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PubMed2000

Effects of cellular repair and proliferation on targeted radionuclide therapy: a modelling study.

A previous targeted radionuclide therapy modelling study has been extended to include the radiobiological effects of cellular repair and proliferation. Dose distributions have been converted into biologically effective dose (BED) distributions using a previously published formulation. With suitable estimated parameters, corrected tumour control probability (TCP) values were derived. The dependence of BED on the physical half-life of the radionuclide was also modelled. Results indicate that the TCP is greater when a shorter physical half-life is employed.

Cell Division↗
PubMed1998

The photobiology of photodynamic therapy: cellular targets and mechanisms.

Photodynamic therapy (PDT) is dependent on the uptake of a photosensitizing dye, often a porphyrin-related macrocycle, by the tumor or other abnormal tissue that is to be treated, the subsequent irradiation of the tumor with visible light of an appropriate wavelength matched to the absorption spectrum of the dye, and molecular oxygen to generate reactive oxygen intermediates. The initial oxidative reactions lead to damage to organelles in which the dye is bound, culminating in cell death and destruction of the tumor or abnormal tissue. Apoptosis is a common mechanism of cell death after PDT both in vitro and in vivo. PDT also triggers the activation of several signal transduction pathways in the treated cells; some of these are stress responses aimed at cell protection, while others are likely to contribute to the cell death process. The photosensitizers of greatest interest in PDT bind to various cytoplasmic membranes but are not found in the nucleus and do not bind to DNA. Nevertheless, some DNA damage is produced that can lead to mutagenesis, the extent of which is dependent on the photosensitizer, the cellular repair properties and the target gene. Thus, in spite of generating some responses common to ionizing radiation and other oxidative stresses, PDT is unique in the subcellular localization of damage, the combination of signaling pathways that are activated, and rapid kinetics of the induction of cell death processes.

Animals↗
PubMed2006

Preparation and use of 131I magic gel as a dosimeter for targeted radionuclide therapy.

Clinical interest in targeted radiotherapy is increasing, but accurate dosimetry studies are difficult to achieve. The aim of this study was to investigate the preparation and use of a "normoxic" polymer gel (with a tissue-equivalent density), known as MAGIC gel, and magnetic resonance imaging (MRI) for nonsealed source dosimetry. MAGIC gel samples were mixed with deionized water (MAGIC95) or a solution of 131I (131I-MAGIC95). By measuring the radioinduced variations of R2 values (relaxivity) of irradiated gels, we analyzed the response of MAGIC95 and MAGIC samples to external photon beam or 131I irradiation (131I-MAGIC95). MRI showed that a homogeneous dose distribution from 131I can be achieved if the MAGIC gel, at a temperature of approximately 35 degrees C, is mixed in 131I solution and the resulting mixture shaken gently for 30 minutes. It is important that the vials are completely filled, as residual air reduces polymerization and causes spontaneous polymerization stripes. Responses of MAGIC95 or MAGIC gels to external photon beam irradiation are similar. The variations of R2 values for 131I-MAGIC95 gel depend on the absorbed dose and not on the duration of the irradiation being reproducible from one batch of gel to another. MAGIC gel responses to 131I or external beam irradiation (EBI) are different. Our preliminary results suggest that radiolabeled "normoxic" polymer can be easily and safely produced. Radiolabeled MAGIC gel may, therefore, be suitable for the creation of phantoms dedicated to nonsealed source dosimetry.

Ascorbic Acid↗
PubMed2003

Random peptide libraries displayed on adeno-associated virus to select for targeted gene therapy vectors.

Characterizing the molecular diversity of the cell surface is critical for targeting gene therapy. Cell type-specific binding ligands can be used to target gene therapy vectors. However, targeting systems in which optimum eukaryotic vectors can be selected on the cells of interest are not available. Here, we introduce and validate a random adeno-associated virus (AAV) peptide library in which each virus particle displays a random peptide at the capsid surface. This library was generated in a three-step system that ensures encoding of displayed peptides by the packaged DNA. As proof-of-concept, we screened AAV-libraries on human coronary artery endothelial cells. We observed selection of particular peptide motifs. The selected peptides enhanced transduction in coronary endothelial cells but not in control nonendothelial cells. This vector targeting strategy has advantages over other combinatorial approaches such as phage display because selection occurs within the context of the capsid and may have a broad range of applications in biotechnology and medicine.

Amino Acid Sequence↗
PubMed2003

How to overcome (and exploit) tumor hypoxia for targeted gene therapy.

