: We assessed the prevalence of elevated blood lead levels (> or = 10 micrograms of lead per deciliter of blood), risk factors, and previous blood lead testing among children in 2 high-risk Chicago, Ill, communities.

Methods: Through high-intensity targeted screening, blood lead levels were tested and risks were assessed among a representative sample of children aged 1 to 5 years who were at risk for lead exposure.

Results: Of the 539 children who were tested, 27% had elevated blood lead levels, and 61% had never been tested previously.

Radioimmunotherapy in non-Hodgkin's lymphoma: trials of yttrium 90-labeled ibritumomab tiuxetan and beyond.

The treatment for non-Hodgkin's lymphoma (NHL) has improved over the past 20 years, but the natural history of the disease has not improved with conventional therapeutics. New modalities using targeted therapy based on molecular biology and immunology hold promise for better outcomes with less toxicity. Major radionuclides available (iodine I 131 and yttrium 90) are discussed and clinical trial data with the 90Y-labeled antibody ibritumomab tiuxetan are presented.

Pure red-cell aplasia and epoetin therapy.

Background: Between 1988 and 1998, antibody-associated pure red-cell aplasia was reported in three patients who had undergone treatment with recombinant human erythropoietin (epoetin). Between 1998 and 2000, 13 such cases were reported from France--12 in patients who had received the Eprex formulation of epoetin alfa and 1 in a patient who had received Neorecormon (a formulation of epoetin beta); both are products that are marketed outside the United States.

Methods: We obtained reports of epoetin-associated pure red-cell aplasia from the Food and Drug Administration and from the manufacturers of Eprex, Epogen (another formulation of epoetin alfa), and Neorecormon.

Motexafin gadolinium generates reactive oxygen species and induces apoptosis in sensitive and highly resistant multiple myeloma cells.

Motexafin gadolinium (MGd), an expanded porphyrin, is a tumor-selective redox-mediator that reacts with many intracellular reducing metabolites. Because redox mechanisms mediate apoptosis in multiple myeloma, we hypothesized that disruption of redox balance by MGd would result in cellular cytotoxicity in myeloma. We examined the effects of MGd on cellular cytotoxicity, apoptosis, reactive oxygen species (ROS) production, and intracellular drug uptake in dexamethasone-sensitive (C2E3), dexamethasone-resistant (1-310 and 1-414) chemotherapy-sensitive (8226-RPMI) and highly chemotherapy-resistant (DOX-10V) myeloma cells.

Rust and corrosion in hematopoietic stem cell transplantation: the problem of iron and oxidative stress.

Iron overload is a common acute and long-term event associated with autologous and allogeneic hematopoietic stem cell transplantation (HSCT). In a state of iron excess, free iron becomes available to catalyze the conversion of reactive oxygen species (ROS) intermediates such as superoxide anion (O2*-) and hydrogen peroxide (H2O2) to highly toxic free radicals such as hydroxyl radical (OH*). ROS may help to promote chronic liver disease, sinusoidal obstruction syndrome, idiopathic pneumonia syndrome and bacterial, fungal and other opportunistic infections.

The potential of arsenic trioxide in the treatment of malignant disease: past, present, and future.

Arsenic trioxide (As2O3) is an effective therapy for acute promyelocytic leukemia (APL), and there has been promising activity noted in other hematologic and solid tumors. The mechanism of action of As2O3 such as differentiation and apoptosis has prompted study into combination therapy. Furthermore, the connection of the sensitivity of diseases such as APL and multiple myeloma to oxidative damage has allowed the investigation of pharmacologic modulation of the cellular redox state for potentiation of As2O3.

Treatment of T-cell non-Hodgkin's lymphoma.

T-cell non-Hodgkin's lymphoma (NHL) represents approximately 10% to 15% of all lymphomas in Western countries. Patients with T-cell NHL are often treated similarly to patients with intermediate grade B-cell NHL, although many reports have demonstrated lower overall survival rates in patients with T-cell NHL compared to patients with B-cell NHL. Updated classifications have recognized specific clinical and pathologic T-cell entities, such as peripheral T-cell lymphoma, not otherwise characterized, angioimmunoblastic lymphoma, systemic anaplastic T-cell lymphoma, adult T-cell leukemia/lymphoma, subcutaneous panniculitis-like T-cell lymphoma, hepatosplenic T-cell lymphoma, extranodal natural killer (NK)/T-cell lymphoma nasal type, and enteropathy-type intestinal T-cell lymphoma.

