Browsing by Subject "Cancer -- Treatment."
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Item Anti-tumor activity of an oncolytic adenoviral construct expressing a small interfering RNA transgene.(Philadelphia, PA : American Association for Cancer Research., 2006-10-01) Samuel, Shirley Kulangara.; Tong, Alex W.; Biomedical Studies.; Baylor University. Institute of Biomedical Studies.Cancer is a leading cause of mortality in the world today. Mutation in the K-ras oncogene is common in most human cancers. K-ras oncogene expression was specifically downregulated by 58.7% by K-ras silencing siRNA, and this was accompanied by 66% growth inhibition of NCI-H441 lung cancer cells. To improve siRNA delivery and cause its stable expression in cancer cells, we used ONYX-411, an oncolytic adenovirus as a backbone to clone the K-ras silencing siRNA. This new adenoviral construct called Internavec, significantly downregulated mutant K-ras expression by 48.9% (p<0.05, n=3) as compared with 11.9% downregulation by parental ONYX-411 in HTB-79 pancreatic cancer cells. The anti-tumor activity of Internavec was examined in various cancer cell lines with and without the relevant K-ras mutation to observe the specificity of the siRNA transgene against the glycine to valine mutation on codon 12. Internavec showed enhanced anti-tumor activity in cell lines with the relevant mutation, compared with ONYX-411. Internavec (5 @ 1x108 pfu) significantly reduced the growth of subcutaneous HTB-79 pancreatic tumor xenografts in vivo by 85.5%, including complete growth suppression in 3 of 5 mice. Parental ONYX-411 or ONYX-411-siRNAGFP was markedly less effective (47.8% and 44.1% growth reduction, p<0.05, respectively). To characterize interferon-inducing activity of Internavec, landmark gene expression of the interferon pathway (OAS1, MX1) was examined following Internavec treatment, using HEK-293 cells as positive control. HEK-293 cells displayed an upregulation of OAS1 and MX1 following Poly (I:C) treatment. However, Internavec did not upregulate these interferon-pathway genes in HEK-293 or H79 lines, suggesting a lack of interferon activation by Internavec. To delineate underlying molecular events contributing to the enhanced growth inhibition, microarray experiments were performed on cells treated with Internavec. Internavec, but not ONYX-411, downregulated the expression of multiple Ras signaling-related genes (MAP4K5, PLCε1, IKBKB, FOXO3A and RAB28). These findings indicate that the knockdown of mutant K-ras serves to enhance oncolytic virus anti-tumor activity through the perturbation of additional cellular signaling events.Item Design, synthesis and biological evaluation of new anti-Cancer nitrogen-containing combretastatins and novel cysteine protease inhibitors for the treatment of Chagas.(2006-05-29T01:54:54Z) Siles, Rogelio.; Pinney, Kevin G.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.In an effort to combat cancer, the development of a relatively new type of anti-cancer drugs known as vascular disrupting agents (VDAs) seems to be a promising clinical approach. VDAs selectively interfere with blood flow in the microvessels that carry nutrients and oxygen to the tumor. Blockage of these vessels will stop tumor growth, produce necrosis, and hence prevent proliferation of cancer cells through the body. The discovery of a group of VDAs known as combretastatins (CA) has sparked an exciting area of anti-cancer drug discovery due to their robust biological activity as evidenced through clinical success, particularly for combretastatin A-4 phosphate (CA-4P) and one nitrogen-based combretastatin CA-4 analogue, AVE8062 which are currently in clinical development. Herein, a small library of seventeen new synthetic oxygen and nitrogen-bearing CA-1 and CA-4 analogues is described. Three of these analogues showed significant inhibition of tubulin assembly (IC50= 2-3 μM) as well as in vitro cytotoxicity against selected human cancer cell lines and in vivo blood flow reduction in SCID mice (23-25% at 10 mg/Kg) suggesting that they have potential for further prodrug modification and development as vascular disrupting agents for the treatment of solid tumor cancers. A separate research project has concentrated on the development of cysteine protease inhibitors, primarily focused toward the inhibition of cruzain, the major cysteine protease of Trypanosoma cruzi which is the agent of the parasitic disease called Chagas’ disease. Currently there is no satisfactory treatment for this disease, and the two accepted drugs, nifurtimox and benznidazole, are associated with significant clinical toxicity. A library of fourteen small non-peptidic thiosemicarbazones has been successfully designed, synthesized and tested against cruzain and cathepsin L from which five compounds showed significant cruzain inhibition in the low namolar range. Although the most active compound synthesized, which is a bromotetrahydronaphthalene thiosemicarbazone, exhibited an IC50=12 nM against cruzain, it also showed activity against cathepsin L (IC50=134 nM). This new pharmacophore introduced may prove useful as a lead compound for further optimization. In addition, this research revealed further insights into the complex structure-activity relationship parameters which may lead to the further development of more selective cruzain inhibitors.Item Design, synthesis and biological evaluation of novel serotonin reuptake inhibitors and novel derivatives of a nitrogen-containing combretastatin analog.