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PubMedDate not supplied

[Recent advances in molecular biology of central nervous system embryonal tumors and development of potential molecular targeted therapies].

Embryonal tumours constitute the largest group of malignant pediatric brain tumours. Their origin and histological classification is debated. Diagnosis is controversial and patients' response to therapy on the basis of morphologic appearance alone, is difficult to predict. Therefore accurate clinical staging remains a critical component of clinical management. In recent years real progress has been made in our understanding of the molecular genetic abnormalities that govern the initiation and/or progression of embryonal tumours. This review is focused on the principal molecular genetic abnormalities so far identified in embryonal brain tumours and discusses their possible biological and clinical applications in developing a molecular risk staging system which hopefully will lead to the molecular targeted therapies, curative non-toxic treatment for all children.

Brain Neoplasms↗
PubMed2004

Denileukin diftitox as novel targeted therapy in non-Hodgkin's lymphoma.

Non-Hodgkin's lymphoma (NHL) is a complex group of hematologic malignancies. The majority are B-cell lineage, with 10%-20% arising from T-cell lineage. Detailed knowledge of the subtypes and staging of NHL is essential to plan treatment and provide effective management of treatment-related side effects. Although numerous regimens have demonstrated efficacy in the treatment of NHL, some subtypes of lymphomas generally are not curable. The recent development of targeted therapies such as denileukin diftitox (Ontak, Ligand Pharmaceuticals, Inc., San Diego, CA) has resulted in potentially significant advances in the treatment of NHL. Oncology nurses must gain a better understanding of the unique mechanism of action of this agent and its side effects to successfully manage patients being treated with this novel therapy.

Antineoplastic Agents↗
PubMed2005

[Targeted therapies and radiotherapy in colorectal cancer].

Growing evidence suggests that intracellular signal pathways play a significant role in radiation response. Promising results have been obtained in experimental studies assessing the combined use of specific inhibitors and radiotherapy. Based on these data, a number of clinical trials were started to enhance tumor responses and thus to decrease the rate of locoregional recurrences. Several prognostic factors on tumoral radiosensitivity have been identified including intracellular signal pathways. Nevertheless, these factors do not correlate with responses to targeted therapies. Concerning rectal cancer, promising results have recently been obtained with concurrent radiotherapy and a monoclonal antibody against VEGF (bevacizumab). Studies combining cetuximab (anti-HER1) and radiotherapy will start soon in this setting. Other specific inhibitors combined with radiotherapy are still in preclinical evaluation.

Colorectal Neoplasms↗
PubMed1991

Use of MG series monoclonal antibodies in the diagnosis and experimental targeting therapy of gastric cancer.

In order to facilitate early diagnosis and improve the treatment of gastric cancer, 12 murine hybridoma cell lines capable of producing monoclonal antibodies (mAb) against gastric cancer were established. These monoclonal antibodies were used in histopathological diagnosis, cytological and serological diagnosis, and radioimmunoimaging (RII). Also, immunoconjugates and immunoliposomes were produced by linking these antibodies with various anticancer agents. In vitro and in vivo studies in mice were carried out to investigate the possible uses of these antibodies in experimental targeting therapy of gastric cancer. This paper presents a review of these studies.

Animals↗
PubMed2000

Targeted therapy of experimental renal cell carcinoma with a novel conjugate of monoclonal antibody 138H11 and calicheamicin thetaI1.