Imexon-induced apoptosis in multiple myeloma tumor cells is caspase-8 dependent.

Purpose: Imexon is a 2-cyanoaziridine agent that has been shown to inhibit growth of chemotherapy-sensitive myeloma cells through apoptosis with decreased cellular stores of glutathione and increased reactive oxygen species (ROS). We examined the mechanism of imexon cytotoxicity in a diverse panel of dexamethasone and chemotherapy-sensitive and -resistant myeloma cell lines.

Experimental Design: We examined cellular cytotoxicity, apoptosis, and changes in redox state in dexamethasone-sensitive (C2E3), dexamethasone-resistant (1-310 and 1-414), chemotherapy-sensitive (RPMI-8226), and chemotherapy-resistant (DOX-1V and DOX-10V) myeloma cell lines.

Expression of the candidate MCT-1 oncogene in B- and T-cell lymphoid malignancies.

Our laboratory has recently discovered a novel candidate oncogene, MCT-1, amplified in human T-cell lymphoma and mapped to chromosome Xq22-24. This region is amplified in a subset of primary B-cell non-Hodgkin lymphoma (NHL), suggesting that increased copy number of a gene(s) located in this region confers a growth advantage to some primary human lymphomas. We examined a diverse panel of lymphoid malignancies for the expression of MCT-1.

Molecular etiology of mature T-cell non-Hodgkin's lymphomas.

T-cell non-Hodgkin's lymphomas (NHL) represent approximately 10-15% of all lymphomas diagnosed in Western countries. Significant progress has been made over the last 2 decades in defining non-random chromosomal abnormalities. Cytogenetic and molecular analyses have enhanced diagnostic capabilities as well as improved classification and prognostication for T-cell NHL.

TTP/HUS occurring in a simultaneous pancreas/kidney transplant recipient after clopidogrel treatment: evidence of a nonimmunological etiology.

Background: One recently reported thrombotic thrombocytopenia purpura/hemolytic uremic syndrome (TTP/HUS) case involved a patient who underwent simultaneous pancreas/kidney (SPK) transplant followed by pancreas rejection and clopidogrel treatment, an antiplatelet agent that has been associated with immunologically mediated TTP/HUS. We present a second case of TTP/HUS developing in an SPK recipient who was also receiving clopidogrel.

Methods: After a stroke, a 48-year-old male SPK transplant recipient received clopidogrel.

Burkitt's and Burkitt-like lymphoma.

Burkitt's and Burkitt-like lymphoma (BL/BLL) are aggressive B-cell malignancies with a high proliferative rate that may be fatal within months if not treated promptly. Furthermore, treatment of BL/BLL requires comprehensive supportive care to avoid disease-related complications such as acute renal failure secondary to tumor lysis syndrome. Improvements in our understanding of the biology of BL and BLL have led to more effective therapeutic protocols.

Intermittent Androgen Suppression as a Treatment for Prostate Cancer: A Review.

Prostate cancer continues as the most common malignancy in men in the United States, with a large number of patients presenting with advanced disease. The current treatment for metastatic prostate cancer, permanent androgen withdrawal, is palliative. Patients treated with permanent androgen withdrawal usually relapse and die secondary to prostate cancer's ability to progress to an androgen-independent state of growth.

Effect of aspartate and glutamate on the oxoglutarate carrier investigated in rat heart mitochondria and inverted submitochondrial vesicles.

Interaction of glutamate and aspartate with the oxoglutarate carrier was investigated in rat heart mitochondria or inverted submitochondrial particles. With mitochondria, glutamate and aspartate had no effect on the initial rate of oxoglutarate or malate uptake. With inverted submitochondrial vesicles, binding experiments indicated that aspartate bound to the oxoglutarate carrier on its matricial face and increased the affinity of the substrate binding site for malate but did not change the affinity for oxoglutarate.

Kinetic study of the aspartate/glutamate carrier in intact rat heart mitochondria and comparison with a reconstituted system.

The homologous exchange of external [14C] aspartate/internal aspartate catalyzed by the aspartate/glutamate carrier of rat heart mitochondria was investigated using aspartate-loaded, glutamate-depleted mitochondria. An inhibitor-stop technique was developed for kinetic studies by applying pyridoxal phosphate. Direct initial rate determinations from the linear phase of [14C] aspartate uptake were insufficiently accurate at high external and/or low internal substrate concentrations.