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Results for “Targeted Therapy”

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At least 577 records · Page 32Linked to original sources
PubMed2003

Epidermal growth factor receptor-targeted therapy potentiates lovastatin-induced apoptosis in head and neck squamous cell carcinoma cells.

PURPOSE: Mevalonate metabolites are vital for a variety of key cellular functions with the biosynthetic products including cholesterol and farnesyl and geranylgeranyl isoprenoids. Inhibition of this pathway using lovastatin induces a potent apoptotic response in a specific subset of human tumor-derived cell lines, including head and neck squamous cell carcinomas (HNSCC). In this study, we evaluated the potential of a number of chemotherapeutics that demonstrate activity in HNSCC, including an inhibitor of epidermal growth factor receptor (EGFR) to potentiate the cytotoxic effects of lovastatin. METHODS: We evaluated the cytotoxic effects of combining a variety of chemotherapeutics with lovastatin using the MTT assay and flow cytometry. The MCF-7 lovastatin-resistant breast adenocarcinoma cell line and the lovastatin-sensitive HNSCC cell lines SCC9 and SCC25 were tested. Expression levels of EGFR and ligand activated EGFR following lovastatin treatment were analyzed by Western blotting. RESULTS: Pretreatment or concomitant treatment of 10 microM lovastatin did not significantly augment the effects of a variety of chemotherapeutic agents tested in these cell lines. Co-administration with actinomycin D or cycloheximide, drugs that inhibit RNA and protein synthesis, respectively, inhibited lovastatin-induced apoptosis in these cell lines. This suggests a requirement for the cellular functions disrupted by these chemotherapeutic agents in lovastatin-induced apoptosis of HNSCC cells. In contrast to the chemotherapeutics analyzed, the AG1478 tyrosine kinase inhibitor of the EGFR demonstrated additive cytotoxic effects in combination with lovastatin in HNSCC cells. Mevalonate metabolites may regulate EGFR function, suggesting that lovastatin may inhibit the activity of this receptor. Indeed, lovastatin treatment inhibited EGF-induced autophosphorylation of the EGFR in the SCC9 and SCC25 cell lines. Pretreatment of SCC9 and SCC25 cell lines for 24 h with 10 microM lovastatin, conditions that demonstrated significant inhibition of EGF-induced EGFR autophosphorylation, induced significant additive effects in combination with AG1478. CONCLUSION: These results demonstrated the ability of EGFR pathway inhibitors to potentiate lovastatin-induced apoptosis and suggested that lovastatin may target the EGFR pathway in HNSCC cells.

Antineoplastic Agents↗
PubMed1996

Tumor necrosis factor alpha (TNF-alpha) gene therapy targeted by ionizing radiation selectively damages tumor vasculature.

Intratumoral injection of an adenoviral vector containing radiation-inducible DNA sequences of the Egr-1 promoter linked to a cDNA encoding tumor necrosis factor (TNF) alpha (Ad.Egr-TNF) enhances the tumoricidal action of ionizing radiation in a human epidermoid carcinoma xenograft (SQ-20B). The dominant histopathological feature in tumor-bearing animals treated with Ad.Egr-TNF and irradiation is extensive intratumoral vascular thrombosis and tumor necrosis. Thrombosis and necrosis are not observed in animals treated with either the viral construct encoding TNF-alpha or radiation and did not occur in irradiated normal tissues adjacent to tumor in animals injected with Ad.Egr-TNF. To determine if the occlusive effects of Ad.Egr-TNF and X-irradiation were specific for tumor vessels, non-tumor-bearing mice were irradiated after receiving i.m. injection of Ad.Egr-TNF at viral titers 20-100 times greater than titers injected intratumorally. No vascular thrombosis was observed in the treated normal tissues. Combined Ad.Egr-TNF and radiation produced occlusion of tumor microvessels without significant normal tissue damage. Taken together, these data suggest that the interaction between radiation inducible TNF-alpha and X-irradiation occurs selectively within the tumor vessels.

Animals↗
PubMed1999

Antibody-targeted therapy for myeloid leukemia.

The availability of antibodies reactive with antigens expressed only by hematopoietic cells has provided clinical investigators with new tools for use in developing therapies for acute myeloid leukemia (AML). Studies performed to date have investigated the use of such antibodies in an unmodified state, combined with potent chemicals to form immunotoxins or combined with various radionuclides. Encouraging results have been obtained in all three settings. The CD33 antigen is expressed by most early myeloid cells and by more than 90% of cases of AML but is not present on the hematopoietic stem cell. Initial in vivo studies with an unmodified murine anti-CD33 antibody in patients with AML demonstrated that the antibody quickly bound to leukemia cells and that the antigen-antibody complex rapidly internalized following cell binding. However, when administered to patients with overt leukemia, unmodified antibody resulted in only brief decreases in peripheral blast counts, not in sustained response. A number of CD33-based immunotoxins have also been studied, including a calicheamicin conjugate, CMA-676. In a phase I dose-escalation study of patients with refractory AML, CMA-676 was well tolerated with the only consistent toxicities being the development of fevers and chills several hours after administration and the subsequent development of temporary pancytopenia. A phase III study has been performed involving patients with AML in first relapse. An interim analysis of the first 23 patients found that in 10, treatment with CMA-676 resulted in elimination of blasts from peripheral blood and marrow. This was achieved with far less toxicity than seen with standard chemotherapy. Radiolabeled antibodies have been explored as a stand-alone treatment or in the context of bone marrow transplantation. In an effort to avoid toxicities to normal stem cells residing alongside leukemic cells in the marrow, studies have been performed to explore the use of 231Bi conjugated to an anti-CD33 monoclonal antibody. The short path length of this alpha-emitter could theoretically allow killing of the targeted leukemic cell without damage to normal neighbors. Of 12 patients with recurrent AML who received this drug, eight had reductions in marrow and peripheral blast counts. Complete remissions (CRs) have not been observed to date. Another set of studies focused on the use of radiolabeled antibodies to deliver radiation specifically to sites of leukemia as part of a transplant preparative regimen. In a phase I clinical trial, 131I-labeled anti-CD45 antibody delivered at least threefold more radiotherapy to spleen and marrow than any other organ. In a phase II trial, among 25 AML patients in first remission, 22 are alive and in remission for periods up to 6 years.