Tumor hypoxia has long been recognized as a critical issue in oncology. Resistance of hypoxic areas has been shown to affect treatment outcome after radiation, chemotherapy, and surgery in a number of tumor sites. Two main strategies to overcome tumor hypoxia are to increase the delivery of oxygen (or oxygen-mimetic drugs), and exploiting this unique environmental condition of solid tumors for targeted therapy. The first strategy includes hyperbaric oxygen breathing, the administration of carbogen and nicotinamide, and the delivery of chemical radiosensitizers. In contrast, bioreductive drugs and hypoxia-targeted suicide gene therapy aim at activating cytotoxic agents at the tumor site, while sparing normal tissue from damage. The cellular machinery responds to hypoxia by activating the expression of genes involved in angiogenesis, anaerobic metabolism, vascular permeability, and inflammation. In most cases, transcription is initiated by the binding of the transcription factor hypoxia-inducible factor (HIF) to hypoxia responsive elements (HREs). Hypoxia-targeting for gene therapy has been achieved by utilizing promoters containing HREs, to induce selective and efficient transgene activation at the tumor site. Hypoxia-targeted delivery and prodrug activation may add additional levels of selectivity to the treatment. In this article, the latest developments of cancer gene therapy of the hypoxic environment are discussed, with particular attention to combined protocols with ionizing radiation. Ultimately, it is proposed that by adopting specific transgene activation and molecular amplification systems, resistant hypoxic tumor tissues may be effectively targeted with gene therapy.

Animals↗
PubMedDate not supplied

Linomide and antibody-targeted superantigen therapy abolishes formation of liver metastases in mice.

Hematogenous spread of tumor cells and metastasis formation in the liver are insidious aspects of cancer progression and are not frequently amenable to curative treatment. We examined the effect of Linomide and antibody-targeted therapy against the formation of hepatic metastases in vivo. For this purpose, syngenic B16 melanoma cells transfected with GA733-2 (a human colon cancer cell surface antigen) were injected into a mesenteric vein of C57/Bl6 mice. To test bacterial superantigen (Sag) targeting for immunotherapy of liver metastases, we used genetically fused proteins consisting of SEA and a Fab moiety of a GA733-2 tumor-reactive antibody (C215Fab-SEA). Linomide dose-dependently reduced hepatic metastases, and at 300 mg/kg this reduction was more than 80%. Treatment with C215Fab-SEA decreased metastases formation by 49% and the combination of Linomide and C215Fab-SEA was found to completely abolish liver metastases (>99% reduction). Taken together, our novel data suggest that Linomide and antibody-targeted superantigen therapy individually markedly reduce and together abolish liver metastases. Considering that current therapy of hepatic metastases is mainly limited to surgical resection in a subgroup of patients, these findings indicate that Linomide alone or in combination with antibody-targeted superantigen may provide a novel approach against liver metastases.

Adjuvants, Immunologic↗
PubMed2005

Receptor-targeted cancer therapy.

Insight into the molecular mechanisms of malignant transformation is changing the way cancer is being treated. Conventional treatment strategies target the DNA of all dividing cells, resulting in a significantly increased risk of collateral toxicity. In addition, the accumulation of multiple mutations leads to drug resistance in many cancer cells. Targeted strategies have now been developed that specifically disrupt oncogenically active cell surface receptors and endogenous signaling molecules. These agents have a much greater selectivity for tumor tissue and decreased risk of side effects. Increased signaling through ErbB receptors via gene amplification, overexpression, and mutation has been implicated in many human cancers and associated with poor prognosis. Interruption of this process has been shown to cause antitumor effects. Downregulation of the ErbB receptors, HER-2/neu, and later EGFR, with monoclonal antibodies was the first demonstration of targeted therapy. Subsequently, the ErbB tyrosine kinase domain has been successfully targeted with small molecule inhibitors. The development of novel ErbB-directed entities is ongoing, with particular promise being shown by strategies targeting receptor interaction in oligomeric complexes.

Animals↗
PubMed2007

Mammalian target of rapamycin is activated in human gastric cancer and serves as a target for therapy in an experimental model.

