Biomedical subjects

Joseph M Tuscano

Publications and source records attributed to Joseph M Tuscano.

9 recordsLinked to original sources

PubMed2005

High-dose radioimmunotherapy combined with fixed, low-dose paclitaxel in metastatic prostate and breast cancer by using a MUC-1 monoclonal antibody, m170, linked to indium-111/yttrium-90 via a cathepsin cleavable linker with cyclosporine to prevent human anti-mouse antibody.

PURPOSE: Although radioimmunotherapy alone is effective in lymphoma, its application to solid tumors will likely require a combined modality approach. In these phase I studies, paclitaxel was combined with radioimmunotherapy in patients with metastatic hormone-refractory prostate cancer or advanced breast cancer. EXPERIMENTAL DESIGN: Patients were imaged with indium-111 (111In)-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-peptide-m170. One week later, yttrium-90 (90Y)-m170 was infused (12 mCi/m2 for prostate cancer and 22 mCi/m2 for breast cancer). Initial cohorts received radioimmunotherapy alone. Subsequent cohorts received radioimmunotherapy followed 48 hours later by paclitaxel (75 mg/m2). Cyclosporine was given to prevent development of human anti-mouse antibody. RESULTS: Bone and soft tissue metastases were targeted by 111In-m170 in 15 of the 16 patients imaged. Three prostate cancer patients treated with radioimmunotherapy alone had no grade 3 or 4 toxicity. With radioimmunotherapy and paclitaxel, two of three prostate cancer patients developed transient grade 4 neutropenia. Four breast cancer patients treated with radioimmunotherapy alone had grade 3 or 4 myelosuppression. With radioimmunotherapy and paclitaxel, both breast cancer patients developed grade 4 neutropenia. Three breast cancer patients required infusion of previously harvested peripheral blood stem cells because of neutropenic fever or bleeding. One patient in this trial developed human anti-mouse antibody in contrast to 12 of 17 patients in a prior trial using m170-radioimmunotherapy without cyclosporine. CONCLUSIONS: 111In/90Y-m170 targets prostate and breast cancer and can be combined with paclitaxel with toxicity limited to marrow suppression at the dose levels above. The maximum tolerated dose of radioimmunotherapy and fixed-dose paclitaxel with peripheral blood stem cell support has not been reached. Cyclosporine is effective in preventing human anti-mouse antibody, suggesting the feasibility of multidose, "fractionated" therapy that could enhance clinical response.

Adult↗

PubMed2005

B cell reductive therapy in the treatment of autoimmune diseases: a focus on monoclonal antibody treatment of rheumatoid arthritis.

The therapeutic approach to patients with autoimmune disorders is in the midst of a dramatic change. Monoclonal antibody technology has allowed us to dissect and now manipulate the human immune system with greater precision. It is now widely recognized that B lymphocytes play a role in the pathogenesis of many autoimmune diseases, though the extent and contribution is a matter of debate and active investigation. There is emerging data to suggest that both antibody-dependent and independent mechanisms contribute to disease pathogenesis. However, given the heterogeneous nature of autoimmune diseases, and the varied responses to B lymphocyte reduction, the role of B lymphocytes is likely disease-specific. The two clinical trials discussed in this review demonstrate remarkable consistency in the ability of B cell reduction to ameliorate the clinical manifestations of rheumatoid arthritis with minimal toxicity. B lymphocyte targeted approaches to autoimmune disease in general, and RA specifically, will not only provide an effective and potentially less toxic alternative treatment option, but also allow for a better understanding of the pathogenesis of these complex and morbid diseases.

Antibodies, Monoclonal↗

PubMed2005

Safety and efficacy of rituximab in patients with rheumatoid arthritis refractory to disease modifying antirheumatic drugs and anti-tumor necrosis factor-alpha treatment.

