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At least 523 records · Page 29Linked to original sources
PubMed2005

Epigenetic and chromatin modifiers as targeted therapy of hematologic malignancies.

Epigenetic regulation of gene expression is mediated through alterations in the DNA methylation status, covalent modifications of core nucleosomal histones, rearrangement of histones, and by RNA interference. It is now abundantly clear that deregulation of epigenetic mechanisms cooperates with genetic alterations in the development and progression of cancer and leukemia. Epigenetic deregulation affects several aspects of tumor cell biology, including cell growth, cell cycle control, differentiation, DNA repair, and cell death. This raises the strong possibility that reversing deregulated epigenetic mechanisms may be an effective treatment strategy for leukemia and cancer. This treatment strategy may either be designed to separately or collectively target the specific perturbations in the epigenetic mechanisms found in human hematologic malignancies. The following review describes our current understanding of the important deregulated epigenetic mechanisms and the preclinical and clinical development of epigenetic and chromatin modifiers in the therapy of these disorders.

Chromatin↗
PubMed1997

Granulocyte-macrophage colony-stimulating factor receptor-targeted therapy of chemotherapy- and radiation-resistant human myeloid leukemias.

Contemporary therapies for acute myeloid leukemia (AML) commonly fail to cure patients because of the emergence of drug resistance. Drug resistance in AML is multifactorial but can be associated with the overexpression of transmembrane transporter molecules, including P-glycoprotein (Pgp) or the multidrug resistance-associated protein (MRP), or associated with inactivation of the p53 tumor suppressor gene, as well as overexpression of the anti-apoptotic protein bcl-2. We are investigating if novel recombinant biotherapeutics can circumvent these resistance mechanisms to effectively treat refractory AML. To target the lethal action of diphtheria toxin (DT) to high affinity granulocyte-macrophage colony-stimulating factor (GMCSF) receptors on AML blasts, we have produced a recombinant chimeric fusion toxin, DTctGMCSF. Since DTctGMCSF enters and kills its target cells by unique mechanisms (GMCSF-receptor binding and protein synthesis inhibition) and is not similar in structure to Pgp or MRP substrates, we postulated that it would be an active agent against therapy-resistant AML. DTctGMCSF was selectively cytotoxic (IC50 1-10ng/ml) to GMCSF-receptor positive AML cells expressing the Pgp- or MRP-associated multi-drug resistant phenotypes, despite high level resistance to conventional chemotherapeutic agents. DTctGMCSF also efficiently killed AML cells deficient in p53 expression, as well as radiation-resistant AML cells and mixed lineage leukemia cells expressing high levels of bcl-2. In addition, DTctGMCSF killed > 99% of primary leukemic progenitor cells from therapy-refractory AML patients under conditions that we have previously found to not adversely affect the proliferative capacity or differentiation of pluripotent normal hematopoietic progenitor cells. DTctGMCSF may prove useful in treating myeloid leukemias that are otherwise resistant to a wide range of conventional therapies.

Antineoplastic Agents↗
PubMed2006

Molecular mediators of cell death in multistep carcinogenesis: a path to targeted therapy.

A consistent, if not invariant, feature of cancer cells is the acquired ability to evade apoptosis. The pioneering work of Dr. Stan Korsmeyer was invaluable in characterizing the molecular foundations of cell death signaling mechanisms during normal development and during multistep carcinogenesis. This foundation now forms the basis for the rational design of therapeutic strategies to selectively activate cell death in cancer cell populations. These strategies are currently being evaluated in an increasing number of clinical trials targeting diverse tumor types.

Animals↗
PubMed2005

Recent advances on multiple tumorigenic cascades involved in prostatic cancer progression and targeting therapies.

Recent advances on differently-expressed gene products and their functions during the progression from localized androgen-dependent states into androgen-independent and metastatic forms of prostate cancer are reported. The expression levels of numerous oncogenes and tumor suppressor genes in distinct prostatic cancer epithelial cell lines and tissues relative to normal prostate cells are described. This is carried out to identify the signaling elements that are altered during the initiation, progression and metastatic process of prostate cancer. Additional information on the interactions between certain deregulated signaling pathways such as androgen receptor (AR), estrogen receptors, epidermal growth factor receptor (EGFR), hedgehog and Wnt/beta-catenin cascades in controlling the proliferation, survival and invasion of tumor prostate epithelial cells during the disease progression is described. The emphasis is on the critical functions of the AR and EGF-EGFR systems at all stages during prostate carcinogenesis. Of therapeutic interest, new strategies for the diagnosis and treatment of localized and metastatic forms of prostate cancer by targeting multiple tumorigenic signaling elements are also reported.

Androgens↗
PubMed2005

Nursing implications of imatinib as molecularly targeted therapy for gastrointestinal stromal tumors.