The mammalian target of rapamycin (mTOR) has become an interesting target for cancer therapy through its influence on oncogenic signals, which involve phosphatidylinositol-3-kinase and hypoxia-inducible factor-1alpha (HIF-1alpha). Since mTOR is an upstream regulator of HIF-1alpha, a key mediator of gastric cancer growth and angiogenesis, we investigated mTOR activation in human gastric adenocarcinoma specimens and determined whether rapamycin could inhibit gastric cancer growth in mice. Expression of phospho-mTOR was assessed by immunohistochemical analyses of human tissues. For in vitro studies, human gastric cancer cell lines were used to determine S6K1, 4E-BP-1 and HIF-1alpha activation and cancer cell motility upon rapamycin treatment. Effects of rapamycin on tumor growth and angiogenesis in vivo were assessed in both a subcutaneous tumor model and in an experimental model with orthotopically grown tumors. Mice received either rapamycin (0.5 mg/kg/day or 1.5 mg/kg/day) or diluent per intra-peritoneal injections. In addition, antiangiogenic effects were monitored in vivo using a dorsal-skin-fold chamber model. Immunohistochemical analyses showed strong expression of phospho-mTOR in 60% of intestinal- and 64% of diffuse-type human gastric adenocarcinomas. In vitro, rapamycin-treatment effectively blocked S6K1, 4E-BP-1 and HIF-1alpha activation, and significantly impaired tumor cell migration. In vivo, rapamycin-treatment led to significant inhibition of subcutaneous tumor growth, decreased CD31-positive vessel area and reduced tumor cell proliferation. Similar significant results were obtained in an orthotopic model of gastric cancer. In the dorsal-skin-fold chamber model, rapamycin-treatment significantly inhibited tumor vascularization in vivo. In conclusion, mTOR is frequently activated in human gastric cancer and represents a promising new molecular target for therapy.

Adenocarcinoma↗
PubMed2005

[Experimental study of dually targeting gene therapy system for pituitary adenomas].

OBJECTIVE: To construct a dually targeting gene therapy system for pituitary adenomas and investigate its effect. METHODS: Promoter hGHp containing human growth hormone gene was obtained from human genome and cloned into the plasmid pcDNA3.1/His A with the promoter cut to construct the recombinant plasmid pcDNA3.1/His A-hGHp. HSV-TK gene was obtained from the plasmid pcDNA3.1/His A-TK and integrated into the plasmid pcDNA3.1/His A-hGHp to construct the recombinant plasmid pcDNA3.1/His A-hGHp-TK. A GE7 gene delivery system-mediated human growth hormone promoter controlled gene therapy system was constructed by adding the mixture of GE7-polylysine and HA20-polylysine into the DNA solution. Human growth hormone-secreting pituitary adenoma cells of the GH3 line, human myeloma cells of the U-2OS line, and human oophoroma cells of the HO8910PM line were cultured and transfected with PBS or GE7 packaged pcDNA3.1/HisA-TK or pcDNA3.1/HisA-hGHp-TK. Western blotting was used to examine the expression of PBS or GE7 packaged pcDNA3.1/HisA-TK or pcDNA3.1/HisA-hGHp-TK protein, MTT method was used to detect the cell survival rate. Another GH3, U-2OS, and HO8910PM cells were cultured and transfected with PBS or GE7 packaged pcDNA3.1/HisA-TK or pcDNA3.1/HisA-hGHp-TK and then ganciclovir (GCV) was added. MTT method was used to examine the cell survival rates. GH3 cells were injected subcutaneously into the right axilla of 200 SD nude rats loaded with human pituitary adenoma. Three weeks after the rats were randomly divided into 5 equal groups: PBS group in which PBS was injected into the tumor and GCV was injected peritoneally; GE7 group in which GE7-polylysine and HA20-polylysine were injected into the tumor and GCV was injected peritoneally; without TK group in which GE7-packaged pcDNA3.1/His A-hGHp was injected into the tumor and GCV was injected peritoneally; without GCV group in which GE7-packaged pcDNA3.1/His A-hGHp-TK was injected into the tumor and PBS was injected peritoneally; and treatment group in which GE7-packaged pcDNA3.1/His A-hGHp-TK was injected into the tumor and GCV was injected peritoneally. Peritoneal injection lasted 21 days for all groups. On the days 3, 7, 14, and 21 eight rats from each group were killed to measure the volume of tumor. The survival rate of the rest 8 rats was observed. RESULTS: A dually targeting gene therapy system for pituitary adenoma was composed successfully. HSV-TK protein was expressed in the GH3 cells but not in the U-2OS and HO8910PM cells after transfection of GE7-packaged pcDNA3.1/HisA-hGHp-TK; and was expressed in the GH3 and HO8910PM cells but not in the U-2OS cells after transfection of GE7-packaged pcDNA3.1/HisA-TK. Transfection of GE7-packaged pcDNA3.1/HisA-hGHp-TK and addition of GCV significantly decreased the survival rate of the GH3 cells, but did not influence the survival rates of the U-2OS and HO8910PM cells. Transfection of GE7-packaged pcDNA3.1/HisA-TK and addition of GCV significantly decreased the survival rate of GH3 and HO8910PM cells but did not influence the survival of the U-2OS and HO8910PM cells. When the GH3 cells were transfected with GE7-packaged pcDNA3.1/HisA-hGHp-TK with the addition of GCV of the concentration of 4 mg/L the survival rate decreased to 10%, when the GCV concentration was raised to 8 mg/L the survival rate of the GH3 cells was < 5%. Three days after the beginning of treatment the tumor volume of different groups of rats increased at different degrees and the tumor was smallest in the treatment group in comparison with the other groups (all P < 0.05). Seven days after the beginning of treatment the tumor volume of the treatment group significantly decreased and the tumors of the other groups still increased (all P < 0.001). The survival time of the treatment group was over 120 days, significantly longer than those of the other groups (all about 40 days). CONCLUSION: GE7 system-mediated hGHp controlled gene therapy system is hopeful to be the targeted therapeutic strategy for pituitary adenomas.

