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At least 325 records · Page 18Linked to original sources
PubMed2002

A 5-fluorodeoxyuridine prodrug as targeted therapy for prostate cancer.

A method for targeted delivery of the cytotoxic agent 5-fluorodeoxyuridine (FudR) (1) to sites of metastatic prostate cancer is described. The prodrug was synthesized by coupling the active drug (FudR) to the PSA-peptide via a self-cleaving diamino acid linker to produce HSSKLQ-Leu-Aib-FudR. This prodrug serves as a substrate for prostate specific antigen (PSA). This approach permitted efficient conversion of the inactive prodrug back to the active cytotoxic state by the enzymatic activity of PSA which is highly expressed by prostate cells.

Cell Death↗
PubMed2005

Immunocompetent mouse model of breast cancer for preclinical testing of EphA2-targeted therapy.

EphA2, a receptor tyrosine kinase, is elevated in many invasive human breast cancers, and the majority of EphA2 remains unphosphorylated. The successful attachment of ligand EphrinA1 present on the surface of adjacent cells to EphA2 initiates EphA2 phosphorylation leading to its turnover. In vivo efficacy of various approaches targeting EphA2 for breast cancer therapy is usually evaluated in nude mice bearing human breast cancer xenografts. In order to establish an immunocompetent mouse model of breast cancer for EphA2-targeted therapies, we evaluated a mouse breast cancer cell line (MT1A2) for EphA2 expression and phosphorylation. Overexpression of EphA2 was observed in MT1A2 cells and the majority of it remained unphosphorylated signifying that EphA2 in MT1A2 cells behaved similar to that of human breast cancer cells. Human adenovirus subtype 5 (HAd5) vectors expressing secretory forms of EphrinA1 were used for in vitro and in vivo targeting of MT1A2-derived EphA2. MT1A2 cells infected with HAd-EphrinA1-Fc (HAd expressing extracellular domain of human EphrinA1 attached to Fc portion of human IgG1 heavy chain) induced EphA2 activation and its turnover. This led to inhibition in MT1A2 cell colony formation in soft agar and cell viability in monolayer culture. In addition, MT1A2 cells-infected with HAd-EphrinA1-Fc failed to form tumors in syngeneic FVB/n mice at least 32 days postinoculation. Moreover, intratumoral inoculation of FVB/n mice-bearing MT1A2-induced tumors with HAd-EphrinA1-Fc slowed the tumor growth and also resulted in the development of vector-specific immune response. These results indicate that FVB/n mice-bearing MT1A2-induced tumors could serve as an immunocompetent model of breast cancer for EphA2-targeted therapeutic strategies.

Adenoviridae↗
PubMed2004

Systemic siRNA-mediated gene silencing: a new approach to targeted therapy of cancer.

OBJECTIVE: RNA interference (RNAi), mediated by small interfering RNA (siRNA), silences genes with a high degree of specificity and potentially represents a general approach for molecularly targeted anticancer therapy. The aim of this study was to evaluate the ability of systemically administered siRNA to silence gene expression in vivo and to assess the effect of this approach on tumor growth using a murine pancreatic adenocarcinoma xenograft model. SUMMARY BACKGROUND DATA: Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is widely overexpressed in human gastrointestinal cancer. Overexpression of CEACAM6 promotes cell survival under anchorage independent conditions, a characteristic associated with tumorigenesis and metastasis. METHODS: CEACAM6 expression was quantified by real-time polymerase chain reaction (PCR) and Western blot. Mice (n = 10/group) were subcutaneously xenografted with 2 x 10 BxPC3 cells (which inherently overexpress CEACAM6). Tumor growth, CEACAM6 expression, cellular proliferation (Ki-67 immunohistochemistry), apoptosis, angiogenesis (CD34 immunohistochemistry), and survival were compared for mice administered either systemic CEACAM6-specific or control single-base mismatch siRNA over 6 weeks, following orthotopic tumor implantation. RESULTS: Treatment with CEACAM6-specific siRNA suppressed primary tumor growth by 68% versus control siRNA (P < 0.05) and was associated with a decreased proliferating cell index, impaired angiogenesis and increased apoptosis in the xenografted tumors. CEACAM6-specific siRNA completely inhibited metastasis (0% of mice versus 60%, P < 0.05) and significantly improved survival, without apparent toxicity. CONCLUSIONS: Our data demonstrate the efficacy of systemically administered siRNA as a therapeutic modality in experimental pancreatic cancer. This novel therapeutic strategy may be applicable to a broad range of cancers and warrants investigation in patients with refractory disease.