Gastrointestinal stromal tumor (GIST), a form of soft-tissue sarcoma, is the most common noncarcinomatous tumor of the gastrointestinal tract. Despite its high incidence of recurrence, the malignant potential of GIST has been under-recognized. Advances in diagnostic technology since 2000 have led to increased diagnoses of GIST, suggesting that GIST is more common than previously suspected. Historically, the only treatment for GIST was surgical resection, but recent advances in the understanding of the pathogenesis of the disease have led to the development of a new treatment. A key factor in the growth and survival of cancerous GIST cells is the uncontrolled activation of a signaling enzyme known as KIT, a receptor tyrosine kinase, which becomes locked in an activated state. The abnormal signaling from the overactive KIT enzyme causes GIST cells to survive and proliferate uncontrollably. Imatinib mesylate is an oral drug designed to inhibit the kinase enzyme activity of KIT. Imatinib has been proven in several clinical trials to be effective against GIST and is currently the firstline medical therapy for malignant metastatic or recurrent GIST. Imatinib is administered as an outpatient oral drug and warrants nursing management with particular attention to potential side effects, significant drug interactions, monitoring, and patient education. This article--based on published trials and clinical experience--summarizes the nursing implications, clinical efficacy, and safety of imatinib as an effective and rationally targeted treatment for GIST.

Administration, Oral↗
PubMed2004

Empowering targeted therapy: lessons from rituximab.

Rituximab, a monoclonal antibody directed against the B cell-specific protein CD20, has revolutionized lymphoma treatment by providing a highly effective form of therapy with relatively mild toxic side effects. Effective as a single agent against some forms of B cell lymphoma, rituximab also has a chemosensitizing effect, enhancing the efficacy of chemotherapy against other forms of the disease. Although the mechanisms whereby rituximab achieves its effects remain incompletely understood, these seem to involve at least three distinct phenomena: (i) antibody-dependent cell-mediated cytotoxicity, (ii) complement-mediated cell lysis, and (iii) stimulation of apoptosis in target cells. The latter occurs through interaction of complexes of rituximab and CD20 in lipid rafts, with elements of a signaling pathway involving Src kinases. Effector molecules trigger various gene expression events, leading to sensitization of malignant cells to proapoptotic stimuli. Lessons learned from the research on rituximab may be applied to the rational development of antibody-based therapies against other forms of cancer.

Animals↗
PubMed2006

Development of engineered antibodies specific for the Müllerian inhibiting substance type II receptor: a promising candidate for targeted therapy of ovarian cancer.

The Müllerian inhibiting substance type II receptor (MISIIR) is involved in Müllerian duct regression as part of the development of the male reproductive system. In adult females, MISIIR is present on ovarian surface epithelium and is frequently expressed on human epithelial ovarian cancer cells. Müllerian inhibiting substance has been found to be capable of inhibiting the growth of primary human ovarian cancer cells derived from ascites and ovarian cancer cell lines. This suggested to us that MISIIR could be an attractive target for antibody-based tumor targeting and growth inhibition strategies. Here, we describe the production of recombinant human MISIIR extracellular domain-human immunoglobulin Fc domain fusion proteins and their use as targets for the selection of MISIIR-specific human single-chain variable fragments (scFv) molecules from a human nonimmune scFv phage display library. The binding kinetics of the resulting anti-MISIIR scFv clones were characterized and two were employed as the basis for the construction of bivalent scFv:Fc antibody-based molecules. Both bound specifically to human ovarian carcinoma cells in flow cytometry assays and cross-reacted with mouse MISIIR. These results indicate that antibody-based constructs may provide a highly specific means of targeting MISIIR on human ovarian carcinoma cells for the purpose of diagnosing and treating this disease.

Antibodies↗
PubMed1996

Targeted therapy for prostate cancer: the Memorial Sloan-Kettering Cancer Center approach.

Carcinoma of the prostate represents a wide range of diseases with differing prognoses. A key to selecting treatment depends on the ability to predict the natural history of the disease for the individual. Thus far, non-hormonal approaches have not demonstrated a survival advantage in randomized comparisons and, clearly, innovative approaches are needed. The clinical trials program developed at Memorial Sloan-Kettering Cancer Center is based on specific manifestations and specific targets of the disease and the predicted prognosis, using prostate-specific antigen and acid phosphatase changes as biomarkers of progression and response. In patients with minimal disease who have received local treatments but progressed systemically, we are studying methods aimed at stimulating their immune systems either by nonspecific immunopotentiation or specific immunization to specific glycoprotein or carbohydrate targets on the cancer cells, or to anti-growth factor receptor antibody aimed at blocking the specific signalling pathways that contribute to hormonal failure. These and other approaches provide an opportunity to treat this disease while maintaining an acceptable quality of life for patients.

Animals↗
PubMed2005

Recent advances in targeted therapy of human myelogenous leukaemia.

