Biomedical subjects

Chadi Nabhan

Publications and source records attributed to Chadi Nabhan.

23 records · Page 2Linked to original sources

PubMed2002

Acute promyelocytic leukemia: evolving therapeutic strategies.

Acute promyelocytic leukemia (APL) is now the most curable subtype of acute myeloid leukemia in adults. All-trans retinoic acid (ATRA), which induces differentiation of the leukemic cells into mature granulocytes, represents the important advance. The incorporation of ATRA in induction results in a high complete remission rate, leads to rapid resolution of the characteristic life-threatening coagulopathy, and, most importantly, decreases the relapse rate compared with treatment with chemotherapy alone. However, ATRA is associated with unique toxicities not observed with conventional cytotoxic chemotherapy. A number of clinical trials have been performed to define the optimal role of ATRA in the treatment of patients. The therapeutic strategies have rapidly evolved as a result of both single institution and large cooperative group trials. Arsenic trioxide and stem cell transplantation are effective treatments for patients with APL who relapse after or are refractory to ATRA-based therapy. As experience with ATRA and arsenic trioxide in patients with APL accumulates, a number of important questions arise that need to be addressed.

Animals↗

PubMed2002

Management of acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) has become the most potentially curable subtype of acute myeloid leukemia (AML) in adults. With current treatment strategies that incorporate all-trans retinoic acid (ATRA), long-term disease-free survival and potential cure rates of 70% to 80% can be expected. Such progress reflects what can be accomplished with insights into the molecular pathogenesis of leukemia, identification of a molecular target, and rapid accrual to a series of clinical trials. The leukemic promyelocytes from patients with APL are uniquely susceptible to a variety of novel agents in addition to ATRA, including arsenic trioxide, and in preliminary studies, gemtuzumab ozogamicin, the immunoconjugate comprised of an anti-CD33 monoclonal antibody linked to the potent cytotoxic agent calicheamicin. Incorporation of such agents into the treatment of patients with high-risk disease may be an important future direction to pursue.

Antibiotics, Antineoplastic↗

PubMed2002

Early phase I/II trials with gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia.

Relapsed acute myeloid leukemia (AML) carries a poor prognosis. Treatment options are limited, and their toxicities are substantial. There is an urgent need for novel therapies that are effective and have acceptable side effects. Gemtuzumab ozogamicin (Mylotarg) is an immunoconjugate targeted against CD33, which is expressed on more than 90% of myeloid leukemic blasts. The antibody is attached to calicheamicin, a potent cytotoxic enediyne antibiotic that inhibits DNA synthesis and induces apoptosis. In vitro studies showed excellent activity of gemtuzumab ozogamicin in leukemic cell lines and encouraged the evaluation of this agent in patients. In this review, early phase I/II studies that led to the US Food and Drug Administration approval of this immunoconjugate for older patients with relapsed AML are discussed. Potential adverse events reported with this agent, particularly the recent data of possible veno-occlusive disease and increased hepatotoxicity, are addressed. This agent is currently being investigated in many clinical trials as a front-line approach in previously untreated individuals, and it is likely that it will have many more indications in the near future.

Aminoglycosides↗

PubMed2002

Conceptual aspects of combining rituximab and Campath-1H in the treatment of chronic lymphocytic leukemia.

Monoclonal antibody-based therapy has emerged as a novel approach in the treatment of hematologic malignancies. The safety and tolerability of monoclonal antibodies make these compounds attractive and easy to administer, even in elderly, heavily pretreated patients. Chronic lymphocytic leukemia is an incurable disease with few therapeutic options once patients fail purine analogue-based therapy. Two monoclonal antibodies have shown activity in this disease. The first is rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA), a chimeric human-mouse anti-CD20 antibody. The second is Campath-1H, a humanized form of a rat antibody active against CD52. We hypothesize that combining both antibodies in patients who have failed conventional therapies and express both CD20 and CD52 might have enhanced efficacy and therapeutic benefit. This concept is being explored at our institution in the context of a phase I/II clinical trial. The outcome and feasibility of this combination opens the way for future combination therapies using novel biologic agents.

Alemtuzumab↗

PubMed2002

Caspase activation is required for gemcitabine activity in multiple myeloma cell lines.

The objective of this study was to determine potential mechanisms of apoptotic activity of gemcitabine, a pyrimidine nucleoside analogue, in the MM1.S multiple myeloma (MM) cell line. A MM cell line that is sensitive to glucocorticoids (MM1.S) was used for this study. Immunoblotting analysis, cell cycle assays, and annexin V staining were performed to determine whether gemcitabine induced apoptosis in this model. Furthermore, we attempted to delineate the apoptotic pathway by measuring caspase-8 and -9 activity using fluorometric assays. Loss of mitochondrial membrane potential was measured by flow cytometry. Gemcitabine treatment caused apoptosis in MM cell lines as measured by an increase in DNA cleavage, an increase in annexin V binding, a decrease in the mitochondrial membrane potential, and activation of caspase activity. Furthermore, cleavage of the caspase substrate poly(ADP-ribose) polymerase and caspase-3 activation were documented as early as 8 h after treatment with gemcitabine. Caspase-8 and -9 were activated by gemcitabine treatment in this cell line, suggesting several mechanisms of action including death receptor pathway and mitochondrial damage. The addition of interleukin 6 to MM1.S cells treated with gemcitabine offered no protection against gemcitabine-induced cell death. Gemcitabine induced apoptosis in the MM1.S cell line, and its activity required caspase activation. There is a suggestion that mitochondrial integrity is being affected with gemcitabine in this system. Gemcitabine acts independently of interleukin 6, suggesting potential important therapeutic implications in MM patients.

Annexin A5↗