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At least 469 records · Page 26Linked to original sources
PubMed1997

Anti-HER2 immunoliposomes for targeted therapy of human tumors.

Anti-HER2 immunoliposomes (ILs) have been constructed by conjugation of Fab' fragments of recombinant humanized monoclonal antibody rhuMAbHER2 to small sterically stabilized unilamellar liposomes, to create a targeted drug delivery vehicle for the treatment of HER2 (c-erbB-2, neu)-overexpressing cancers. Parameters affecting in vitro binding and internalization of ILs include liposome composition, Fab' linkage site and Fab' density. Anti-HER2 ILs have been constructed to optimize intracellular drug delivery. Doxorubicin (dox)-loaded ILs are highly stable and exhibit prolonged circulation in rats. In nude mice bearing HER2-overexpressing tumor xenografts, anti-HER2 ILs administered i.v. resulted in efficient tumor localization, with penetration of the ILs throughout the tumor mass and accumulation within tumor cells. In contrast, non-targeted liposomes resulted in extracellular tumor accumulation only. In multiple HER2-overexpressing human breast tumor xenograft models, treatment with dox-loaded anti-HER2 ILs produces significantly increased antitumor cytotoxicity as compared to free dox or dox-loaded non-targeted liposomes and significantly less systemic toxicity than free dox. To explore further the intracellular delivery advantages of ILs, anti-HER2 ILs bearing cationic lipids are being developed for nucleic acid delivery. These cationic immunoliposomes mediate efficient and specific transfection of target cells with reporter genes, as well as intracellular delivery of labeled oligonucleotides. Thus, anti-HER2 ILs represent an efficient and feasible strategy to achieve targeted intracellular delivery of therapeutic agents.

Antibodies, Monoclonal↗
PubMed2001

[Target therapy for CML--applying maxizyme].

Hammerhead type ribozyme, which have been frequently used for the purpose of specifically cleaving RNA at the GUC triplets in the experimental setting, can not be generally applicable for the gene therapy of leukemia with gene translocation. This is because the translocated sequence does not necessarily have the GUC triplets at the site of translocation. The introduction of new strategy which can specifically digest the chimera gene is considered to open new leukemia therapy with gene translocation. Maxizyme, a newly developed heterodimeric shortened ribozymes, can theoretically digest any types of chimeric genes at the site of translocation. In this review, our interesting results suggested the possible application of this maxizyme system for the treatment of chronic myelogenous leukemia with bcr/abl gene translocation.

Animals↗
PubMed2006

Targeted therapies in melanoma.

In the last decade the incidence of melanoma has been rising. Despite this, survival remains substantially constant because early diagnosis of thin lesions has increased. By contrast, metastatic melanoma continues to have a poor prognosis and it still represents a challenge for oncologists. Response rates with single agent dacarbazine range from 10% to 25% with median survival of 8 months. The advent of new drugs with specific mechanisms of action could help to improve the poor results of traditional therapies. In this review, we focused on the novel agents that entered clinical trials in melanoma patients. We show the results of some clinical trials with target-oriented drugs in melanoma patients. Moreover pre-clinical data and rationale for use in melanoma was explained. Trials with protein-kinase inhibitors, anti-CTLA-4 agents, pro-apoptotic oligonucleotides and anti-angiogenic agents were reviewed. Combinations with chemotherapeutic agents, immunotherapy and vaccine therapy were also analyzed.

Adjuvants, Immunologic↗
PubMed1994

[Targeting therapy for renal cancer].

Renal cancer is a typical tumor most insensitive to standard chemotherapy, but this hypervascular tumor has an anatomical feature by which its main feeding artery is readily accessible to transarterial targeting treatments. Effects of arterial chemoembolization, a prototype targeting chemotherapy, on renal cancer were reviewed.

Brachytherapy↗
PubMed2004

Intravenous RNA interference gene therapy targeting the human epidermal growth factor receptor prolongs survival in intracranial brain cancer.