Adenocarcinoma↗
PubMed2006

Anti-cancer therapy: targeting the mevalonate pathway.

The mevalonate pathway has become an important target for anti-cancer therapy. Manipulation of this pathway results in alteration of malignant cell growth and survival in cell culture and animal models, with promising potential for application in human cancers. Mevalonate is synthesized from 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA). Mevalonate is further metabolized to farnesyl pyrophosphate (FPP), which is the precursor for sterols. In addition, the farnesyl moiety from FPP is utilized for post-translational modification of proteins including small GTPases, such as Ras and Ras related proteins, which play a role in malignant transformation of cells. FPP is a precursor for geranylgeranyl pyrophosphate (GGPP), which is similarly involved in post-translational modification of proteins. There has been intense interest in manipulating the pathway through HMG-CoA reductase inhibition. More recently, the focus has been on manipulating the pathway by post-translational modification of key regulatory proteins through farnesyl prenyl transferase (FPTase) or geranylgeranyl prenyl transferase (GGPTase) inhibition. This review focuses on the mevalonate pathway and the application of rational drug therapies to manipulate this pathway. Included in the review are a summary of agents demonstrating success in preclinical investigations such as; farnesyl transferase inhibitors, geranylgeranyl transferase inhibitors, dual inhibitors, statins, bisphosphonates, histone deacetylase inhibitors and other compounds. While these agents have shown preclinical success, translation to success in clinical trials has been more difficult. These clinical trials are reviewed along with evaluation of some of the potential problems with these agents in their clinical application.

Animals↗
PubMed2004

RNA interference: a potential strategy for isoform-specific phosphatidylinositol 3-kinase targeted therapy in ovarian cancer.

Phosphatidylinositol 3-kinase (PI3-kinase) is a novel intracellular transducer involved in a wide range of cancer-associated signaling pathways, which comprises various isoforms and splice variants with distinct biologic activities and clinical implications. Especially, the class Ia PI3-kinase 110 kD catalytic subunit alpha (PIK3CA) is the most important isoform in tumorigenesis and possibly, tumor angiogenesis. Several strategies have been developed to block PI3-kinase for cancer therapy; however, the approach to target specific PI3-kinase isoform has not been explored to date. In the present study, we show that RNA interference (RNAi) through small interfering (siRNA) sequences targeting PIK3CA has potential applications in isoform-specific "knock-down" of PI3-kinase. This strategy provides a novel tool to study the function of various PI3-kinase isoforms and may contribute to isoform-specific targeting of PI3-kinase in human cancer.

Animals↗
PubMed2005

Resistance to epidermal growth factor receptor-targeted therapy.

The epidermal growth factor receptor (EGFR) has been a major target of molecular anticancer therapy. Two approaches have been developed, involving monoclonal antibodies and receptor tyrosine kinase inhibitors, and both have demonstrated benefit in clinical trials. However, evidence of resistance to these drugs has been described. Cellular levels of EGFR do not always correlate with response to the EGFR tyrosine kinase inhibitors, indicating acquired resistance to these drugs. Since EGFR antagonists interfere with the activation of several intracellular pathways that control cell proliferation, survival, apoptosis, angiogenesis, invasion and metastasis, acquired resistance can occur as a result of several different molecular mechanisms: autocrine/paracrine production of ligand, receptor mutation, constitutive activation of the downstream pathway and activation of alternative pathways. We will describe here potential mechanisms that can cause resistance to EGFR-targeted drugs. Combinations of EGFR antagonists with inhibitors targeting different signaling mechanism(s) - such as insulin-like growth factor receptor and vascular endothelial growth factor receptor - that share the same downstream mediator (e.g., phosphatidylinositol 3-kinase/Akt, mitogen-activated protein kinase), may circumvent or delay the development of resistance to EGFR antagonists resulting in enhanced antitumor activities.