In search for a new therapeutic approach for metastasized renal cell carcinoma (RCC), we evaluated the cytotoxicity of a novel prodrug chemoimmunoconjugate with monoclonal antibody (mAb) 138H11 and the DNA-cleaving enediyne calicheamicin thetaI1 (Camtheta) in vitro and in vivo. Previously, mAb 138H11, produced against human renal gamma-glutamyltransferase, stained over 99% clear cell and papillary RCC on frozen sections, showing a membranous expression of the target antigen. In contrast, in normal kidneys gammaGT was restricted to the brush-border in the lumen of proximal tubules and not accessible to the circulation. Thus, human tumor-bearing kidneys perfused in an extra-corporeal system with 99mTc-138H11 revealed a high, specific uptake into the tumor. In this study, fluorescence-activated cell sorting analysis showed binding of mAb 138H11 to RCC cell lines, whereas squamous cell carcinoma lines, fibroblasts, and the murine RENCA were negative. XTT cell proliferation assays revealed efficient killing of the Caki-1 cell line by the 138H11-Camtheta conjugate using SPDP (EC50 = 5 x 10(-11) M) as a covalent linker. For in vivo testing, five groups of eight nude mice each were injected with 2.5 x 10(6) Caki-1 cells s.c. and treated with the following: (a) PBS; (b) 138H11; (c) Camtheta; (d) a mixture of 138H11 and Camtheta; and (e) 138H11-Camtheta conjugate. Treatment started on day 1 after tumor induction and was repeated three times. The data show a highly significant inhibition of tumor growth with the 138H11-Camtheta conjugate versus PBS (P = 0.004). Only mice treated with 138H11-Camtheta showed a tumor shrinkage to minimal residues. In a second experiment, lower doses of the 138H11-Camtheta conjugate were compared with an antineuroblastoma mAb (ch14.18), confirming targeted killing of RCC by the 138H11-Camtheta conjugate at tolerable toxicity in vivo. In conclusion, these combined results encourage further studies for targeted therapy of metastatic RCC with mAb 138H11 conjugates.

Aminoglycosides↗
PubMed2002

Targeted therapies in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia.

Imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ; Glivec, Novartis Pharma AG, Basel, Switzerland), a signal transduction inhibitor with preferential effects against the tyrosine kinase activity of the protein product of the ABL proto-oncogene, induced hematologic responses in >or=90% of patients with chronic-phase chronic myeloid leukemia (CML). In Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL), the BCR-ABL translocation is the main transforming event, making it another hematologic malignancy targeted by this ABL-tyrosine kinase inhibitor. In an international multicenter phase II trial, imatinib-induced hematologic responses (typically brief) were achieved in 60% of patients with relapsed or refractory Ph(+) ALL. Subsequently, the German Multicenter Study Group for Adult ALL (GMALL) analyzed 59 patients treated in two successive nonrandomized phase II trials of imatinib in patients with relapsed or refractory Ph(+) ALL. Peripheral blood blasts cell clearance occurred within 8 to 14 days in most patients. However, in a significant proportion, blast counts subsequently increased 16 to 50 days after treatment onset. Imatinib mesylate was particularly effective in patients with relapse after stem cell transplantation (SCT); 75% of patients achieved complete leukemic response. Rapid development of resistance during treatment with imatinib mesylate remains a major problem. Further research efforts should explore the mechanisms of resistance to imatinib mesylate; effectiveness of other targeted therapies (eg, farnesyl transferase inhibitors [FTIs]); combination therapies; and inclusion of strategies for immune response modification (eg, donor lymphocyte infusions, interferon-alpha) for Ph/BCR-ABL-positive leukemias.

Antineoplastic Agents↗
PubMed2004

The role of new targeted therapies in small-cell lung cancer.

Lung cancer is the leading world-wide cause of cancer death. Small-cell lung cancer (SCLC) accounts for 20-25% of lung carcinomas. Chemotherapy is the cornerstone of treatment of SCLC. In limited disease, median survival is about 12-16 months with 4-5% of long-term survivors, in extensive disease median survival is 7-11 months. Improving the survival rate of patients with SCLC requires a better understanding of tumour biology and the subsequent development of novel therapeutic strategies. Several targeted agents have been introduced into clinical trials in SCLC and some phase III studies have already produced definitive results. Currently, the minority of these new agents offers a promise of improved outcomes, and negative results are more commonly reported than positive ones. To date, no targeted therapy has been approved for use in the treatment of patients with SCLC. This review will focus on the main novel biologic agents investigated in the treatment of SCLC.

Antineoplastic Agents↗
PubMed2005

Targeted therapy for the treatment of advanced non-small cell lung cancer: a review of the epidermal growth factor receptor antagonists.

