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Biomedical subjects

J E Karp

Publications and source records attributed to J E Karp.

At least 37 records · Page 2Linked to original sources
PubMed1998

Molecular pathogenesis and targets for therapy in myelodysplastic syndrome (MDS) and MDS-related leukemias.

The myelodysplastic syndromes (MDS) are a family of disorders that are characterized by ineffective hematopoiesis and evolution to acute myelogenous leukemias (AMLs) that are strikingly refractory to current therapeutic approaches. A substantial proportion of these complex diseases arise in the setting of exposures to environmental or occupational toxins, including cytotoxic therapy for a prior malignancy or other disorder (secondary MDS/AML). On the genomic level, MDS is typified by losses and translocations involving certain key gene segments, with disruption of the normal structure and function of genes that control the balance of proliferation and differentiation in hematopoietic precursors. In addition, MDS cells display impaired responses to diverse cytokines in terms of activating signaling intermediaries that trigger both proliferation and differentiation, and the disruption of the normal flow of biochemical information along the pathways translates into ineffective multilineage hematopoiesis and bone marrow failure. MDS/AMLs provide a fertile testing ground for the development of novel agents and the concomitant molecular dissection of the mechanisms by which these agents induce growth inhibition, terminal differentiation, and eventual cell death.

Chromosome Aberrations↗
PubMed1998

Topoisomerase II and the response to antileukemic therapy.

A number of recent studies have investigated the expression of topoisomerase II in clinical leukemia specimens. Here we outline the rationale for these studies, identify potential pitfalls, summarize recent results, and discuss unanswered questions in this area.

Acute Disease↗
PubMed1997

The molecular pathogenesis of treatment-induced (secondary) leukemias: foundations for treatment and prevention.

Acute myeloid leukemia (AML) developing after exposure to genotoxic agents has been recognized as a distinctive entity for more than 40 years. Secondary, or therapy-related, AML accounts for 10% to 20% of all AML cases. The basic and clinical investigation of these complex malignancies can be approached from four major vantage points: (I) dissection of the molecular structure of the induced genetic lesions and identification of the functional consequences of these changes, thereby providing clues to the pathogenesis of secondary AML and potentially serving as a basis for innovative therapeutic interventions; (2) identification and characterization of mechanisms of DNA damage and the orderly repair of such damage; (3) identification and application of accurate biomarkers of leukemogenesis for the purpose of risk prediction and quantification, potentially allowing recognition of patients especially susceptible to the leukemogenic effects of chemotherapy (for genetic or acquired reasons) and allowing their treatment for cancer to be modified based on this susceptibility; and (4) design and implementation of longitudinal clinical and genetic monitoring of high-risk populations (ie, individuals undergoing cytotoxic therapies for primary malignancies). In this article, we build on these themes, and attempt to integrate these seemingly disparate areas of research so that they can be more effectively used together to address the problem of secondary AML. Ultimately, the evaluation of these areas will inform our understanding of de novo leukemia and serve as a springboard for the development of new concepts of therapy and prevention.

Acute Disease↗
PubMed1997

Progress in clinical chemoprevention.

Chemoprevention has four goals: (1) inhibition of carcinogens, (2) logical intervention for persons at genetic risk for cancer, (3) treatment of precancerous lesions, and (4) confirmation and translation of leads from dietary epidemiology into intervention strategies. The National Cancer Institute has described a multidisciplinary, cancer science-based program for chemopreventive drug development that addresses these objectives, and has collaborated with the US Food and Drug Administration to provide consensus guidance for applying this approach. A critical component is the identification and characterization of intermediate biomarkers of cancer and their validation as surrogate end points for cancer incidence in clinical chemoprevention trials. More than 40 agents in the program are currently on the clinical development path (preclinical toxicology and phase I clinical safety studies or phase II/III efficacy trials), with the major effort in phase II studies to identify and characterize intermediate biomarkers. The continually advancing knowledge of molecular and tissue-based carcinogenesis mechanisms will provide leads to new chemopreventive agents with increased specificity for carcinogenesis-related activities and, hence, reduced toxicity by virtue of minimal effects on normal cell and tissue functions. Results from the Human Genome Project will help identify and evaluate the potential for chemopreventive intervention in cohorts at genetic risk and will provide specific target lesions for intervention strategies.