Animals↗
PubMedDate not supplied

[Therapeutic advances in neoplastic hematology: target therapy anti-CD33].

Antibodies capable to recognize antigen expressed on cancer cells represents the ideal approach for targeted anti neoplastic therapies. The CD33 antigen is present on 90% of acute myeloid leukemia blasts and is shared on normal hemopoietic cells only on the non stem dillerentiating fraction. Gemtuzumab Ozogamicin (GO) is an engineered humanized antibody anti-CD33 conjugated with a potent intercalating agent, named calicheamicin, which is release only at intracellular level (lower pH), following a selective binding to CD33-positive cells, thus representing a promising approach for target anti-leukemia therapy. GO was approved conditionally by the Federal Drug Administration in May 2000 as a single therapy for first recurrence of Acute Myeloid Leukemia (AML) in a subset of older patients. Since 2000, treatment trials and pilot studies have revealed potential expanded applications along with potential limitations. Phase II trials have confirmed the activity and the efficacy of GO as single agent in the treatment of relapsed AML. More recently, clinical trials on induction and post-remission treatment of adult AML have shown efficacy of GO in combination chemotherapy. The strong and homogeneous CD33 expression in Acute Promyelocytic Leukemia (APL), have resulted in an effective treatment of this disease with GO used as salvage treatment, as well as innovative approach for molecular relapsed patients. However, the incidence of veno-occlusive disease, better defined as sinusoidal occlusive syndrome (SOS), must be taken into account as potential complication associated with the GO administration, especially in patients treated with ablative regimens. In conclusion, the extension of the approval in Italy to AML CD33+ in relapsed, regardless age limitation, along with the ongoing evaluation by the European EMEA, represent the basis for a large clinical application of GO in myeloid malignancies potentially extended to paediatric patients with AML and to ALL CD33+.

Acute Disease↗
PubMed2005

[Basic and clinical studies of the gene product-targeting therapy based on leukemogenesis--editorial].

In the last twenty years, using all-trans retinoic acid (ATRA) as a differentiation inducer, Shanghai Institute of Hematology has achieved an important breakthrough in the treatment of acute promyelocytic leukemia (APL), which realized the theory of reversing phenotype of cells and provided a successful model of differentiation therapy in cancers. Our group first discovered in the world the variant chromosome translocation t(11;17)(q23;q21) of APL, and cloned the PML-RAR alpha, PLZF-RAR alpha and NPM-RAR alpha fusion genes corresponding to the characterized chromosome translocations t(15;17); t(11;17) and t(5;17) in APL. Moreover, establishment of transgenic mice model of APL proved their effects on leukemogenesis. The ability of ATRA to modify the recruitment of nuclear receptor co-repressor with PML-RAR alpha but not PLZF-RAR alpha caused by the variant chromosome translocation elucidated the therapeutic mechanism of ATRA from the molecular level and provides new insight into transcription-modulating therapy. Since 1994, our group has successfully applied arsenic trioxide (As(2)O(3)) in treating relapsed APL patients, with the complete remission rate of 70% - 80%. The molecular mechanism study revealed that As(2)O(3) exerts a dose-dependent dual effect on APL. Low-dose As(2)O(3) induced partial differentiation of APL cells, while the higher dose induced apoptosis. As(2)O(3) binds ubiquitin like SUMO-1 through the lysine 160 of PML, resulting in the degradation of PML-RAR alpha. Taken together, ATRA and As(2)O(3) target the transcription factor PML-RAR alpha, the former by retinoic acid receptor and the latter by PML sumolization, both induce PML-RAR alpha degradation and APL cells differentiation and apoptosis. Because of the different acting pathways, ATRA and As(2)O(3) have no cross-resistance and can be used as combination therapy. Clinical trial in newly diagnosed APL patients showed that ATRA/As(2)O(3) in combination yields a longer disease-free survival time. With the median survival of 18 months, none of the 20 cases in combination treatment relapsed, whereas 7 relapsed in 37 cases in mono-treatment. This is the best clinical effect achieved in treating adult acute leukemia to this day, possibly making APL the first adult curable leukemia. Based on the great success of the pathogenetic gene target therapy in APL, this strategy may extend to other leukemias. Combination of Gleevec and arsenic agents in treating chronic myeloid leukemia has already make a figure both in clinical and laboratory research, aiming at counteracting the abnormal tyrosine kinase activity of ABL and the degradating BCR-ABL fusion protein. In acute myeloid leukemia M(2b), using new target therapy degradating AML1-ETO fusion protein and reducing the abnormal tyrosine kinase activity of c-kit will also lead to new therapeutic management in acute leukemias.

