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Cancer Therapeutics (cancer + therapeutics)
Selected AbstractsPatents and Innovation in Cancer Therapeutics: Lessons from CellProTHE MILBANK QUARTERLY, Issue 4 2002Avital Bar-Shalom How scientific knowledge is translated into diagnostic and therapeutic tools is important to patients with dread diseases as well as to regulators and policymakers. Patents play a crucial role in that process. Indeed, concern that the fruits of federally funded research would languish without commercial application led to the passage of the Bayh-Dole Act (PL 96-517), which reinforced incentives to patent the results of inventions arising from federally funded research (Eisenberg 1996). Subsequently, rates of patenting among U.S. academic institutions have increased (Henderson, Jaffe, and Trajtenberg 1988). A recent survey by the Association of University Technology Managers counted 20,968 licenses and options from 175 academic institutions and 6,375 patent applications filed in fiscal year 2000 (Pressman 2002). Analysis suggests that the number of academic patents was already rising when the Bayh-Dole Act was passed in 1980 (Mowery et al. 2001), but it is clear that the act reinforced the patenting norm in research universities and mandated a technology transfer infrastructure at those universities that had not yet established a technology licensing office. This article discusses the interaction between intellectual property and cancer treatment. CellPro developed a stem cell separation technology based on research at the Fred Hutchinson Cancer Center. A patent with broad claims to bone marrow stem cell antibodies had been awarded to Johns Hopkins University and licensed to Baxter Healthcare under the 1980 Bayh-Dole Act to promote commercial use of inventions from federally funded research. CellPro got FDA approval more than two years before Baxter but lost patent infringement litigation. NIH elected not to compel Hopkins to license its patents to CellPro. CellPro went out of business, selling its technology to its competitor. Decisions at both firms and university licensing offices, and policies at the Patent and Trademark Office, NIH, and the courts influenced the outcome. [source] Small-Molecule Inhibitors of the Hedgehog Signaling Pathway as Cancer TherapeuticsCHEMMEDCHEM, Issue 4 2010Stefan Peukert Dr. Abstract Inhibitors of the Hedgehog (Hh) molecular signaling pathway have emerged in recent years as a promising new class of potential therapeutics for cancer treatment. Numerous drug discovery efforts have resulted in the identification of a wide variety of small molecules that target different members of this pathway, including Smoothened (Smo), Sonic hedgehog protein (Shh), and Gli1. Several Smo inhibitors have now entered human clinical trials, and successful proof-of-concept studies have been carried out in patients with defined genetic mutations in the Hh pathway. This review provides a general overview of three main topics in this rapidly expanding area: 1),the various types of biological assays and in,vivo models that have been employed for the identification and optimization of Hh pathway inhibitors; 2),Smo inhibitors reported to date, including recent clinical results where available; and 3),efforts toward the identification and characterization of inhibitors of other members of the Hh pathway. [source] Cancer therapeutics: an update on its effects on oral healthPERIODONTOLOGY 2000, Issue 1 2007Andrei Barasch First page of article [source] LBY135, a novel anti-DR5 agonistic antibody induces tumor cell,specific cytotoxic activity in human colon tumor cell lines and xenografts,DRUG DEVELOPMENT RESEARCH, Issue 2 2008Jing Li Abstract TRAIL (TNF-related apoptosis-inducing ligand) induces apoptosis on binding to DR4 and DR5 receptors on the surface of tumor cells. These receptors are of particular interest in the development of cancer therapeutics as they preferentially mediate tumor cell apoptosis. We have generated a chimeric anti-DR5 agonistic antibody, LBY135, from its murine parental antibody, LCR211, identified using hybridoma technology. Both LCR211 and LBY135 specifically bind to DR5 with nanomolar affinity, mimic TRAIL to induce cell death in tumor cells, and have little effect on non-transformed cells in vitro. The anti-DR5 antibody reduced viability in 45% of a panel of 40 human colon cancer cell lines with IC50 values of 20,nM or less. In vivo, using human colorectal tumor xenograft mouse models, LCR211 induced tumor regression and showed enhanced efficacy when combined with 5-FU. Both in vitro evaluation of ADCC (antibody-dependent cell-mediated cytotoxicity) and CDC (complement-dependent cytotoxicity), and in vivo studies using a non-functional DR5 specific antibody or SCID-Beige mice, suggested ADCC and CDC are unlikely to be the mechanism to ablate tumors in vivo. LBY135 and LCR211 appear to mediate cell death and tumor regression mainly through apoptosis, as demonstrated by the activation of caspase 3, caspase 8, M30, and TUNEL assay. In addition, the discovery of synergy between cross-linked LBY135 and TRAIL not only revealed the unique epitope of LBY135, but also demonstrated an additional mechanism of action for LBY135 in vivo. LBY135 demonstrates promise as a novel therapeutic for cancer treatment and is currently in Phase I clinical trials. Drug Dev Res 69: 69,82, 2008. © 2008 Wiley-Liss, Inc. [source] FLT3 Antibody-based therapy for leukemiaDRUG DEVELOPMENT RESEARCH, Issue 6 2006Yiwen Li Abstract Technological advances in antibody generation and production have facilitated recent