Anticarcinogenic Agents↗
PubMed1996

The secondary leukemias: challenges and research directions.

Acute myelogenous leukemia (AML) arising following exposure to genotoxic agents has been recognized as a distinctive entity for more than 40 years. Secondary, or therapy-related, AML accounts for 10%-20% of all AML cases. This review addresses four overarching areas of investigation focused on secondary AMLs: 1) dissection of the molecular structure of the induced genetic lesions and identification of the functional consequences of these changes, thereby providing clues to the pathogenesis of secondary AML and potentially serving as a basis for innovative therapeutic interventions; 2) identification and characterization of mechanisms of DNA damage and the orderly repair of such damage; 3) identification and application of accurate biomarkers of leukemogenesis for the purpose of risk prediction and quantification, potentially allowing recognition of patients especially susceptible to the leukemogenic effects of chemotherapy (for genetic or acquired reasons) and allowing their treatment for cancer to be modified on the basis of this susceptibility; and 4) design and implementation of longitudinal clinical and genetic monitoring of high-risk populations (i.e., individuals under-going cytotoxic therapies for primary cancers). This review of the literature relating to these areas builds upon these themes and attempts to synthesize these seemingly disparate areas of research so that they can be more effectively utilized together to address the problem of secondary AML. Ultimately, the evaluation of these areas will improve our understanding of de novo leukemia and will serve as a springboard for the development of new concepts of therapy and prevention.

Animals↗
PubMed1996

AIDS-related Kaposi's sarcoma. A template for the translation of molecular pathogenesis into targeted therapeutic approaches.

AIDS-related Kaposi's sarcoma (KS) represents a complex interaction of host and viral factors. There are a number of fundamental questions surrounding the interplay between the disparate factors that can contribute to the pathogenesis and pathophysiology of this disease. Targets such as the enhancement of immune function, inhibition of angiogenic factors or immunostimulatory cytokines, inhibition of viral proteins such as Tat, or hormonal manipulations are now or will in the future become the focus of research to develop innovative anti-KS therapy and prevention measures. Antiviral approaches aimed at HIV or other viruses may potentially target a number of steps in KS pathogenesis. This article reviews diverse modalities--cytotoxic, antiviral, gene-directed, growth factor-targeted, and antiangiogenesis--that singly, or more likely in combination, stand to make an impact on the cure and prevention of AIDS-related KS.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Addition of etoposide to initial therapy of adult acute lymphoblastic leukemia: a combined clinical and laboratory study.

The role of high-dose etoposide in the initial treatment of newly diagnosed adult ALL was assessed in a combined clinical and laboratory study. Therapy on protocol JH8802 consisted of two induction modules, module 1 containing prednisone, vincristine, high-dose etoposide and L-asparaginase (L-asp), followed by module 2 containing cytarabine (Ara-C) and daunorubicin (DNR). Patients achieving a complete remission (CR) underwent bone marrow transplantation (BMT) or intensive maintenance therapy. Results were compared to the preceding protocol (JH8302), which was similar except for omission of etoposide and L-asp. The CR rate following module 1 was 45% on protocol JH8802 and 9% on protocol JH8302 (p < 0.0002). Nonetheless, the two protocols had similar CR rates following module 2 (69% on protocol JH8302; 77% on JH8802) and indistinguishable survivals. Laboratory investigations performed on blasts harvested prior to chemotherapy revealed two factors that could potentially contribute to decreased etoposide sensitivity in ALL blasts. A flow microfluorimetry-based assay of nuclear DNR accumulation detected small P-glycoprotein (Pgp)-mediated decreases in drug accumulation in a quarter of the samples. Western blotting demonstrated that topoisomerase II was present in all samples but was diminished in amount compared to the Molt3 human ALL cell line. Immunoperoxidase staining with affinity-purified antibodies revealed that topo II alpha, the target for etoposide, was detectable in only a minority of the blasts (median 7.5%, range < 1-35%) at diagnosis. These observations raise the possibility that alterations in drug accumulation and diminished target enzyme levels might both limit the long-term efficacy of a single course of high dose etoposide administered early in the treatment of adult ALL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Changes in topoisomerase I levels and localization during myeloid maturation in vitro and in vivo.