Antineoplastic Agents↗
PubMed2005

Monoclonal antibody-based targeted therapy in breast cancer.

Advances in molecular biology have identified tumor markers that not only predict prognosis and therapeutic response but may also function as potential therapeutic targets. Activated growth factor receptors induce breast cancer cells to proliferate, invade, and metastasize in experimental models. Overexpression of growth factor receptors has been associated with a poor clinical outcome in breast cancer patients. Biological therapy with monoclonal antibody directed against growth factor receptor pathways became important targeted therapy in breast cancer and is being pursued on various fronts. The anti-HER2 antibody trastuzumab is approved in the metastatic setting and is now trying to find the place in the adjuvant setting. Phase II and III studies with antibodies directed against VEGF and EGFR are also ongoing.

Animals↗
PubMed2005

Molecularly-targeted therapies for non-small cell lung cancer.

Targeting cell-signalling pathways that confer survival advantage to cancer cells has become a major focus of investigation for the treatment of various malignancies. Non-small cell lung cancer (NSCLC), a disease with wide molecular heterogeneity, has become a main testing ground for the evaluation of various targeted agents. Inhibition of the epidermal growth factor pathway with erlotinib results in improved survival and symptom control for patients with advanced NSCLC who progressed following one or two prior chemotherapy regimens. Gefitinib, the first epidermal growth factor receptor (EGFR) inhibitor to be approved by the FDA, failed to demonstrate survival advantage over placebo in a large Phase III trial for patients with advanced NSCLC. The results of this study have raised several important clinical and biological issues that may be relevant for the development of other targeted agents. Recent identification of mutations in the ATP-binding pocket of the EGFR is the first step towards proper patient selection for therapy with an EGFR tyrosine kinase inhibitor. In addition, predictive potential has also been seen with EGFR gene amplification. It is unclear whether monoclonal antibodies against the EGFR may be active independent of the EGFR mutation, as the site of action is different from tyrosine kinase inhibitors. A recent randomised clinical trial that combined the antiangiogenic agent bevacizumab with chemotherapy has demonstrated survival advantage over chemotherapy alone for certain subsets of patients with advanced NSCLC. The exciting results of this study represent an important advance in the treatment of patients with advanced NSCLC.

Animals↗
PubMed2005

Pediatric malignancies provide unique cancer therapy targets.

