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Results for “tumor therapy”

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At least 19 recordsLinked to original sources
PubMed2004

Inducible release of TRAIL fusion proteins from a proapoptotic form for tumor therapy.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively kill neoplastic cells and control of its activity could enhance tumor therapy. We have developed means to control the secretion of a novel recombinant (r) TRAIL fusion protein using a viral protease. This system uses the endoplasmic reticulum (ER) as a storage depot for rTRAIL, because TRAIL acts by binding to its cognate receptors on the cell surface. We have engineered two TRAIL variants: (a) a secretable form that enhances apoptosis via a bystander effect; and (b) an ER-targeted TRAIL that is retained in the ER until selectively released by the viral protease. Gene delivery can be monitored in vivo by systemic administration of a near infrared fluorescent (NIRF) probe activated by the protease. This study serves as a template for design of recombinant proteins to enhance and control apoptosis of tumor cells via specific viral proteases and for use of viral proteases as in vivo reporters for cancer therapy.

Animals↗
PubMed2003

The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy.

Tumor hypoxia negatively regulates cell growth and causes a more malignant phenotype by increasing the expression of genes encoding angiogenic, metabolic and metastatic factors. Of clinical importance, insufficient tumor oxygenation affects the efficiency of chemotherapy and radiotherapy by poorly understood mechanisms. The hypoxia-inducible factor (HIF)-1 is a master transcriptional activator of oxygen-regulated genes and HIF-1 is constitutively upregulated in several tumor types. HIF-1 might thus be implicated in tumor therapy resistance. We found that transformed mouse embryonic fibroblasts deficient for HIF-1alpha are more susceptible to the treatment with carboplatin, etoposide and ionizing radiation than wild-type cells. Increased cell death in HIF-1alpha-deficient cells was because of apoptosis and did not involve p53 induction. Tumor chemotherapy of experimental fibrosarcoma in immunocompromised mice with carboplatin and etoposide confirmed the enhanced susceptibility of HIF-1alpha-deficient cells. Agents that did not cause DNA double-strand breaks, such as DNA-synthesis inhibitors or a DNA single-strand break-causing agent equally impaired cell growth, independent of the HIF-1alpha genotype. Functional repair of a fragmented reporter gene was decreased in HIF-1alpha-deficient cells. Thus, hypoxia-independent basal HIF-1alpha expression in tumor cells, as known from untransformed embryonic stem cells, is sufficient to induce target gene expression, probably including DNA double-strand break repair enzymes.

Animals↗
PubMed2005

Isolation and characterization of a scFv antibody specific for tumor endothelial marker 1 (TEM1), a new reagent for targeted tumor therapy.

Tumor endothelial marker 1 (TEM1) is a protein predominantly expressed on the cell surface of endothelial cells in newly developing blood vessels and on tumor cells. It is therefore ideally suited as a target for anti-angiogenic tumor therapy. Using phage display technology a single chain antibody fragment (scFv-CM6) was isolated that specifically binds to the extracellular part of TEM1. Antibody specificity was determined in ELISA, by Western analysis, fluorescence microscopy and flow cytometry performed with TEM1-expressing cells. ScFv-CM6 was further functionalized and coupled to liposomes. Such immunoliposomes loaded with the cytotoxic drug N4-octadecyl-1-beta-D-arabinofuranosylcytosine-(5'-5')-3'-C-ethinylcytidine showed increased binding affinity and up to 80% higher cytotoxic activity towards TEM1-expressing IMR-32 tumor cells compared with control liposomes.

Antibody Specificity↗
PubMed1976

Effect of bleomycin on cell survival and some implications for tumor therapy.

Tumor is normally composed of cells growing and non-growing and, therefore, of cells having different responses to exogenous agents. Hence, it is not possible to treat a tumor with an unitary principle. As far as the tumor cell sterilization by bleomycin is concerned, the growing fraction of tumor should be managed by fractional schedule, while plateau phase cells by continuous infusion. Based on the cell sterilization kinetics, further improvement of chemotherapy by bleomycin must be sought. The investigation will duly involve the studies on the nature of resistance induction and PLD repair.

Animals↗
PubMed2001

Salmonella-based tumor-targeted cancer therapy: tumor amplified protein expression therapy (TAPET) for diagnostic imaging.