(2006-10-13T16:13:02Z) Miranda, Maria Graciela.; Pinney, Kevin G.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.Depression is a common and serious illness that affects one out of every ten Americans each year. Since the 1980's, selective serotonin reuptake inhibitors (SSRIs) have been the pharmaceuticals of choice for the treatment of depression and related disorders. Despite their indisputable efficacy, there is still room for improvement in SSRIs, especially in regard to their onset of action and adverse reaction profile. The research presented herein focused on the design and synthesis of a library of thirty-three novel bivalent molecules that could combine into one molecular entity an enhanced antagonism towards the 5-HT2A receptors while keeping a highly selective inhibition of the serotonin transporter (SERT). These bivalent molecules were constructed by covalently coupling two types of fluoxetine hydrochloride structural homologues (for SERT affinity) with a series of nine functionalized piperazines and piperidines (for 5-HT2A antagonism). Preliminary biological evaluation shows that two of the synthesized molecules, 16b and 17b, exhibit the desired dual activity (Ki = 237 and 195 nM respectively for the 5-HT2A receptor and Ki = 1.2 and 1.8 microM respectively for SERT). The complete set of biological data will outline the potential of the synthesized molecules as a new generation of improved antidepressants. Although remarkable advances have been made in cancer pharmacotherapy, the American Cancer Society declared this disease as the top killer of Americans in January, 2005. Therefore, a second research project presented herein focused on the development of a bivalent drug candidate for the treatment of cancer, which could combine into one molecular entity two distinct forms of cancer treatment, vascular disruption and bioreduction. Although the desired target molecule was not achieved, two unexpected and structurally unique products were obtained, which were fully characterized in regards to their structure. Preliminary biological evaluation indicates that compound 73 shows significant inhibition of tubulin assembly (IC50 = 3.3 microM), while compound 74 shows potent and selective in vitro cytotoxicity towards three human cancer cell lines. Therefore, the continuation of this line of research aimed at an improved treatment option for cancer patients is strongly encouraged.Item Design, synthesis and evaluation of di-nitrogen derivatives of combretastatin and novel cruzain inhibiting compounds for the treatment of Chagas disease.(2008-03-03T17:32:22Z) Ackley, J. Freeland.; Pinney, Kevin G.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.Over the past years cancer statistics have continued to rise to the point that the World Health Organization said that in 2005 cancer was leading cause of death worldwide. Years of research have resulted in many new promising therapies and treatment agents and very recently the field of vascular targeting therapies has grown in a strong proportion. One especially promising technique focuses on the use of vascular disrupting agents (VDAs). This clinical approach targets the endothelial cells partially composed of the tubulin-microtubule protein system in microvessels in the tumor microenvironment. The vascular damage caused by these drugs has seen to be highly selective due, in part, to the chaotic nature of the vessels created by these rapidly proliferating endothelial cells in the tumor microenvironment. The continued success of combretastatin A4 and combretastatin A1 in human clinical development indicate the importance of preparing new synthetic analogs to further understand the role of these anti-mitotic agents. Accordingly, a small library of eleven functionalized Z-stilbenes was created containing various nitro and amine moieties substituted in a 2,3, 3,5, and 2,3 pattern. These compounds have showed impressive biological results with the leading compound 18 demonstrating an IC50 value of 2.8 [mu]M for the inhibition of tubulin assembly and in vitro GI50 values in selected human cancer cell lines that are sub-nanomolar. A separate research project has recently been focused on the design and synthesis of new cruzain inhibitors modeled around an initial small library of molecules previously prepared by the Pinney Research Group at Baylor University. These thiosemicarbazone bearing molecules were designed to target the major cysteine protease of Trypanosoma cruzi also known as cruzain. Selected compounds were successfully designed and synthesized and are awaiting biochemical and biological evaluation.Item Design, synthesis, biochemical and biological evaluation of benzocyclic and enediyne analogs of combretastatins as potential tubulin binding ligands in the treatment of cancer.(2008-03-03T17:33:50Z) Sriram, Madhavi.; Pinney, Kevin G.