PURPOSE OF REVIEW: Improving overall survival and reducing morbidity are major goals of childhood cancer research. This review explores an old idea that increased survival in childhood cancer can be achieved by inhibiting specific cancer targets. Specific therapeutic targeting would theoretically cause reduced morbidity as well as increased survival. Tumor-specific translocation-generated fusion proteins appear to be ideal tumor-specific therapeutic targets. This review will describe advances in aspects of target identification, potential for small molecule screening, and the evolution of clinical resistance to this new generation of pharmaceuticals. RECENT FINDINGS: Advances in molecular biology have identified new protein targets along with increased understanding of the biologic role of these proteins. Ewing sarcoma family of tumors research has benefited from new target discovery and enhanced biologic understanding of the EWS-FLI1 fusion protein. Congenital (infantile) fibrosarcoma and cellular mesoblastic nephroma have been grouped based on the presence of a common translocation fusion protein, ETV6-NTRK3. Functional knowledge of ETV6-NTRK3 has advanced so that strategies for screening small molecule inhibitors can proceed. Patients with chronic myeloid leukemia have benefited from the discovery of the BCR-ABL kinase inhibitor imatinib mesylate (Gleevec), thus showing how a molecular therapeutic target can be inactivated for improved therapy. This review will describe challenges raised by clinical resistance to imatinib mesylate as a paradigm for how resistance might evolve in other disease models. This review also describes how patients with synovial sarcoma might benefit from future therapy directed towards the SYT-SSX family of fusion proteins. SUMMARY: The increased utilization of small molecules to disrupt or inactivate tumor-specific molecular targets is rapidly evolving. The use of these small molecules to probe biology and treat disease is advancing towards a new generation of anticancer therapies.

Child↗
PubMed2006

Targeted therapy with a Salmonella typhimurium leucine-arginine auxotroph cures orthotopic human breast tumors in nude mice.

We report here a modified auxotrophic strain of Salmonella typhimurium that can target and cure breast tumors in orthotopic mouse models. We have previously reported development of a genetically modified strain of S. typhimurium, selected for prostate tumor targeting and therapy in vivo. The strain, termed S. typhimurium A1, selectively grew in prostate tumors in xenograft models causing tumor regression. In contrast, normal tissue was cleared of these bacteria even in immunodeficient athymic mice with no apparent side effects. A1 is auxotrophic (leucine-arginine dependent) but apparently receives sufficient nutritional support only from tumor tissue. The ability to grow in viable tumor tissue may account, in part, for the unique antitumor efficacy of the strain. In the present report, to increase tumor-targeting capability of A1, the strain was reisolated after infection of a human colon tumor growing in nude mice. The tumor-isolated strain, termed A1-R, had increased targeting for tumor cells in vivo as well as in vitro compared with A1. Treatment with A1-R resulted in highly effective tumor targeting, including viable tumor tissue and significant tumor shrinkage in mice with s.c. or orthotopic human breast cancer xerographs. Survival of the treated animals was significantly prolonged. Forty percent of treated mice were cured completely and survived as long as non-tumor-bearing mice. These results suggest that amino acid auxotrophic virulent bacteria, which selectively infect and attack viable tumor tissue, are a promising approach to cancer therapy.

Animals↗
PubMed2006

Gene therapy targeting kidney diseases: routes and vehicles.

Renal gene therapy may offer new strategies to treat diseases of native and transplanted kidneys. Several experimental techniques have been developed and employed using nonviral, viral, and cellular vectors. The most efficient viral vector for in vivo transfection appears to be adenovirus. In addition, enhanced naked plasmid techniques, such as the hemagglutinating virus of Japan (HVJ)-liposome method, electroporation, the hydrodynamic method, and ultrasound with microbubbles, are promising. Trapping genetically modified macrophages in the inflamed kidneys is an elegant method for site-specific gene delivery. The choice of delivery vehicle as well as the administration route determines the site of transduction. In conclusion, for both in vivo and ex vivo renal transfection, enhanced naked plasmids, adenoviruses, and modified cell vectors offer the best prospects for effective clinical application. Moreover, the development of safer and nonimmunogenic vectors may realize clinical renal gene therapy in the near future.

Adenoviridae↗
PubMed2003

Down's syndrome-associated Single Minded 2 gene as a pancreatic cancer drug therapy target.