Lung cancer is the most common cause of cancer death. The vast majority of patients present with non-small cell lung cancer (NSCLC) in advanced inoperable stages. The current first-line treatment for patients with advanced NSCLC includes chemotherapy and palliative radiotherapy, but most patients relapse and eventually succumb to the disease. Advances in our knowledge of cancer cell biology have led to the development of specific molecular-targeted therapeutic agents. Mutations in the epidermal growth factor receptor (EGFR) have been identified in NSCLC cells, and overexpression of the EGFR and its ligands is a common feature of many cancers; therefore, EGFR has become an attractive target for various antitumor strategies. Aberrant signaling from the EGFR is known to be important in the development and progression of NSCLC. Two oral EGFR inhibitors, gefitinib and erlotinib, are small-molecule agents that selectively inhibit the intracellular tyrosine kinase activity of the EGFR. Both have demonstrated antitumor activity in patients with advanced NSCLC who have failed all prior treatment regimens. In addition, the anti-EGFR monoclonal antibody cetuximab has shown promising activity in both first-line and second-line settings in patients with advanced NSCLC. Furthermore, patients with severe comorbidities who would not be eligible for systemic chemotherapy are candidates for these targeted therapies. Finally, these agents have also been shown to be effective for relieving symptoms, maintaining stable disease, and improving quality of life without the adverse events that may be associated with cytotoxic cancer therapies. This report will review the mechanism of action, indications, contraindications, patient selection, and efficacy and side effects of this new class of compounds. It is important for pulmonologists to be aware of this class of compounds, as they can provide benefit to patients with NSCLC who may not have been previously considered for antitumor therapy.

Carcinoma, Non-Small-Cell Lung↗
PubMed2006

Pharmaceutical prerequisites for a multi-target therapy.

The quality of a phytomedicine is defined by the quality of the herbal drug, the manufacturing of the drug preparations and the properties of the finished product, taking into account the special requirements of the individual herbal species in accordance with Good Manufacturing Practice (GMP) standards [2003. Medicinal Products for Human and Veterinary Use. Eudralex, vol. 4 (2003/94/EC)]. The quality control of the complete process is based on pharmacognostic methods, characteristic fingerprint chromatograms, defined amounts of marker substances, physicochemical characteristics and microbiological monitoring. For a herbal multi-component preparation used in multi-target therapy, these pharmaceutical prerequisites have to be ensured for all components and for their combination, as is exemplified by Iberogast((R)) (STW 5) a fixed combination of hydroethanolic extracts of bitter candytuft (Iberis amara), angelica root (Angelicae radix), milk thistle fruit (Silybi mariani fructus), celandine herb (Chelidonii herba), caraway fruit (Carvi fructus), liquorice root (Liquiritiae radix), peppermint herb (Menthae piperitae folium), balm leaf (Melissae folium) and chamomile flower (Matricariae flos) using in the therapy of gastrointestinal complaints (Rösch et al., 2006). The prerequisites for the quality of each of its components according to actual standards are at first the cultivation of the plant material according to the Guidelines for Good Agricultural Practice (GAP) conditions of Medicinal and Aromatic Plants [1998. Z. Arzn. Gew. Pfl. 3, 166-178] to yield a defined raw material of high quality. Characteristic compounds of the extracts had to be identified and different analytical methods such as HPLC, with low coefficients of variation had to be developed to analyze each of the standardized ethanolic extracts and the finished product. At the example of the extract of I. amara these necessary investigations are described. The variability of the plant material in its natural habitats, the identification of characteristic compounds and exemplary chromatograms for fingerprint evaluation and quantification are shown. These data are required for characterization of the profile of the active substances in the finished product.

Brassicaceae↗
PubMed2002

New cytotoxic agents and molecular-targeted therapies in the treatment of metastatic breast cancer.

Cytotoxic chemotherapy is important for treatment of patients with hormone-insensitive advanced breast cancer. A variety of new cytotoxic agents are promising alone or in combination. The originality, the clinical activity and side effects, as well as the current development status of these agents are reviewed. These agents include the new antimicrotubules (analogues of taxanes and vinorelbine; epothilone derivatives), oral formulations of 5-fluorouracil and other antimetabolites (tomudex, alimta, gemcitabine), liposomal anthracyclines, platinum analogues, topoisomerase I inhibitors and other compounds such as ET-743. Finally, new molecular-targeted therapies of potential interest in the treatment of metastatic breast cancer are reviewed. The growing availability of such biological therapies given alone and mainly in combination with hormonal and chemotherapeutic agents may improve in the near future the outcome of patients with metastatic breast cancer.