Despite major advances in the diagnosis and treatment of myelogenous leukaemia during the past few decades, this group of diseases remains a serious medical concern with > 15,000 new cases each year and a mortality rate of approximately 10,000 in the US alone. Current available conventional therapies, including chemotherapy and bone marrow transplantation, often cause severe side effects owing mainly to the lack of specificity of the treatment. In the past years, significant progress has been made towards understanding the pathogenesis of myelogenous leukaemia from the molecular standpoint. To this end, a growing number of approaches are being exploited for the identification and validation of new therapeutic targets suitable for more potent and specific or 'targeted' intervention. In this review, the authors focus their discussion on the four most promising myelogenous leukaemia-associated molecular targets currently being pursued by major pharmaceutical and biotechnology companies, fms-like tyrosine kinase 3 (FLT3), CD33, farnesyl transferase and BCR-Abl, with emphasis on recent progress on the clinical development of therapeutic agents, including both kinase inhibitors and monoclonal antibodies, to these targets.

Antibodies, Monoclonal↗
PubMed2002

Molecular markers and targeted therapy with novel agents: prospects in the treatment of non-small cell lung cancer.

Detection of genomic differences predictive of drug response or resistance in individual patients may allow therapy to be customized to the characteristics of particular tumors. Preliminary findings are that non-small cell lung cancer patients overexpressing ERCC1 mRNA have lower response to cisplatin chemotherapy, while those overexpressing ribonucleotide reductase mRNA have limited benefit from gemcitabine. In addition, overexpression of beta-tubulin III and stathmin can influence the sensitivity to microtubule interacting drugs, like vinorelbine and paclitaxel. The introduction of biological agents which target highly specific intracellular pathways offers the promise of enhancing the efficacy of cytotoxic chemotherapy. Among many promising biological agents is the monoclonal antibody C225, which blocks the EGFR receptor. The addition of C225 appears to induce responses in a proportion of colon cancer patients refractory to 5-FU or irinotecan, supporting pre-clinical evidence of synergistic activity. It also appears from xenograft data that C225 enhances the sensitivity of tumors to radiation and docetaxel or the combination.

Antibodies, Monoclonal↗
PubMed2002

Imatinib and chronic myeloid leukemia: validating the promise of molecularly targeted therapy.

The Bcr-Abl tyrosine kinase inhibitor imatinib (Glivec, formerly STI571, Novartis Pharma AG, Basel, Switzerland) produces complete hematologic and cytogenetic responses in a substantial percentage of chronic myeloid leukemia patients. Imatinib is effective in chronic phase, accelerated phase and blast crisis, with lower response rates in patients with more advanced disease. Although responses have been durable in chronic phase patients, relapses have been common in blast crisis. Relapse has been associated with reactivation of Bcr-Abl kinase activity. The clinical development of imatinib illustrates the effectiveness of targeting molecular pathogenetic events. Hopefully, this example can be extended to other malignancies.

Antineoplastic Agents↗
PubMed2004

Current and emerging nonsteroidal anti-inflammatory therapies targeting specific mechanisms in asthma and allergy.

Today inhaled corticosteroids (ICS) are regarded as the first-line controller anti-inflammatory treatment in the management of asthma. However, there is an increasing awareness of the risk of long-term adverse effects of ICS and that asthma is not only an organ-specific disease but also a systemic and small airway disease. This thinking has called for systemic treatment alternatives to treat asthma targeting more disease-specific mechanisms without influencing normal physiologic functions. Blocking of disease-specific mediators is a mechanism utilized by anti-leukotrienes and anti-immunoglobulin E treatment, each proven to be effective in both asthma and allergic rhinitis.Different cytokine-modifying strategies have been tested in clinical trials with variable results, some disappointing and some encouraging. Anti-interleukin (IL)-5 monoclonal antibody treatment effectively reduces the number of eosinophils locally in the airways and in peripheral blood in asthmatic patients. Unfortunately, this marked effect on eosinophils was not associated with an improvement in bronchial hyperresponsiveness and/or symptoms. Clinical trials with a recombinant soluble IL-4 receptor have been somewhat more successful at improving asthma control and allowing reduction of ICS therapy in asthma. Treatment with recombinant IL-12 had an effect on bronchial hyperresponsiveness and eosinophilic response, but was associated with unacceptable adverse effects. Other interesting cytokine-modulating treatments include those targeting IL-9, IL-10, IL-12 and IL-13.Immune-modulating treatment with bacterial antigens represents another strategy, originating from the hypothesis that some bacterial infections guide the immune system towards a T helper (Th) type 1 immune response. Mycobacterium vaccae, Bacille Calmette-Guerin (BCG) and immunostimulatory DNA sequences have all been tested in clinical trials, with encouraging results. Future asthma and allergy treatment will probably include not only one but also two or more disease-modifying agents administered to the same patient.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

The epidermal growth factor receptor signaling network in head and neck carcinogenesis and implications for targeted therapy.