clinical and commercial success with antibody-based cancer therapeutics. The class III receptor tyrosine kinase FLT3 is highly expressed on the blast cells in most cases of acute myelogenous leukemia (AML) and B-cell acute lymphoblastic leukemia (ALL). Activating mutations of FLT3 are detected in approximately 37% AML patients. FLT3 expression in normal tissue is limited to myeloid and B-cell precursor cells. Therefore, over-expressed or mutated FLT3 is an attractive target for therapeutic intervention using monoclonal antibodies. This review will discuss recent progress in the development of anti-FLT3 antibodies as well as their therapeutic potentials in the treatment of AML and other hematological malignancies. Drug Dev. Res. 67:495,500, 2006. © 2006 Wiley-Liss, Inc. [source] Role of Bcl-2 family of proteins in malignancyHEMATOLOGICAL ONCOLOGY, Issue 2 2002Belinda C. Baliga Abstract B cell lymphoma gene-2 (Bcl-2) is the prototypic member of a growing family of proteins that play evolutionarily conserved, key regulatory roles in apoptosis. The Bcl-2 family members are characterized by the presence of one or more Bcl-2 homology domains and are comprised of both the prosurvival and proapoptotic proteins. Bcl-2 itself is a prosurvival member of the family and its aberrant expression has been linked to a variety of different cancers, including several hematological malignancies. Although the exact mechanism of action of Bcl-2 family of proteins in regulating apoptosis is still a matter of some debate, these proteins appear to act upstream of caspase activation. Many recent studies have shown the therapeutic potential of targeting Bcl-2 family members for the treatment of cancer. This article summarizes what is currently known about Bcl-2-like proteins and how the evolving understanding of the biology of these proteins is paving way for the development of novel cancer therapeutics. Copyright © 2001 John Wiley & Sons, Ltd. [source] Polycarbonate microspheres containing tumor necrosis factor-, genes and magnetic powder as potential cancer therapeuticsJOURNAL OF APPLIED POLYMER SCIENCE, Issue 5 2008Bin Hu Abstract Amphiphilic polycarbonate copolymers including methoxy-terminated poly(ethylene glycol)- co -poly (5,5-dimethyl trimethylene carbonate) [Poly(PEG- b -TMC)] and poly(ethylene glycol)- co -poly(trimethylene carbonate) [Poly(PEG- b -DTC)] were synthesized. The water-in-oil-in-water (W/O/W) solvent evaporation technique was adopted to produce anticancer magnetic Poly(PEG- b -DTC) microspheres containing tumor necrosis factor-, (TNF-,) genes and Fe3O4 magnetic ultrafine powder. Drug release studies showed that the microspheres can sustain a steady release rate of TNF-, genes in 0.1M phosphate buffer saline solution in vitro for up to 60 h. In vitro cytotoxicity assays demonstrated that the microspheres have high inhibition and antitumor action to human hepatocellular carcinoma (Bel-7204) cells in vitro. In vivo inhibition on the growth of hepatic carcinomas and histopathologic observation indicated that the microspheres possess a markedly high antitumor activity to human hepatocellular carcinoma (Bel-7204). © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2008 [source] Pro-metastasis function of TGF, mediated by the smad pathwayJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2006Yibin Kang Abstract The transforming growth factor beta (TGF,) signaling pathway plays a vital role in the development and homeostasis of normal tissues. Abnormal function of this pathway contributes to the initiation and progression of cancer. Smad proteins are key signal transducers of the TGF, pathway and are essential for the growth suppression function of TGF,. Smads are bona fide tumor suppressors whose mutation, deletion, and silencing are associated with many types of human cancer. However, the involvement and functional mechanism of Smad proteins in cancer metastasis are poorly defined. Recent studies using genetically modified cancer cells and mouse tumor models have provided concrete evidence for a Smad-dependent mechanism for metastasis promotion by TGF,. Understanding the dual roles of Smad proteins in tumor initiation and progression has important implications for cancer therapeutics. J. Cell. Biochem. © 2006 Wiley-Liss, Inc. [source] A paradigm for the treatment of prostate cancer bone metastases based on an understanding of tumor cell,microenvironment interactionsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2005Robert D. Loberg Abstract The pliability of cancer cells to mutate into several different phenotypes in an attempt to find one that will survive and colonize at the metastatic site is a tremendous "hurdle" to overcome in designing novel cancer therapeutics. New targets of therapy are essential if we are to effectively overcome the evasiveness of cancer. The interaction between the tumor cell and the surrounding microenvironment creates a vicious cycle that perpetuates disease survival and progression. The future of cancer therapy resides in the ability to focus on the recruited and exploited relationships of the cancer cell with the host environment. These therapies target cancer cell growth early and interrupt the vicious cycle that is created by the tumor cells interacting with bone components by inhibiting osteoclasts, osteoblasts, stromal cells, and endothelial cells. They alter the bone microenvironment, creating a hostile "soil" that prevents the "seed" from developing into bone metastases and represent a potential new platform for the development of prostate cancer therapeutics. © 2005 Wiley-Liss, Inc. [source] The