PURPOSE: The human epidermal growth factor receptor (EGFR) plays an oncogenic role in solid cancer, including brain cancer. The present study was designed to prolong survival in mice with intracranial human brain cancer with the weekly i.v. injection of nonviral gene therapy causing RNA interference (RNAi) of EGFR gene expression. EXPERIMENTAL DESIGN: Human U87 gliomas were implanted in the brain of adult scid mice, and weekly i.v. gene therapy was started at day 5 after implantation of 500000 cells. An expression plasmid encoding a short hairpin RNA directed at nucleotides 2529-2557 within the human EGFR mRNA was encapsulated in pegylated immunoliposomes. The pegylated immunoliposome was targeted to brain cancer with 2 receptor-specific monoclonal antibodies (MAb), the murine 83-14 MAb to the human insulin receptor and the rat 8D3 MAb to the mouse transferrin receptor. RESULTS: In cultured glioma cells, the delivery of the RNAi expression plasmid resulted in a 95% suppression of EGFR function, based on measurement of thymidine incorporation or intracellular calcium signaling. Weekly i.v. RNAi gene therapy caused reduced tumor expression of immunoreactive EGFR and an 88% increase in survival time of mice with advanced intracranial brain cancer. CONCLUSIONS: Weekly i.v. nonviral RNAi gene therapy directed against the human EGFR is a new therapeutic approach to silencing oncogenic genes in solid cancers. This is enabled with a nonviral gene transfer technology that delivers liposome-encapsulated plasmid DNA across cellular barriers with receptor-specific targeting ligands.

Animals↗
PubMed2003

Imatinib mesylate (STI 571)--a new oral target therapy for chronic myelogenous leukemia (CML).

The publication provides an up-to-date review of the significance of cytogenetic abnormalities in chronic myelogenous leukemia (CML) and the development of a promising agent with specific molecular target against tyrosine kinase, product of the BCR-ABL fusion gene, namely imatinib mesylate (STI 571, Glivec). The publication summarizes the achieved results with this compound in the chronic phase CML (in patients resistant to interferon and in newly diagnosed patients) further in patients in the accelerated phase and in blast crisis and in patients in relapse after allogeneic stem cells transplantations for CML. The results in Ph+ acute lymphoblastic leukemia are also presented. The mechanisms of resistance to imatinib mesylate and the possibilities how to overcome or circumvent it are mentioned (escalation of the dosage, combination of imatinib with some other treatment modalities as immunotherapy, interferon or convention chemotherapy and development of new drugs).

Administration, Oral↗
PubMed2004

Emerging role of EGFR-targeted therapies and radiation in head and neck cancer.

The treatment of head and neck cancer has been at the forefront of novel therapeutic paradigms. The introduction of drugs that interact with selective biologic pathways in the cancer cell has generated considerable attention recently. A wide variety of new compounds that attempt to target growth-signaling pathways have been introduced into the clinic. A majority of studies in the clinic have focused on epidermal growth factor receptor (EGFR) antagonists, but future studies will likely build upon or complement this strategy with agents that target angiogenic or cell-cycle pathways. EGFR activation promotes a multitude of important signaling pathways associated with cancer development and progression, and importantly, resistance to radiation. Since radiation therapy plays an integral role in managing head and neck squamous cell cancer (HNSCC), inhibiting the EGFR pathway might improve our efforts at cancer cure. The challenge now is to understand when the application of these EGFR inhibitors is relevant to an individual patient and how or when these drugs should be combined with radiation or chemotherapy. Are there molecular markers available to determine who will respond to EGFR inhibitors and who should be treated with alternative approaches? What are the mechanisms behind intrinsic or acquired resistance to targeted agents, and how do we prevent this problem? We need to formulate integrated laboratory/clinical research programs that address these important issues.

Antibodies, Monoclonal↗
PubMed2000

Targeted therapy of acute myeloid leukemia with monoclonal antibodies and immunoconjugates.

Traditional chemotherapy for acute leukemia often causes life-threatening toxic effects due to a lack of specificity for hematopoietic cells. Monoclonal antibodies and fusion proteins that target cell surface antigens on leukemic blasts are being evaluated for their cytotoxic effects and as a means of delivering chemotherapeutic agents or radiation directly to malignant cells. It is hoped that this strategy might selectively ablate malignant cells without many of the toxic effects commonly associated with conventional chemotherapy. In acute myeloid leukemia (AML), the cell surface antigens CD33 and CD45 are especially suitable targets. Although CD33 is expressed on AML blast cells from about 90% of patients, normal hematopoietic stem cells lack this antigen, as do essentially all nonhematopoietic tissues. For that reason, anti-CD33 antibodies have been created to target malignant myeloid and immature normal cells selectively while sparing normal stem cells. Anti-CD33 antibodies have also been used to deliver radiation or a cytotoxic agent directly to leukemic cells. Since the vast majority of leukemias and normal stem cells express the cell surface antigen CD45, another targeting approach allows the delivery of myeloablative radiation to bone marrow and spleen, common sites of leukemic involvement. Consequently, 131I-labeled anti-CD45 antibody has been combined with traditional preparative regimens for patients receiving bone marrow transplantation for acute leukemia. Finally, fusion proteins such as those combining diphtheria toxin with granulocyte-macrophage colony-stimulating factor (GM-CSF) to target the GM-CSF receptor are now being evaluated in clinical trials. Both unconjugated and conjugated antibodies have shown promise in early clinical trials, and may represent appealing therapeutic alternatives for patients with AML.