Improved understanding of the molecular signaling pathways that mediate cellular transformation has led to the development of novel strategies for the treatment of cancer. The epidermal growth factor receptor (EGFR), a transmembrane protein with intrinsic tyrosine kinase activity, transduces important signals from the surface of epithelial cells to the intracellular domain. Aberrant signaling through EGFR plays a key role in the carcinogenesis of squamous cell carcinomas of the head and neck (SCCHN). SCCHN tend to express high levels of EGFR, and the degree of expression correlates with poor clinical outcome. Since EGFR is present at much higher levels in cancerous lesions than in normal epithelial tissue, the receptor has been implicated as a highly specific therapeutic target for the treatment of SCCHN. EGFR can be abrogated at the extracellular level using either monoclonal antibodies or toxin conjugates that compete with the natural ligand at the binding site of the receptor, and targeting of the EGFR intracellular domain has been achieved by specific inhibitors of tyrosine kinase activity. Antisense strategies use synthesized DNA or RNA oligonucleotides to block the translation of the mRNA sequences that code for the production of the EGFR or other proteins with a role in EGFR-mediated cell signaling. Clinical evaluation of EGFR-specific monoclonal antibodies and tyrosine kinase inhibitors has demonstrated limited toxicity in SCCHN patients, and concurrent administration with standard cytotoxic therapies has produced additive or synergistic antitumor effects.

Antisense Elements (Genetics)↗
PubMed1988

Interleukin 2 receptor-targeted therapy--rationale and applications in organ transplantation.

Despite major advances in immunopharmacology for use in clinical organ transplantation, graft rejection and drug-induced side effects remain the major problems with currently available immunosuppressive modalities. Recent advances in hybridoma technology have produced relatively effective and reproducible biological immunosuppression with monoclonal antibodies; indeed, OKT3 and anti-T12 mAbs have been employed with considerable success as adjuncts to chemical suppression in treating rejection. Nonetheless, the use of such antibodies broadly reactive to differentiation antigens on T lymphocytes does not solve the problems of side effects caused by general immunosuppression. An ideal therapeutic agent should target only lymphocytes that participate in rejection of foreign tissue without affecting physiological host immune surveillance and normal defense mechanisms. Theoretically, this goal could be achieved by "antigenic suicide," or by using the appropriate antiidiotypic antibodies or mAbs against the antigen combining site of T cell receptors. However, because of the intense polymorphism of transplantation antigens and the vast genetic repertoire encoding for the T cell antigen receptor, success of such forms of specific immunosuppression, at least at this time, is highly improbable.

Animals↗
PubMed1996

A new in vitro model of specific targeting therapy of cancer: retargeting of PWM-LAK cells with bispecific antibodies greatly enhances cytotoxicity to hepatocellular carcinoma.

For the purpose of establishing a new in vitro model of adoptive immunotherapy, we synthesized two kinds of bispecific antibodies (BsAbs), i.e., (OK x L) BsAbs constructed with both OKT-3 (anti-CD3) and L-7-6 (anti-HCC), and (3G x L) BsAbs constructed with 3-G-8 (anti-CD16) and L-7-6 antibodies. These two BsAbs, having pairs of binding arms on their single molecule, showed similar binding to target cells as the parental monoclonal antibodies (OKT-3, 3-G-8 and L-7-6), when examined with FACS. Newly devised in vitro cytotoxicity tests revealed that LAK or PWM-stimulated LAK (PWM-LAK) cells did not show any significant cytotoxic activity to HCC cells, while both effector cells equally showed greatly enhanced cytotoxicity to HCC even at a low effector/target (0.3) in the presence of BsAbs (OK x L) for the efficient retargeting of the effector cells. Inasmuch as PWM-LAK cells proliferate in vitro 3-5 times faster than LAK cells, adoptive immunotherapy using PWM-LAK cells in combination with (OK x L) BsAbs should be very promising.

Antibodies, Bispecific↗
PubMed1997

[Recombinant immunotoxins and chimeric toxins for targeted therapy in oncology].

Immunotoxins and chimeric toxins are hybrid molecules constituted of antibodies, growth factor or cytokines coupled to peptide toxins. They are designed to selectively eliminate tumor cells. Some of these chimera have been shown to induce complete tumor regressions of human tumor xenografts in immunodeficient mice. In clinical trials, higher anti tumor response were observed in lymphoma, brain tumor, breast and colon cancers. Problems arose with normal tissue toxicity and the production of neutralising antibodies. Should the latest recombinant toxins conceived by rationale designed, solved these problems, chimeric toxins would be an alternative approach to target tumor cells and vascular endothelial cells in solid tumors.

Animals↗