In preclinical studies, genetically engineered Salmonella have the ability to localize, selectively accumulate, and persist within transplantable murine tumors, spontaneous murine tumors and human tumor xenographs, and can express therapeutic proteins at high levels. These strains of engineered non-virulent Salmonella typhimurium display the capacity to accumulate and grow selectively in a variety of tumor types and to inhibit the growth of primary and metastatic tumors following intravenous injection into tumor-bearing mice. One strain of the bacteria (VNP20009) which has endogenous antitumor activity is currently in Phase I clinical trials. The bacteria are highly attenuated and genetically stable. The combination of the lipid mutation and the purine auxotrophy attenuate the virulence of the bacteria by greater than 10000-fold and enhance the specificity of the bacteria for tumor tissue. These bacteria have been found to be safe in mice, pigs and monkeys when administered intravenously. Second-generation Salmonella vectors will be developed to include transgenes that will express therapeutic agents and reporter transgenes for non-invasive imaging. We have performed a preliminary study to demonstrate localization of [(14)C]FIAU in tumored mice pretreated with Salmonella expressing HSV1-TK. The [(14)C]FIAU radioactivity and bacterial count data strongly support a Salmonella(TK)-dependent [(14)C]FIAU accumulation of at least 30-fold higher in tumor tissue compared to muscle tissue. These data warrant further investigation on the use of genetically engineered Salmonella as a systemically administered tumor-specific agents for tumor therapy and delivery of diagnostic imaging markers.

Animals↗
PubMed1990

[Goals, results and limitations of multimodal tumor therapy].

Multimodal tumor therapy, or the employment of two or more treatment modalities in combination, had led to several advances in the cure or long-term survival of patients with various tumor types. The individual established indications for multimodal tumor therapy are listed and described. Other indications remain controversial or are under evaluation in prospective randomized studies. In certain tumor types no advantage from the use of multimodal treatment has been demonstrated as yet. Aside from the advantages of multimodal therapy, the problems involved and possible side effects, especially in regard to short-, mid- and long-term toxic effects are described.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

[Monoclonal antibodies and mediators--immunologic tumor therapy].

Immunological tumor therapy includes the use of interferons, interleukins, tumor necrosis factor, and monoclonal antibodies. Clinical tests performed on about 20 types of solid tumors and 10 types of leukemias and lymphomas showed rather limited success. In many cases the side effects are considerable, resulting in the interruption or cessation of therapy. Improvements can be achieved by gene technology. Only the interferons have been approved as official drugs to treat cancer.

Antibodies, Monoclonal↗
PubMed2005

Current status of therapy of solid tumors: brain tumor therapy.

Treatment of malignant brain tumors with conventional approaches is largely unsuccessful because curative doses generally cannot be delivered without excessive toxicity to normal brain. Radioimmunotherapy is emerging as an attractive alternative for glioma therapy because of the potential for more selectively irradiating tumor cells while sparing normal tissues. Several institutions are engaged in phase I and phase II trials investigating the therapeutic potential of monoclonal antibodies (mAbs) labeled with the beta-emitters (131)I and (90)Y and the alpha-emitter (211)At in patients with recurrent and newly diagnosed brain tumors. The current status of these trials will be discussed with regard to efficacy, toxicity, and future directions.

Animals↗
PubMed1987

Tumor therapy of neoplastic diseases with tumor cells and neuraminidase: experimental studies on chessboard vaccination in transplantation tumors.

The therapeutic effect of intradermal (i.d.) injection of tumor cells mixed with VCN on growth of spontaneous metastases in transplantable tumors in mice (3-Lewis lung adenocarcinoma; B16-melanoma) and rats (R-3230 mammary adenocarcinoma) was investigated. Intradermal injection was done in a chessboard-like manner; increasing numbers (10(5), 10(6) and 10(7)) of Mitomycin-treated tumor cells (M-TC) were each mixed with increasing amounts (10, 50 and 100 mU) of Vibrio cholerae Neuraminidase (VCN). These different mixtures were injected i.d. at different sites one day after resection of the primary tumor graft to mice and rats, suffering from minimal residual disease. The therapeutic effect of this so-called chessboard vaccination on minimal residual disease was compared to that of the subcutaneous or i.d. injection of VCN-treated M-TC (10(5), 10(6), 10(7) or 10(8) cells) or of single mixtures of M-TC and VCN. The results show that compared to VCN-treated M-TC or single mixtures of M-TC and VCN, chessboard vaccination is the only procedure that is therapeutically effective on metastasation of Lewis lung adenocarcinoma. The therapeutic effect could be abrogated by heat-inactivation of VCN. Incomplete chessboard vaccinations (10(5), 10(6), 10(7) tumor cells, each mixed with 5 mU VCN only) were likewise ineffective. However, treatment with incomplete chessboard vaccinations in combination with a low dose of cyclophosphamide (which is not immunosuppressive, but partly inhibits tumor growth) had a synergistic therapeutic effect on minimal residual disease of Lewis lung adenocarcinoma. In contrast, growth of metastases of B16-melanoma and R-3230 adenocarcinoma could not significantly be influenced by any of those treatments. The DTH response of tumor bearing animals against i.d. applied tumor cells was neither significantly enhanced by the admixture of enzymatically active VCN nor did the DTH response seem to be predictive for a tumor-therapeutic effect. Thomsen-Friedenreich antigens could serologically be detected on untreated cells of Lewis lung adenocarcinoma, B16-melanoma and R-3230 adenocarcinoma. Exposure of Thomsen-Friedenreich antigens after treatment with VCN was enhanced on cells of all tumors except Lewis lung adenocarcinoma. As chessboard vaccination only proved to be successful in Lewis lung adenocarcinoma, but not in the other tumors, it can be concluded that the exposure of Thomsen-Friedenreich antigen plays no decisive role in tumor therapy with tumor cells and VCN. Chessboard vaccination was tolerated without any side effects. Tumor enhancement was not observed.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed2006