Antineoplastic Agents↗
PubMed2006

TRAIL receptor-targeted therapy.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines. Based on its ability to induce apoptosis selectively in a wide variety of cancer cell lines and human tumor xenografts, TRAIL has been in drug development as a potential biological agent for cancer therapy. A variety of chemotherapy agents have been shown to enhance the cytotoxic effects of TRAIL. The potential benefits of TRAIL as an anticancer therapy have been further indicated by its ability to enhance the efficacy of radiotherapy. Preclinical studies have shown the potential use of agonistic monoclonal antibodies that selectively bind TRAIL death receptors for cancer therapy. This review provides an overview of TRAIL receptor-mediated apoptosis of tumor cells, with TRAIL or agonistic monoclonal antibodies only or with chemotherapy drugs. Treatment of tumor xenografts with these ligands, alone or in combination with chemotherapy or radiation, are discussed along with preliminary information about early clinical trials. Additional clinical trials with TRAIL receptor ligands in combination treatment regimens are required to determine their potential for targeted therapy of cancer.

Animals↗
PubMed2006

Epidermal growth factor receptor pathway targeted therapy in patients with aerodigestive malignancies.

PURPOSE OF REVIEW: The present review will describe progress in the utilization of epidermal growth factor receptor (EGFR) inhibitors in the treatment of nonsmall-cell lung cancer and the treatment of squamous cell carcinoma of the head and neck. Recent findings regarding clinical activity as well as markers associated with sensitivity to these agents will be reviewed. RECENT FINDINGS: The EGFR pathway plays a crucial role in human carcinogenesis by contributing to relevant processes in tumor development and progression, including cell proliferation, differentiation, regulation of apoptotic cell death, metastatic potential, and blood vessel formation. Anti-EGFR agents include monoclonal antibodies that target the EGFR extracellular receptor domain, and small molecule tyrosine kinase inhibitors that target the EGFR intracellular domain. Both strategies have demonstrated encouraging results as monotherapies and in combination with chemotherapy and radiotherapy in areodigestive malignancies. SUMMARY: These dramatic successes have led to further clinical studies of EGFR targeted therapy in aerodigestive malignancies, making a significant impact on the clinical care of patients with nonsmall-cell lung cancer and squamous cell carcinoma of the head and neck.

Antineoplastic Agents↗
PubMed2002

Targeted therapy in non-small cell lung cancer.

Cytotoxic chemotherapy for advanced non-small cell lung cancer (NSCLC) offers only modest benefits over best supportive care alone by modestly prolonging survival, reducing symptoms, and improving quality of life. Despite the introduction of a number of new agents over the past decade, we have seen no convincing improvements in efficacy and safety with platinum-based regimens. It appears that a plateau has been reached in the development of traditional cytotoxic chemotherapy and a new paradigm is needed. Novel treatment modalities have emerged from advances in the understanding of tumor cell biology. These sophisticated new agents home in on and neutralize specific targets in the biologic pathway of cancer. This "targeted therapy" represents a new generation of anticancer treatment and a chance to revitalize the moribund state of NSCLC treatment.

Angiogenesis Inhibitors↗
PubMed2005

The management of skin reactions in cancer patients receiving epidermal growth factor receptor targeted therapies.

The use of epidermal growth factor receptor (EGFR) inhibitors for the treatment of solid tumours is increasing. However, the tolerability profile for EGFR-inhibitors, such as the monoclonal antibody cetuximab and the tyrosine kinase inhibitor erlotinib, is characterised by a unique group of skin reactions dominated by an acneiform eruption, xerosis, eczema and changes in the hair and nails. The possibility that this skin toxicity correlates with anti-tumour activity offers the potential to titrate dosing on a case-by-case basis. These skin effects may constitute a significant obstacle to treatment compliance. Accordingly, there is a need for consistent, multi-disciplinary management strategies that will allow patients to receive the recommended dosages of such targeted therapies. The eruption responds well to some acne therapies and xerosis can be controlled by standard emollients. Here we present an overview of the treatment options for skin reactions that are available today, and evaluate some of the ways in which the treatment of such EGFR-inhibitor-related skin reactions may be improved in the future. Evidence-based studies are needed to determine the best way to manage these effects.

Antibodies, Monoclonal↗
PubMed1996

Gene therapy: targeting tumor cells for destruction.