We report here a pancreatic cancer drug therapy utility of a gene involved in Down's syndrome. Single Minded 2 gene (SIM2) from Down's Syndrome Critical Region was expressed in pancreatic cancer-derived cell lines as well as in tumor tissues, but not in the normal pancreas. A related member of the SIM family, SIM1, did not show similar specificity. Inhibition by antisense technology of one of the isoforms of SIM2, the short-form (SIM2-s) expression in the CAPAN-1 pancreatic cancer cell line, caused a pronounced growth inhibition and induced cell death through apoptosis. The specificity of antisense was inferred from inhibition of SIM2-s mRNA but not the related members of SIM family. In view of the high mortality rate of pancreatic cancer patients, these findings have important implications for the future of pancreatic cancer treatment.

Apoptosis↗
PubMed1994

[Targeting therapy of gastric and colorectal cancer].

Clinically applied targeting cancer chemotherapy against gastric and colo-rectal cancer were reviewed. The results of such new treatment was not satisfactory. Especially the results of the treatment against colo-rectal cancer was unsatisfactory and new approaches using drug delivery system should be developed. Some of new preclinical experimental approaches were introduced.

Colorectal Neoplasms↗
PubMed2006

New target therapies in advanced pancreatic cancer.

The recent elucidation both of the mechanisms involved in pancreatic cancer carcinogenesis and the related molecular events, has led to several distinct therapeutic advances, including many novel target agents, such as monoclonal antibodies against EGFR, EGFR-tyrosine kinase inhibitors, monoclonal antibody against VEGF, farnesyl transferase inhibitors, matrix metalloproteinase inhibitors, COX 2 inhibitors, and the development of gene therapy to target pancreatic cancer. This review highlights recent findings in the treatment of pancreatic cancer by using these novel therapeutic approaches.

Cyclooxygenase 2 Inhibitors↗
PubMed2005

Follicular lymphoma: management options in the era of targeted therapy.

For the vast majority of patients diagnosed with follicular lymphoma, the disease is never cured. As a result, it becomes a "chronic disease" that must be managed over many years. A wide array of management options exist, and it is difficult to claim that one strategy is better than another. It remains to be proven that a particular initial therapy or a particular sequence of therapies is superior, if one defines "superior" as affecting survival. It also remains to be proven that immediate treatment is superior to a "watch and wait" approach in patients with low tumor burden. However, newer targeted approaches to treatment are providing additional treatment options, and they generally have more favorable side-effect profiles than traditional cytotoxic therapies. The challenge is determining how to best incorporate such targeted therapies into traditional treatment. Additionally, determining the true impact of newer therapies is not entirely straightforward, as selection bias often confounds trial results in follicular lymphoma. A new follicular lymphoma prognostic index should aid in the interpretation of future clinical trials.

Antibodies, Monoclonal↗
PubMed2002

Integrin alpha(v)beta3 targeted therapy for Kaposi's sarcoma with an in vitro evolved antibody.

Here, we define integrin alpha(v)beta3 as a molecular target for antibody therapy for Kaposi's sarcoma (KS). We previously reported, using a new phage display strategy based on designed combinatorial V gene libraries, the humanization of mouse monoclonal antibody LM609 directed to human integrin alpha(v)beta3. In the present study, we describe the in vitro affinity maturation of humanized LM609 by using a phage display strategy for the sequential and parallel optimization of three complementarity determining regions of the antibody molecule. The evolved Fab had an affinity of 150 pM and was converted into IgG1 by use of a new mammalian expression vector. The resulting whole antibody, designated JC-7U IgG1, was found to selectively target human KS in a nude mouse model and inhibit tumor growth at a therapeutically relevant dose. Because of its high affinity and its high degree of humanization, JC-7U IgG1 is an excellent drug candidate for therapeutic applications that involve integrin alpha(v)beta3 as the molecular target. Of particular interest is therapy for KS, breast cancer, melanoma, and other cancers in which integrin alpha(v)beta3 is expressed on both angiogenic endothelial cells and tumor cells, which would allow a dual antiangiogenic and antitumor strike with a single drug.

Animals↗