Adenoma↗
PubMed2004

LEAPT: lectin-directed enzyme-activated prodrug therapy.

Targeted drug delivery to selected sites allows reduced toxicity, enhanced efficiency and interchangeable target potential [Langer, R. (2001) Science 293, 58-59 and Molema, G. & Meijer, D. K. F., eds. (2001) Drug Targeting (Wiley-VCH, Weinheim, Germany)]. We describe a bipartite drug-delivery system that exploits (I) endogenous carbohydrate-to-lectin binding to localize glycosylated enzyme conjugates to specific, predetermined cell types followed by (II) administration of a prodrug activated by that predelivered enzyme at the desired site. The carbohydrate structure of an alpha-L-rhamnopyranosidase enzyme was specifically engineered through enzymatic deglycosylation and chemical reglycosylation. Combined in vivo and in vitro techniques (gamma scintigraphy, microautoradiography and confocal microscopy) determined organ and cellular localization and demonstrated successful activation of alpha-L-rhamnopyranoside prodrug. Ligand competition experiments revealed enhanced, specific localization by endocytosis and a strongly carbohydrate-dependent, 60-fold increase in selectivity toward target cell hepatocytes that generated a >30-fold increase (from 0.02 to 0.66 mg) in protein delivered. Furthermore, glycosylation engineering enhanced the serum-uptake rate and enzyme stability. This created enzyme activity (0.2 units in hepatocytes) for prodrug therapy, the target of which was switched simply by sugar-type alteration. The therapeutic effectiveness of lectin-directed enzyme-activated prodrug therapy was shown through the construction of the prodrug of doxorubicin, Rha-DOX, and its application to reduce tumor burden in a hepatocellular carcinoma (HepG2) disease model.

Animals↗
PubMed2004

Targeted molecular therapy for malignant gliomas.

Advances in our understanding of the molecular changes and resultant cellular effects in malignant glioma are expanding the opportunities for novel targeted therapies. At present, chemotherapy and radiation followed by chemotherapy with nonselective cytotoxic agents is emerging as a standard treatment option for patients with malignant glioma. Unfortunately significant improvements in response and survival have not occurred for the majority of patients. The continued improvement in patient outcomes will require the incorporation of glioma-specific therapies either in the form of compounds specifically targeted to glioma-specific receptors or that inhibit signaling pathways promoting glioma survival and progression.

Glioma↗
PubMed2003

Cancer therapy: new targets for chemotherapy.

The number two cause of mortality in developed countries is cancer. Despite the enormous effort put into cancer prevention, early diagnosis and treatment, it is likely that the incidence of the cancer morbidity and mortality will increase for the foreseeable future. This is due to various factors such as increased life expectancy, changes in environment and also the socio-economic situation around the world. Some cancer attracts more attention than others and increasingly epidemiological information is reaching the general public and is beginning to influence behavior. It is now well recognized that, for example, 1 of 8 women in the industrialized world will be diagnosed with breast cancer. Additionally, a strong correlation was established between lung cancer incidence and smoking and it is broadly accepted that the incidence of colon cancer is directly related to age and diet, and has been increasing over time. The current failure of preventive measures to significantly reduce the increasing incidence of these common tumors illustrates the importance of effective cancer treatment strategies, including chemotherapy. The combination of various anticancer drugs, given together with surgery and radiotherapy, gives hope to many patients. There has been recent evidence of improved therapeutic outcome with recent approaches and newer agents but for continuing effective chemotherapeutic treatment there is a need for a detailed understanding of their mechanisms of action and on the rationale of their application. This review attempts to provide up-to-date information regarding the development of new and innovative treatment strategies for cancer chemotherapy. Virtually, every year several of new targets for cancer therapy on both, cellular and molecular levels, are identified and new drugs enter not only clinical trials but also are included in well accepted and documented therapeutic protocols. As this review is in addition to our review published previously (Medical Principles and Practice 11, 2002, 117-125), we have tried to include new and innovative targets and drugs that attract attention at present. Although it is not possible to provide a complete list of all achievements and cover all work done in this field, we hope to be able to give some insight into this rapidly developing area.