OBJECTIVE: To determine the safety and efficacy of rituximab treatment in patients with active seropositive rheumatoid arthritis (RA) who had experienced an inadequate response to treatment with anti-tumor necrosis factor-alpha agents and/or traditional disease modifying antirheumatic drugs. METHODS: Rituximab was administered to 17 patients as weekly infusions for 4 consecutive weeks. Patients continued their baseline therapy and were followed for 28 weeks. RESULTS: All patients were evaluable for safety, and 13 for efficacy. Profound B cell depletion occurred by 12 weeks and was sustained at 24 weeks, whereas T cell, complement, and immunoglobulin levels remained within normal ranges. Rituximab was well tolerated, with no infusion related reactions and only mild/moderate adverse events. American College of Rheumatology 20% response (ACR20) was achieved in 55% of patients by Week 5, 75% by Week 8, 50% at Week 16, and 67% at Week 28. Corresponding ACR50 and ACR70 responses were achieved in 36% and 18%, 25% and 17%, 42% and 25%, and 33% and 17% of patients at Weeks 5, 8, 16, and 28, respectively. There were significant improvements over baseline in tender and swollen joint counts (p < 0.0001), physician's global assessment of disease activity (p = 0.0001), and patient assessed pain (p = 0.0005) and disability (p = 0.0386). Erythrocyte sedimentation rate (p = 0.0361) and rheumatoid factor titers (p < 0.0001) also decreased significantly. CONCLUSION: These results support the hypothesis that B cells play an important role in RA pathophysiology, and suggest that rituximab is effective and well tolerated, with a rapid onset of clinical benefit, in patients with refractory, seropositive active RA.

Aged↗

PubMed2004

Increased cyclooxygenase-2 (COX-2): a potential role in the pathogenesis of lymphoma.

B cell lymphomas are a diverse group of clinicopathologic diseases with an increasing incidence. As with other malignancies, the accumulation of genetic abnormalities are required for malignant transformation of human lymphocytes. Cyclooxygenase-2 (COX-2) is a key biosynthetic enzyme in prostaglandin synthesis and has been implicated in the pathogenesis of numerous malignancies including colon, breast, and lung cancer. There is little data on the potential role of COX-2 in lymphoma pathogenesis. In this study, several B lymphoma cell lines and primary B cells obtained from normal volunteer controls were examined for COX-2 protein expression. Immunoblot analysis demonstrated between an approximately 2.2-4.3-fold increase in COX-2 protein expression relative to primary B cells in all lymphoma cell lines examined. Increased COX-2 phosphorylation was found in the BJAB, BL41, and Raji cells whereas the levels in Daudi, Namalwa, and Ramos did not differ from that of primary B cells. Treatment with 25-100 microM celecoxib (CEL) resulted in decreased proliferation as measured by [3H]thymidine in all cell lines examined, and the effect was dose-dependent, and not significantly enhanced by chlorambucil (CHL). The effect of COX-2 inhibition on apoptosis in lymphoma cells was examined and revealed apoptotic induction of greater than 85% in all cell lines examined at 50 microM celecoxib. The pro-apoptotic effect was dose-dependent, and was not significantly enhanced by chlorambucil. Examination of apoptosis-related proteins by immunoblot analysis revealed levels of BCL-2, BCL-X(L), and Bax to be unaffected by celecoxib. In contrast, levels of Akt, MCL-1, and phosphorylated SAP-kinase were all decreased after incubation with 50 microM celecoxib. These findings suggest that increased COX-2 expression and activity, contributes to the pathogenesis of B cell lymphomas and point to a possible role for COX-2 inhibition in their treatment.

Apoptosis↗

PubMed2003

Anti-CD22 ligand-blocking antibody HB22.7 has independent lymphomacidal properties and augments the efficacy of 90Y-DOTA-peptide-Lym-1 in lymphoma xenografts.

CD22 is a membrane glycophosphoprotein found on nearly all healthy B-lymphocytes and most B-cell lymphomas. Recent in vitro studies have identified several anti-CD22 monoclonal antibodies (mAbs) that block the interaction of CD22 with its ligand. One of these mAbs, HB22.7, has been shown to effectively induce apoptosis in several B-cell lymphoma cell lines. Lymphoma xenograft studies with Raji-xenograft mice were used to assess the toxicity and efficacy of HB22.7 alone and with combined modality immunotherapy (CMIT) with yttrium (90)Y-DOTA-peptide-Lym-1 radioimmunotherapy (RIT). The effect of the sequence of these agents on the combined treatment was assessed by administering HB22.7 24 hours before, simultaneously with, or 24 hours after RIT. Within the groups treated with RIT alone or with RIT and HB22.7 (CMIT), the reduction in tumor volume was the greatest when HB22.7 was administered simultaneously with and 24 hours after RIT, and in the RIT treatment groups, this translated into the greatest overall response and survival, respectively. Overall survival rates at the end of the 84-day CMIT trial were 67% and 50% in the groups treated with HB22.7 simultaneously and 24 hours after RIT, respectively. This compared favorably with the untreated and the RIT alone groups, which had survival rates of 38% and 43% at the end of the trial. Surprisingly, when compared with untreated controls and all other treatment groups, the greatest cure and overall survival rates were observed in the group treated with HB22.7 alone, with 47% cured and 76% surviving at the end of the 84-day trial. RIT clearance was not affected by treatment with HB22.7. When compared with RIT alone, there was no significant additional hematologic (white blood cell, red blood cell, or platelet count) toxicity when HB22.7 was added to RIT. Nonhematologic toxicity (assessed as change in body weight) was also unchanged when HB22.7 was added to RIT. Thus the anti-CD22 ligand-blocking antibody HB22.7 has independent lymphomacidal properties and augments the efficacy of (90)Y-DOTA-peptide-Lym-1 in lymphoma xenografts without significant toxicity.