Acute Disease↗
PubMed2006

VEGF-targeted therapy in renal cell carcinoma: active drugs and active choices.

Several molecular pathways are implicated in renal cell carcinoma (RCC) pathogenesis, including von Hippel--Lindau (VHL) gene inactivation leading to vascular endothelial growth factor (VEGF) expression. Therapeutic targeting of VEGF and related pathways has been undertaken in metastatic RCC. Substantial clinical activity has been reported for multiple agents, leading to several clinical questions regarding the optimal use of these agents. The biology, clinical results, and future considerations regarding VEGF-targeted agents in RCC are presented in this article.

Angiogenesis Inhibitors↗
PubMed2006

Atrasentan: a rationally designed targeted therapy for cancer.

Endothelin axis deregulation triggers a series of events that ultimately activates proliferation, invasion, escape from programmed cell death, new vessel formation, abnormal osteogenesis and alteration of nociceptive stimuli. Atrasentan is a novel agent that effectively targets this pathway and is able to inhibit and/or reverse several of these events. Biologic and clinical activity in patients with prostate cancer have been demonstrated in a phase III, placebo-controlled setting by the suppression of markers of biochemical prostate cancer progression and a delay in time to disease progression. Atrasentan may represent a therapeutic option in the management of prostate and other cancers that is worthy of continued investigation.

Animals↗
PubMed2006

Novel tumor marker REG4 detected in serum of patients with resectable pancreatic cancer and feasibility for antibody therapy targeting REG4.

Pancreatic ductal adenocarcinoma (PDAC) shows the worst mortality rate among common malignancies, with a 5-year survival rate of only 4%, and the majority of PDAC patients are diagnosed at an advanced stage in which no effective therapy is available at present. Although the proportion of curable cases is still not so high, surgical resection of early stage PDAC is the only way to cure the disease. Hence, establishment of a screening strategy to detect early stage PDAC by novel serological markers is required urgently, and development of novel molecular therapies for PDAC treatment is also eagerly expected. We here report overexpression of REG4, a new member of the regenerating islet-derived (REG) family, in PDAC cells on the basis of genome-wide cDNA microarray analysis as well as reverse transcription-polymerase chain reaction and immunohistochemical analysis. We also detected significant elevation of REG4 in the serum of some patients with early-stage PDAC using our enzyme-linked immunosorbent assay system, indicating the possibility of REG4 as a new serological marker of PDAC. Furthermore, we found that knockdown of endogenous REG4 expression in PDAC cell lines with small interfering RNA caused a decrease in cell viability. Concordantly, addition of recombinant REG4 to the culture medium enhanced growth of a PDAC cell line in a dose-dependent manner. A monoclonal antibody against REG4 neutralized its growth-promoting effects and attenuated significantly the growth of PDAC cells. These findings indicate that REG4 is a promising tumor marker to screen early-stage PDAC, and also that neutralization of REG4 by the antibody may offer novel potential tools for the treatment of PDAC.

Adenocarcinoma↗
PubMed1998

Targeted therapy with a novel enediyene antibiotic calicheamicin theta(I)1 effectively suppresses growth and dissemination of liver metastases in a syngeneic model of murine neuroblastoma.

The suppression of metastases in malignant diseases is one of the major goals in targeted chemotherapy. This was achieved with an antibody drug conjugate between a novel, rationally designed enediyene antibiotic calicheamicin theta(I)1 of exceptionally high cytotoxic potency and an antiganglioside GD2 monoclonal antibody 14G2a. Effective suppression of hepatic metastases was demonstrated in a novel syngeneic model of murine neuroblastoma that simulates the situation in patients in terms of antigen heterogeneity and presence of the target antigen on normal tissues. Here, we describe the first successful use of calicheamicin theta(I)1 for targeted chemotherapy in a clinically relevant syngeneic metastasis model.