Alkyl and Aryl Transferases↗
PubMed2004

Novel approaches for targeted cancer therapy.

The clinical use of chemotherapeutic agents against malignant tumors is successful in many cases but suffers from major drawbacks. One drawback is lack of selectivity, which leads to severe side effects and limited efficacy; and another is the emergence/selection of drug-resistance. To limit non-specific toxicity and to improve the efficiency of cancer therapy, "tumor markers", which are proteins generally overexpressed on the surface of tumor cells, can be selectively targeted. Growth factor receptors are one of the most extensively studied tumor markers. The implication of growth factor receptors in the pathogenesis and evolution of cancer has clearly been established and therefore, provides a rationale for therapeutic intervention. The targeting of cytotoxic substances to tumor markers with "magic bullets" is an old idea that raised high expectations but also disappointment. Over the past decade, newly gained understanding of mechanisms for targeted therapy have brought new hopes. Pharmacological agents that selectively target and block the action of growth factors and their receptors have been attempted, such as monoclonal antibodies (mAbs) (whole molecule or fragments), bispecific antibodies, mAbs conjugated to drugs, toxins or radioisotopes, small peptidic and peptidomimetic molecules in free form or conjugated to drugs, anti-sense oligonucleotides, immunoliposomes-encapsulated drugs, and small molecule inhibitors. This review will focus on current developments of selective targeting and bypassing drug resistance in the management of growth factor receptor-overexpressing tumors.

Animals↗
PubMed2003

New targets for therapy in prostate cancer: modulation of stromal-epithelial interactions.

Changes in genomic and phenotypic expression of progressing prostate tumors and their stroma occur in a dynamic fashion based on bidirectional signaling from stromal-epithelial interactions. These interactions may underlie the ability of prostate cancer cells to survive and proliferate in the prostate and bone. By investigating the phenotypic and genotypic changes of stromal cells adjacent to cancer cells and the reciprocal changes of cancer cells, novel molecular markers may be developed to diagnose cancer earlier before pathologic appearance of cancer cells at the primary site. Attacking epithelial and stromal elements together is a unique approach to both localized and metastatic prostate cancer therapy. Co-targeting both tumor cells and stroma requires identifying a reliable tumor and tissue-specific cis-DNA element, such as osteocalcin (OC) promoter. OC expression is elevated in prostate tumor cells and in prostate and bone stromal cells interdigitating with both localized and metastatic prostate epithelium. We have previously designed an adenovirus-based therapeutic gene vehicle and demonstrated that a replication-competent adenoviral vector (Ad vector) is highly efficient in blocking the growth of cancer cells in culture, including cells without androgen receptor as well as cells that do or do not make prostate-specific antigen. In vivo, intravenous administration of an Ad-OC vector was effective against preexisting human prostate cancer subcutaneous and bone xenografts. The addition of vitamin D(3) enhanced further viral replication at target sites. Co-targeting tumor cells and stroma using systemic Ad vector is a viable and promising option for treatment of both localized and metastatic prostate cancer.

Adenocarcinoma↗
PubMed2004

Surface antigens/receptors for targeted cancer treatment: the GnRH receptor/binding site for targeted adenocarcinoma therapy.