Changes in topoisomerase I (topo I) levels and localization were examined during the course of granulocytic maturation in vitro and in vivo. Western blotting revealed that granulocytic maturation in DMSO-treated HL-60 human leukemia cells was accompanied by a 5-fold decrease in topo I polypeptide content. Consistent with this result, 3- to 5-fold higher concentrations of the topo I poison camptothecin were required to stabilize topo I-DNA adducts in DMSO-treated HL-60 cells compared to untreated cells. Northern blotting revealed that these changes occurred without any decrease in topo I message. Immunolocalization studies revealed that these quantitative changes were accompanied by redistribution of topo I away from the nucleoli, where it was prominently accumulated in untreated HL-60 cells, to a more uniform nuclear distribution in DMSO-treated cells. Similar changes occurred during granulocytic maturation in human marrow in vivo. Western blotting revealed that topo I levels in normal progranulocytes were 50% as high as those in HL-60 cells, levels in metamyelocytes were 35% as high as HL-60 cells, and levels in peripheral blood granulocytes were 5% as high as HL-60 cells. Two other polypeptides that are concentrated in nucleoli, poly(ADP-ribose) polymerase and B23/nucleophosmin, also decreased during the course of granulocytic maturation. These changes were accompanied by an alteration in topo I localization similar to that observed in HL-60 cells during the course of granulocytic maturation. Conversely, treatment of human lymphocytes with the mitogenic lectin concanavalin A resulted in a 3-fold increase in topo I polypeptide content concomitant with a prominent increase in the amount of nucleolar antigen. These observations not only provide a context for understanding the recent observation that topo I levels are higher in human leukemia specimens than in normal marrow but also raise the possibility that elevated topo I levels in other cells might reflect alterations in nucleolar structure and function.

Cell Nucleus↗
PubMed1995

Increased expression of the multidrug resistance-associated protein gene in relapsed acute leukemia.

Quantitative reverse transcriptase polymerase chain reaction (RT-PCR) was used to determine relative levels of transcripts for MDR1 and the recently described multidrug resistance-associated protein (MRP) in normal lymphohematopoietic cells and in 62 bone marrow aspirates of newly diagnosed and recurrent acute leukemia. Levels of MRP expression in newly diagnosed AML samples were similar to those observed in normal bone marrow cells (CD34-negative and CD34-positive) and in unselected HL60 human promyelocytic leukemia cells, which were used as an internal control throughout this study. In contrast, samples of AML obtained at the time of relapse contained approximately twofold higher levels of MRP RNA (P < .01). Analysis of paired samples, the first obtained at diagnosis and the second at relapse, from 13 acute myelogenous leukemia (AML) and four acute lymphocytic leukemia (ALL) patients showed that MRP expression was increased at the time of relapse in greater than 80% of patients. In contrast, no consistent changes of MDR1 expression at relapse were observed. These results raise the possibility that increased MRP expression might contribute to leukemic relapse.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

New avenues of translational research in leukemia and lymphoma: outgrowth of a Leukemia Society of America-National Cancer Institute workshop.