knockdown of endogenous replication factor C4 decreases the growth and enhances the chemosensitivity of hepatocellular carcinoma cellsLIVER INTERNATIONAL, Issue 1 2009Masaaki Arai Abstract Aims: To identify differentially expressed genes and thereby detect potential molecular targets for future therapies directed against hepatocellular carcinoma (HCC). Methods: To isolate differentially expressed genes between HCC and adjacent non-cancerous liver tissues, cDNA microarray and quantitative reverse transcriptase polymerase chain reaction analyses were performed. Gene knockdown experiments in HepG2 cells were also performed using small interfering RNAs (siRNAs). Proteins were detected by immunostaining, and cell proliferation was analysed using the MTT/WST-8 assay. Apoptosis and cell cycle analyses were performed using flow cytometry. Results: After an intensive screening for differentially expressed genes in HCC tissues, we isolated 23 upregulated genes in these lesions. Among these, we focused on the replication factor C4 (RFC4) gene. The expression of endogenous RFC4 proteins in HepG2 cells was found to be significantly reduced by RFC4 -specific siRNA. This inhibition of RFC4 expression correlated with a decrease in cellular proliferation, increased levels of apoptosis and a sensitizing of the cells to the DNA-damaging chemotherapeutic agents, doxorubicin and camptothecin. Conclusion: The replication factor C4 gene may be a novel target for developing cancer therapeutics, which can enhance the antitumour activity of chemotherapeutic agents that induce DNA damage. [source] Current and emerging concepts in tumour metastasis,THE JOURNAL OF PATHOLOGY, Issue 1 2010Caroline Coghlin Abstract Disseminated cancer accounts for most deaths due to malignancy. Despite this, research has focused predominantly on tumour development and progression at the primary site. Recently, attention has shifted towards the field of tumour metastasis. Several new and exciting concepts that have emerged in the past few years may shed light on this complex area. The established canonical theory of tumour metastasis, as a process emerging from a stepwise accumulation of genetic events fuelled by clonal evolution, has been challenged. New evidence suggests that malignant cells can disseminate at a much earlier stage than previously recognized in tumourigenesis. These findings have direct relevance to clinical practice and shed new light on tumour biology. Gene-profiling studies support this theory, suggesting that metastatic ability may be an innate property shared by the bulk of cells present early in a developing tumour mass. There is a growing recognition of the importance of host factors outside the primary site in the development of metastatic disease. The role of the ,pre-metastatic niche' is being defined and with this comes a new understanding of the function of bone marrow-derived progenitor cells in directing the dissemination of malignant cells to distant sites. Current research has highlighted the crucial roles played by non-neoplastic host cells within the tumour microenvironment in regulating metastasis. These new concepts have wide-ranging implications for our overall understanding of tumour metastasis and for the development of cancer therapeutics. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] The basic and clinical implications of ABC transporters, Y-box-binding protein-1 (YB-1) and angiogenesis-related factors in human malignanciesCANCER SCIENCE, Issue 1 2003Michihiko Kuwano In our laboratories, we have been studying molecular targets which might be advantageous for novel cancer therapeutics. In this review, we focus on how ATP-binding cassette (ABC) transporter superfamily genes, Y-box-binding protein-1 (YB-1), and tumor angiogenesis-associated factors could contribute to the development of novel strategies for molecular cancer therapeutics. ABC transporters such as P-glycoprotein/MDR1 and several MRP family proteins function to protect cells from xenobiotics, drugs and poisons, suggesting that ABC transporters are a double-edged sword. In this regard, P-glycoprotein/MDR1 is a representative ABC transporter which plays a critical role in the efflux of a wide range of drugs. We have reported that gene amplification, gene rearrangements, transcription factor YB-1 and CpG methylation on the promoter are involved in MDR1 gene overexpression in cultured cancer cells. Among them, two mechanisms appear to be relevant to the up-regulation of MDR1 gene in human malignancies. We first reported that MDR1 gene promoter is activated in response to environmental stimuli, and is modulated by methylation/demethylation of CpG sites on the MDR1 promoter. We also demonstrated that YB-1 modulates not only transcription of various genes associated with cell growth, drug resistance and DNA synthesis, but also translation, mRNA stabilization and DNA repair/self-defense processes. Angiogene-sis is also involved in tumor growth, invasion and metastasis of various malignancies, and so angiogenesis-related molecules also offer novel molecular targets for anticancer therapeutics. (Cancer Sci 2003; 94: 9,14) [source] Identification and Validation of a Potent Type,II Inhibitor of Inactive Polo-like Kinase,1CHEMMEDCHEM, Issue 11 2009Sarah Keppner Virtual screening using a homology model of human polo-like kinase,1 (Plk1) in an inactive conformation led to the identification of a selective Plk1 inhibitor that decreases proliferation and induces apoptosis. This suggests that type,II Plk1 inhibitors may be considered for the development of cancer therapeutics. [source] | ||||||||||