Antibodies, Monoclonal↗
PubMed1993

Strontium-89--precursor targeted therapy for pain relief of blastic metastatic disease.

Strontium-89 is a radioactive calcium analog that provides an energetic beta particle for radiation therapy of osteoblastic disease. Strontium-89 is used as palliative therapy with the primary goal being pain relief. More than 500 patients with painful blastic metastatic disease were treated at University of Kansas Medical Center since the initiation of the first clinical trial there 15 years ago. Most patients have had metastatic prostate cancer to bone or breast cancer, as these tumors are commonly associated with bone pain as their primary clinical management problem. Improvement (decrease in pain, increase in physical activity level) was noted in 80% of patients with prostate carcinoma and 81% of patients with metastatic breast cancer to bone. Marrow toxicity levels were acceptable. The therapy can be repeated at 3-month intervals. Strontium-89 is a safe and effective systemic therapy for painful blastic metastatic disease. There is no longer any reason why the vast majority of persons with painful blastic metastatic disease should continue to hurt.

Bone Neoplasms↗
PubMed2003

Targeted therapy and pharmacogenomic programs.

The goal in administering chemotherapeutics is to develop the ability to predict the outcome of therapy in terms of response and toxicity. Technology has been developed to allow tumor profiling with measurement of protein expression, gene expression levels of markers, and even genetic polymorphisms, which may predict response to particular chemotherapeutics. The chemotherapeutics for which particular markers have been shown to predict outcome include the fluoropyrimidines and platinums. The next step is to develop clinical trials that will assess prospectively the benefits of profiling a patient's particular tumor, which should translate into an improvement in response and toxicity.

Antineoplastic Agents↗
PubMed2007

Targeted therapy for threatened preterm labor based on sonographic measurement of the cervical length: a randomized controlled trial.

OBJECTIVE: False positive diagnosis of preterm labor is common. As a consequence, medications including corticosteroids to promote fetal lung maturity and tocolysis are prescribed unnecessarily. We tested the hypothesis that management of threatened preterm labor based on measurement of cervical length by ultrasonography can reduce the number of women who receive inappropriate treatment. METHODS: Forty-one women with threatened preterm labor for whom a clinical decision was made to prescribe antenatal corticosteroids and tocolysis were randomized to have their cervical length measured by transvaginal ultrasound (n=21) or to receive therapy as planned (n=20). Fourteen women in the ultrasound group had a cervix longer than 15 mm and the therapy was withheld, while the other seven with a short cervix were managed in the same way as the control group. RESULTS: Three women (14%) in the ultrasound group were treated inappropriately with antenatal corticosteroids because they remained undelivered for more than a week. This compared favorably with the control group where 18 out of 20 (90%) received corticosteroids unnecessarily (relative risk (RR) 0.16; 95% confidence interval (CI), 0.05-0.39). Tocolysis was given to only seven women (33.3%) in the ultrasound group compared with 20 (100%) in the control group (RR 0.3; 95% CI, 0.15-0.54). There were no babies in either group who were born prematurely without being given a full course of antenatal corticosteroid therapy. CONCLUSION: Women with threatened preterm labor and cervical length more than 15 mm should not receive tocolysis. The issue of the safety of withholding corticosteroid therapy in this clinical scenario warrants further study.

Adrenal Cortex Hormones↗
PubMed2002

Targeted therapy of respiratory syncytial virus in African green monkeys by intranasally administered 2-5A antisense.

Respiratory syncytial virus (RSV) is a leading cause of respiratory disease in infants, young children, immunocompromised patients, and the institutionalized elderly. Previous work had shown that RNase L, an antiviral enzyme of the interferon system, could be recruited to cleave RSV genomic RNA by attaching tetrameric 2prime prime or minute-5prime prime or minute-linked oligoadenylates (2-5A) to an oligonucleotide complementary to repetitive gene-start sequences within the RSV genome (2-5A antisense). A 2prime prime or minute-O-methyl RNA-modified analog of the lead 2-5A anti-RSV chimera is shown here to have enhanced antiviral activity in cell culture studies while also cleaving RSV genomic RNA in an RNase L- and sequence-specific manner. When administered intranasally to RSV-infected African green monkeys, this chimera reduced nasal RSV replication by up to four log(10) units in a dose- and time-dependent manner.

Adenine Nucleotides↗