Human gene therapy involves the transfer of genetic material into cells of a patient, either in vitro or in situ, for the therapeutic purpose of correcting or ameliorating genetic defects, alleviating disease, inhibiting infectious agents or destroying cancer cells. After identification of an appropriate disease target (inherited or acquired) for treatment, a number of basic technical issues underlie any gene therapy strategy. These include the choice of genetic material to be transferred, target cell or organ for gene modification, delivery systems and representative animal models of the targeted human disease. Tumor gene therapy represents a somewhat special category for gene therapy because its intended goal is the destruction of tissue rather than its correction or preservation. For an experimental therapeutic, cancer represents a useful target due to the paucity of effective treatments and the terminal nature of the disease. Viral vectors, currently the most widely used agents for gene delivery, generally fall into two classes; defective, which are unable to replicate; and replication-competent, which are able to replicate and spread within defined cell types. The strategies employed for cancer gene therapy range from cytotoxicity, either direct or through a 'suicide' gene-producing, to induction of a host antitumor immune response. Gene therapy is rapidly moving into the clinic, yet its efficacy remains to be demonstrated. Research into the underlying fundamentals of gene therapy discussed in this review will be critical to the ultimate success of this therapeutic modality.

Animals↗
PubMed2003

Specific targeted therapy of chronic myelogenous leukemia with imatinib.

Chronic myeloid leukemia (CML) is characterized by the Philadelphia translocation that fuses BCR sequences from chromosome 22 upstream of the ABL gene on chromosome 9. The chimerical Bcr-Abl protein expressed by CML cells has constitutive tyrosine kinase activity, which is essential for the pathogenesis of the disease. Imatinib, an ATP-competitive selective inhibitor of Bcr-Abl, has unprecedented efficacy for the treatment of CML. Most patients with early stage disease achieve durable complete hematological and complete cytogenetic remissions, with minimal toxicity. In contrast, responses are less stable in patients with advanced CML. This review highlights the pathogenesis of CML, its clinical features, and the development of imatinib as a specific molecularly targeted therapy. Aspects of disease monitoring and side effects are covered as well as resistance to imatinib and strategies to overcome resistance, such as alternative signal transduction inhibitors and drug combinations. Perspectives for further development are also discussed.

Animals↗
PubMed2004

Imatinib mesylate (Gleevec/Glivec) a molecular-targeted therapy for chronic myeloid leukaemia and other malignancies.

Imatinib mesylate (Gleevec/Glivec, Novartis, Basel, Switzerland), formerly called STI571, is a specific and potent inhibitor of the BCR-ABL tyrosine kinase, the molecular hallmark of chronic myeloid leukaemia. Several clinical trials have demonstrated the efficacy of imatinib in different phases of this disease. On the other hand, imatinib is also active against other tyrosine kinases, such as ABL, the stem cell factor receptor (c-kit) and the platelet-derived growth factor receptor, whose inhibition might have potential implications for the treatment of several malignancies. In this regard, imatinib has already shown a remarkable activity in patients with hypereosinophilic syndrome and gastrointestinal stromal tumours. Imatinib is an example of how a better understanding of the pathogenetic mechanisms of a neoplastic disease can lead to the development of a molecular-targeted therapy.

Antineoplastic Agents↗
PubMed2003

STI571 as a targeted therapy for CML.

Chronic myelogenous leukemia (CML) is a clonal hematopoietic stem cell disorder that progresses through distinct phases as the malignant clone progressively loses the capacity for terminal differentiation. It is characterized by the (9;22) translocation and resultant production of the Bcr-Abl tyrosine kinase. Bcr-Abl functions as a constitutively activated tyrosine kinase, and this kinase activity is absolutely required for the transforming function of the Bcr-Abl protein. In preclinical studies, STI571 (Gleevec, imatinib mesylate), a Bcr-Abl tyrosine kinase inhibitor, specifically inhibited the proliferation of Bcr-Abl-expressing cells in vitro and in vivo. STI571 has shown remarkable results in all phases of CML. Although responses are seen in all phases of the disease, durable responses are most common in earlier stage patients. Thus, STI571 has emerged as a paradigm for gene product targeted therapy, offering expanded treatment options for patients with CML.

Antineoplastic Agents↗