Translational regulation of p53 as a potential tumor therapy target.

The tumor suppressor p53 is a central player in apoptosis induction in response to oncogenic stimuli and DNA damage. As activation of p53 has been suggested as a prime strategy for future tumor therapy, inhibition of negative regulators of p53 activity would be a similarly desirable strategy. The small worm Caenorhabditis elegans is a model organism in which many conserved biological pathways, including the core apoptotic machinery, were elucidated. The discovery of a worm p53 homolog cep-1/p53 (which stands for C. elegans p53) that specifically induces apoptosis upon DNA damage through a pathway that is conserved from worm to man opened the way for the use of C. elegans genetics to uncover regulatory mechanisms - and hence novel therapeutic targets - of p53-mediated apoptosis. The authors have recently reported a novel mechanism of C. elegans cep-1/p53 regulation through germ line defective-1-mediated translational repression. This review discusses the potential of the worm system to screen for apoptosis-inducing cancer drugs and to identify novel p53 regulators whose human counterparts might become potential tumor therapy targets.

Animals↗
PubMed1998

Synthesis of a lipophilic daunorubicin derivative and its incorporation into lipidic carriers developed for LDL receptor-mediated tumor therapy.

PURPOSE: Many tumors express elevated levels of LDL receptors (apoB, E receptors) on their membranes. Selective delivery of anti-neoplastic drugs to tumors by incorporation of these drugs into LDL or LDL-resembling particles should improve the efficacy of tumor therapy and minimize the severe side-effects. Since the apolipoproteins on the particles are essential for the LDL receptor recognition, drugs should preferably be incorporated into the lipid moiety. Most anti-tumor agents are too hydrophilic for incorporation into these carriers. METHODS: We synthesized LAD, a lipophilic prodrug of daunorubicin, by coupling the drug via a lysosomally degradable peptide spacer to a cholesteryl oleate analog. RESULTS: The overall yield of the synthesis was 50% with a purity of > 90%. Radioactively ([3H]) labeled LAD was obtained via a slightly modified procedure (yield 40%). The octanol/water partition coefficient of LAD is 30-fold higher than that of daunorubicin. LAD could be incorporated into triglyceride-rich lipid emulsions and small liposomes, which, if provided with apoE, have been demonstrated earlier to be cleared in vivo via the LDL receptor. The liposomes contained approximately 10 molecules of LAD per liposomal particle. Analysis of differently sized LAD-containing emulsions suggests that LAD associates with the surface of lipidic particles. In the presence of human serum, LAD did not dissociate from the emulsion particles, indicating a firm association of LAD with the carrier. CONCLUSIONS: The coupling of a cholesterol ester analog to daunorubicin results in a lipophilic prodrug that can be firmly anchored into lipidic carries. LAD-loaded emulsions and liposomes provided with recombinant apoE will be tested in the near future for their ability to deliver LAD to tumor tissue in vivo via the LDL receptor.

Antibiotics, Antineoplastic↗
PubMed2004

Drug delivery systems for brain tumor therapy.

Brain tumors are one of the most lethal forms of cancer. They are extremely difficult to treat. Although, the rate of brain tumor incidence is relatively low, the field clearly lacks therapeutic strategies capable of overcoming barriers for effective delivery of drugs to brain tumors. Clinical failure of many potentially effective therapeutics for the treatment of brain tumors is usually not due to a lack of drug potency, but rather can be attributed to shortcomings in the methods by which a drug is delivered to the brain and into brain tumors. In response to the lack of efficacy of conventional drug delivery methods, extensive efforts have been made to develop novel strategies to overcome the obstacles for brain tumor drug delivery. The challenge is to design therapeutic strategies that deliver drugs to brain tumors in a safe and effective manner. This review provides some insight into several potential techniques that have been developed to improve drug delivery to brain tumors, and it should be helpful to clinicians and research scientists as well.

Animals↗