Aminoglycosides↗
PubMed1995

Treatment of unresectable hepatocellular carcinoma: targeted therapies using iodized oil.

Arterially administered iodized oil (Lipiodol) localizes selectively in HCCs for prolonged periods. Lipiodol-based intra-arterial chemotherapy and chemoembolization have yielded tumor response rates and survival benefits better than those offered by other therapies for unresectable Okuda Stage I and II HCC. Further trials are indicated to compare the different Lipiodol-cytotoxic-embolic regimens available. Early results of Lipiodol-targeted radiotherapy are available. This is a promising therapeutic development, and warrants comparison with chemoembolization in a large prospective randomized trial.

Carcinoma, Hepatocellular↗
PubMed2005

VEGF-targeting therapy for breast cancer.

Vascular Endothelial Growth Factor (VEGF) plays an important role in multiple physiologic and pathologic processes involving endothelial cells. Several preclinical and clinical sources of evidence suggest its importance in human breast cancer. Based on the presumed biologic relevance of VEGF in human breast cancer, clinical trials using agents targeting VEGF were launched beginning in the late 1990s. This clinical trial effort came to fruition in 2005 with the success of the first large, prospective randomized trial of anti-VEGF therapy in patients with front-line metastatic breast cancer, which demonstrated the benefit of adding the monoclonal anti-ligand antibody bevacizumab to the chemotherapeutic agent paclitaxel. Based upon this success, numerous anti-VEGF agents are now being tested in patients with breast cancer, and adjuvant therapy trials are in development. Nevertheless, important questions remain regarding the biology and clinical development of these agents in breast cancer.

Angiogenesis Inhibitors↗
PubMed2006

Raloxifene, an oestrogen-receptor-beta-targeted therapy, inhibits androgen-independent prostate cancer growth: results from preclinical studies and a pilot phase II clinical trial.

OBJECTIVES: To determine, in preclinical in vivo animal and in clinical studies, whether raloxifene (a selective oestrogen-receptor (ER) modulator that targets ER-beta and induces apoptosis in vitro in androgen-independent prostate cancer, AIPC cells) affects prostate cell differentiation, proliferation and carcinogenesis, and in the pilot phase II clinical trial, the response rate and duration of patients with AIPC treated with a daily oral dose of raloxifene. PATIENTS, MATERIALS AND METHODS: Tumour proliferation rate in response to raloxifene treatment, and molecular markers of cell cycle and apoptosis, were evaluated in established ER-beta-positive androgen-dependent (AD) CWR22 and AI CWRSA9 human xenograft prostate cancer models. Twenty-one patients with AIPC and evidence of disease progression were enrolled into the clinical trial and given daily oral raloxifene. RESULTS: There was significant growth inhibition by raloxifene in the ADPC and AIPC xenograft models (CWR22 68%, P < 0.010; CWRSA9 64%, P < 0.001), with no tumour regression. There was evidence of G1 arrest by increased p27kip1 expression in the raloxifene-treated group. Eighteen patients comprised the efficacy analysis, as three withdrew before the first evaluation. At the first evaluation, five men had stable disease and continued on the study for a median of five cycles. The longest response was 17 cycles. Drug related toxicity was minimal. CONCLUSION: Raloxifene has activity in xenograft models, slowing disease progression. This translated to possible disease stabilization in patients with AIPC. Further studies are warranted.

Aged↗
PubMed2006

Possible molecular target therapy with rapamycin in MDS.

The authors previously reported the mRNA expression of Glutathione S-transferases theta (GSTT)-1, wild type (623 bp) and mutant (500 bp) in MDS patients. The deletion of 123 bp creates a sequence that is homologues to mammalian target of rapamycin (mTOR). To analyse the function of mutant GSTT-1 gene, stable transformants for the mutant and wild-type GSTT-1 gene, respectively, were established. In this study, the expression of wild and mutant type GSTT-1 gene of those stable transformants and bone marrow cells from MDS patients by RT-PCR was observed in the presence or absence of rapamycin. In result, exposure of rapamycin led to the disappearance of just the mutant gene band. This phenomenon possibly indicates that rapamycin only attacked the mutant GSTT-1 expressing clone.

Bone Marrow Cells↗