The workshop was organized on the premise that truly innovative approaches are needed if we are to significantly change the clinical outcomes for leukemias and lymphomas. Several new concepts and pioneering approaches surfaced during the workshop discussions, as summarized above. The design and implementation of translational clinical trials that emphasize these innovative strategies were encouraged as a way to test the concepts put forward at the workshop. Representatives of the Leukemia Society of America and the National Cancer Institute plan to continue their dialogue to develop recommendations regarding the priorities for linked clinical-laboratory investigations on the hematopoietic malignancies and the optimal ways in which to foster such translational research. To this end, the explosion in basic science discoveries during the last two decades and especially during the last 5 years is producing a critical mass of knowledge. This knowledge, in turn, allows us to view leukemia from new perspectives that span molecular pathogenesis, epidemiology, early detection of minimal disease, and the selective targeting of critical leukemogenic mechanisms for therapeutic and ultimately preventive purposes. As in previous decades, during which leukemia has served as the testing ground for precedent-setting concepts of curative therapy (dose-intensity, non-cross-resistance-inducing combinations and aggressive therapy in the minimal residual disease state), leukemia should again serve as a clinical beacon for the identification and exploitation of new molecular targets for therapy. Any impact on curability and duration and quality of survival will be achieved only by building on the cumulative knowledge accrued at multiple levels--molecular and cellular levels as well as in the intact patient--and augmenting the momentum of the bidirectional exchange of information between the laboratory and the clinic that has characterized leukemia research from its incipience. The challenge is formidable and worthy of our most creative and concerted efforts.

Animals↗
PubMed1994

Oncology and hematology.

Net overexpression or derangements of PTK-encoding oncogenes and ras serve as critical driving forces in the evolution of many epithelial and lymphohematopoietic cancers. The ability to impede signal transduction through ras-based pathways could provide a powerful molecular target for therapy and prevention of a broad spectrum of malignant neoplasms.

Hematology↗
PubMed1994

Topoisomerase II levels and drug sensitivity in adult acute myelogenous leukemia.

The topoisomerase (topo) II-directed agents etoposide, daunorubicin (DNR), and amsacrine (m-AMSA) are widely used in the treatment of acute myelogenous leukemia (AML). In the present study, multiple aspects of topo II-mediated drug action were examined in marrows from adult AML patients. Colony-forming assays revealed that the dose of etoposide, DNR, or m-AMSA required to diminish leukemic colony formation by 90% (LD90) varied over a greater than 20-fold range between different pretreatment marrows. Measurement of nuclear DNR accumulation in the absence and presence of quinidine revealed evidence of P-glycoprotein (Pgp) function in 8 of 82 samples at diagnosis and 5 of 36 samples at first relapse, but the largest quinidine-induced increment in DNR accumulation (< 2-fold) was too small to explain the variations in drug sensitivity. Restriction enzyme-based assays and sequencing of partial topo II alpha and topo II beta cDNAs from the most highly resistant specimens failed to demonstrate topo II gene mutations that could account for resistance. Western blotting of marrow samples containing greater than 80% blasts revealed that the content of the two topo II isoenzymes varied over a greater than 20-fold range, but did not correlate with drug sensitivity in vitro or in vivo. In addition, levels of topo II alpha and topo II beta in 46 of 47 clinical samples were lower than in human AML cell lines. Immunoperoxidase staining showed that these low topo II levels were accompanied by marked cell-to-cell heterogeneity, with topo II alpha being abundant in some blasts and diminished or absent from others. There was a trend toward increasing percentages of topo II alpha-positive cells in pretreatment marrows that contained more S-phase cells. Consistent with this observation, treatment of patients with granulocyte-macrophage colony-stimulating factor for 3 days before chemotherapy resulted in increases in topo II alpha-positive cells concomitant with increases in the number of cells traversing the cell cycle. These observations have implications for the regulation of topo II in AML, for the use of topo II-directed chemotherapy, and for future attempts to relate drug sensitivity to topo II levels in clinical material.

ATP Binding Cassette Transporter, Subfamily B, Mem↗