Animals↗

PubMed2003

B lymphocytes contribute to autoimmune disease pathogenesis: current trends and clinical implications.

Abnormal B lymphocytes influence the pathogenesis of many autoimmune diseases, in addition to serving as the origin of pathogenic autoantibodies. Although aberrant B cell function and autoimmunity have complex polygenic origins, recent studies in mouse models of autoimmune diseases have revealed overlapping defects in signal transduction pathways that alter B cell survival or activation, and lead to an autoimmune phenotype. Discovery of these important signaling pathways in mice has lead to an intense search for B cell abnormalities that correlate with autoimmune diseases in humans. This search has identified potential targets for therapeutic intervention that are the focus of planned and ongoing human clinical trials. This promises an arsenal of highly targeted, less toxic therapies focused on restoring normal B cell function that will eliminate pathogenic autoantibodies and replace the current use of immunosuppressive drugs.

Animals↗

PubMed2003

Applications of one-bead one-compound combinatorial libraries and chemical microarrays in signal transduction research.

The "one-bead-one-compound" (OBOC) combinatorial library method synthesizes millions of random compounds such that each bead displays only one compound. Bead libraries are screened, and positive beads are isolated for structure analysis. Peptide substrates and inhibitors of protein kinases, and peptide ligands for cell surface receptors have been identified using this method. A novel encoding strategy for OBOC libraries has been developed to identify peptidomimetic and small-molecule ligands that specifically interact with cellular proteins. These ligands will be tested for their effects on cell signaling and used to construct chemical microarrays for further characterization of ligand-protein interactions.

Combinatorial Chemistry Techniques↗

PubMed2002

Acetaminophen and diphenhydramine as premedication for platelet transfusions: a prospective randomized double-blind placebo-controlled trial.

Non-hemolytic transfusion reactions (NHTR) occur in up to 30% of patients receiving platelet transfusions. Premedication with acetaminophen and diphenhydramine is a common strategy to prevent NHTR, but its efficacy has not been studied. In this prospective trial, transfusions in patients receiving pre-storage leukocyte-reduced single-donor apheresis platelets (SDP) were randomized to premedication with either acetaminophen 650 mg PO and diphenhydramine 25 mg IV, or placebo. Fifty-one patients received 98 transfusions. Thirteen patients had 15 NHTR: 15.4% (8/52) in the treatment arm and 15.2% (7/46) in the placebo arm. Premedication prior to transfusion of pre-storage leukocyte reduced SDP does not significantly lower the incidence of NHTR as compared to placebo.

Acetaminophen↗

PubMed2002

Phosphorylation abnormalities: NZB mice exhibit a B-cell signalling defect.

NZB mice demonstrate common and consistent abnormalities in B-cell activation and signalling. One of the hallmark characteristics of lupus disease is the prevalent hypergammaglobulinaemia, composed primarily of anti-nuclear antibodies. In addition to the hyperproliferation seen in mice exhibiting disease, the B cells also demonstrate a marked degree of hyperactivity in response to B-cell receptor occupancy. This points to an intrinsic defect in the signalling pathways regulating the response to an activation event. Correspondingly, B cells of NZB mice exhibit a significant lack of phosphatase activity, both at baseline and in response to stimulation. This is directly reflected by a higher level of phosphorylation of tyrosine residues. Individually, SAPK and SHIP-1, both players in the B-cell receptor signalling cascade, are also found to be abnormally phosphorylated in the NZB mouse.

Animals↗