Colon, breast and lung adenocarcinomas - three of the major malignancies occurring in humans, together with ovarian, endometrial, kidney and liver adenocarcinomas, account for more then 50% of cancer-related death. As the number of cancer-related deaths has not decreased in recent years, major efforts are being made to find new and more specific drugs for cancer treatment. One of the approaches developed in recent years for targeted cancer therapy is the construction and use of chimeric proteins. Chimeric cytotoxins are a class of targeted molecules designed to recognize and specifically destroy cells over-expressing specific receptors. These molecules, designed and constructed by gene fusion techniques, comprise both the cell-targeting and the cell-killing moieties. Our laboratory has developed a number of chimeric proteins based on an analog of Gonadotropin Releasing Hormone (GnRH) as their targeting moiety. These chimeras recognize a GnRH-binding site that, we found, was over-expressed on a surprisingly wide variety of cancers, all confined to the adenocarcinoma type. A GnRH analog was fused to a large number of killing moieties, including bacterial or human pro-apoptotic proteins. All GnRH-based chimeric proteins selectively killed adenocarcinoma cells both in vitro and in vivo. Utilizing GnRH-based chimeric proteins for targeted therapy could open up new vistas in the fight against adenocarcinomas in humans. This review summarizes the latest developments in the area of targeted cancer therapy via specific antigens/receptors, as well as our latest findings in targeting GnRH-binding sites using GnRH-based chimeric proteins for specific and targeted adenocarcinoma therapy in humans.

Adenocarcinoma↗
PubMed2005

Inhibition of phosphatidylinositol-3-kinase causes cell death through a protein kinase B (PKB)-dependent mechanism and growth arrest through a PKB-independent mechanism.

PURPOSE: To identify whether inhibition of phosphatidylinositol-3-kinase (PI3K) causes apoptosis through inhibition of protein kinase B (PKB), implicating PKB as an important therapeutic target in prostate cancer. METHODS AND MATERIALS: After treatment with the PI3K inhibitor, LY294002, proliferation and apoptosis of the prostate cancer cell line, LNCaP, were measured by cell cycle analysis and cleavage of poly (ADP-ribose) polymerase. To test the hypothesis that inhibition of PKB is responsible for the LY294002-induced apoptosis, LNCaP cells expressing a constitutively active form of PKB were generated. RESULTS: Treatment of LNCaP cells with the PI3K inhibitor, LY294002, caused inactivation of PKB, growth arrest, and apoptosis. LY294002-induced apoptosis was increased in the absence of serum. The G1 growth arrest was associated with an increase in p27(kip1) expression. Cells expressing constitutively active PKB were protected from apoptosis induced by LY294002, but not from the G1 growth arrest induced by PI3K inhibition. CONCLUSION: These data suggest that PKB activity regulates apoptosis, but not G1 arrest, and identify PKB as a potential critical target for cancer therapy. Targeted therapy against kinases might complement more conventional therapies, including androgen suppression for prostate cancer.

Apoptosis↗
PubMed2003

Strategies to target HER2/neu overexpression for cancer therapy.

Amplification or overexpression of the HER2/neu (also known as erbB-2) gene has been noted in various types of human cancers. In addition to malignant transformation, the activation of signaling pathways of HER2/neu enhances various metastasis-associated properties and may render cancer cells resistant to conventional therapies. This, at least partially, contributes to the poor prognosis and lower survival rate of patients. Many studies have demonstrated that repression of HER2/neu overexpression suppresses the malignant phenotypes of cancer cells. Therefore, various novel HER2/neu-blocking agents have been developed, several of which have been tested in clinical trials with satisfactory results, including trastuzumab, a HER2/neu monoclonal antibody that has been approved by the FDA in the treatment of HER2/neu-overexpressing breast cancer patients. In this article, we intend to discuss the biological relevance and significance of HER2/neu overexpression in tumorigenesis, metastasis, and resistance to conventional therapy. We also summarize the currently available strategies and combination therapies targeting HER2/neu-overexpressing cancer cells. Although the optimal treatment for HER2/neu-overexpressing cancer patients remains elusive, the initial success of trastuzumab indicates that HER2/neu is a good target for cancer therapy. Further elucidation of HER2/neu-mediated pathways and downstream molecules is critical to provide alternative therapies, overcome drug resistance, and improve the therapeutic outcome for HER2/neu-overexpressing cancer patients.

Animals↗
PubMed2002

CC Chemokine Receptor 4 as a Possible Target for Therapy of Atopic Dermatitis.

The CC chemokine receptor CCR4 is selectively expressed on Th2-type CD4(+) T cells. Therefore, its ligands, thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine, can facilitate the recruitment, activation and development of Th2 polarized cells. The allergic inflammation of atopic dermatitis is characterized by a predominance of Th2-type cells. Some reports suggest that CCR4 and TARC are important for the pathogenesis of atopic dermatitis. The future aspects of atopic dermatitis therapy that specifically targets CCR4 are discussed. (c) 2002 Prous Science. All rights reserved.

Journal Article↗