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.One out of four deaths per day in the United States will be caused by cancer in the year 2007. Cancer still remains the second major cause of mortality both in developed as well as developing countries. Small molecule vascular disrupting agents (VDAs) selectively damage the rapidly proliferating tumor vasculature resulting in hypoxia and eventual necrosis. Examples of VDAs currently in clinical development include CA4P, Oxi4503, and AVE8062. Certain VDAs such as CA4P bind to tubulin (following the conversion of CA4P to CA4) at the colchicine binding site, and cause cytoskeletal disruption of the endothelial cells lining the vasculature in the tumor microenvironment. Based on SAR studies, we have designed a series of novel molecules that bear structural resemblance to certain of the combretastatins, displaying the 1, 2-diarylethene and biaryl scaffold respectively. The synthetic ligands designed also include structural features bearing benzocyclic moieties such as indanes, dihydronapthalenes, benzosuberenes and benzocyclo-octanes. The benzocyclic analogs were synthesized and analyzed for their ability to inhibit microtubule polymerization as well as inhibition of growth in selected human cancer cell lines in vitro. Anti-tumor antibiotics such as calicheamycins, comprise enediyne as one of the pharrmacophores which undergoes Bergman cyclization to generate bi-radicals that damage DNA and cause apoptosis. A series of enediyne and ketodiyne analogs bearing combretastatin structural scaffolds were also designed. The enediyne and ketodiyne analogs were designed from the speculation of their dual activity in both DNA intercalation and vascular disruption. Only one such analog was synthesized and analyzed for it ability to inhibit tubulin polymerization. Protocol for the synthesis of radiolabelled prodrug of CA1 (OX16C) was also carried out successfully as a team effort. The trans-analog of OX16C was also synthesized for the purpose of comparative biological studies between the cis- and trans-isomers of CA1 prodrug. The synthesis of both cis- and trans-OX16C were performed following previously established procedures.Item Discovery and development of unique small molecule chromene based ligands and combretastatin analogs as potential second generation vascular disrupting agents towards cancer chemotherapy.(2006-05-29T02:07:12Z) Arthasery, Phyllis.; Pinney, Kevin G.; Chemistry and Biochemistry.; Center for Drug Discovery.; Baylor University. Dept. of Chemistry and Biochemistry.; Baylor University. Center for Drug Discovery.Cancer is a devastating disease, which remains one of the leading causes of death worldwide. In our continuing quest to help find a cure for cancer, we have discovered and developed new small molecule vascular disrupting agents also known as VDAs for the treatment of cancer. Vascular disrupting agents, by definition, cause a rapid collapse in tumor blood flow, and an effective agent will cause a prolonged period of vascular shutdown, culminating in extensive tumor cell necrosis. The possibility of targeting a tumor's vasculature using small molecule VDAs is currently under active investigation and lead compounds, like combretastatin-A4P, combretastatin-A1P, AC7700 and ZD6126 are in clinical trials for the treatment of cancer, here in the US and in the UK. In this study, a small library of thirteen unique chromenes have been synthesized and evaluated for their anti-cancer efficacy against a panel of human cancer cell lines, and against the P388 mouse leukemia cell line. The inhibition of tubulin assembly data has also been obtained for some of the compounds. Two of the chromenes synthesized show remarkable cytotoxicity (GI50 values) against prostate, lung, CNS-Giobl, and breast adenocarcinoma cancer cell lines. Their ED50 values against the P388 cancer cell line are better than one of the lead compounds combretastatin-A1 (CA-1). In addition, one of these compounds has an IC50 value of 2-4 µM which is comparable to that of bench lead compounds. This compound, therefore, has the potential for further development as a clinical candidate for the treatment of cancer. Further, combretastatin-A4 (CA-4) and CA-1 analogs have been synthesized and their biological activity has been evaluated. Collaborative research efforts (as a member of a research team of the Pinney laboratory) for the synthesis of a dihydronaphthalene analog, trouble shooting in a project centered on the synthesis of a precursor of CA-1 which would ultimately be suitable for radiolabeling, and a scaling up project of OXi8007 were also undertaken. OXi8007 is now in advanced preclinical development for the treatment of cancer and ophthalmology studies. A significant attempt has also been undertaken for the total synthesis of ZD6126 phenol whose phosphate prodrug was recently evaluated in clinical trials for the treatment of cancer. ZD6126 is currently prepared by semi-synthesis starting from colchicine.Item Inhibitors of human cathepsin L and cruzain as therapeutic agents.(2009-04-01T18:21:12Z) Arispe Angulo, Wara Milenka.; Trawick, Mary Lynn.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.Increased human cathepsin L activity is linked to invasive and metastatic cancers where it promotes degradation of the extracellular matrix. This major cysteine protease found in cell lysosomes and secreted from tissues, also plays a role in the pathology of degenerative cartilage and neurological disorders, and is reported to be required for the SARS coronavirus infection. A library of 59 small non-peptidic thiosemicarbazone and α, β-unsaturated carbonyl derivatives of benzophenone, propiophenone, α- and β-tetralone, 4-chromanone, and 4-thiochromenone were evaluated as inhibitors of human cathepsin L. While most of the compounds had IC50 values in the range of 0.4 µM or greater, four were very effective inhibitors of cathepsin L: the benzophenone thiosemicarbazones 2 (IC50= 1.5 nM), 55 (IC50= 44 nM), 38 (IC50= 60 nM), 32 (IC50= 66 nM), and 37 (IC50= 140 nM) and a sulfone analog of the bromo substituted thiochroman-4-one 22 (IC50= 1 nM). Kinetics studies were used to gain understanding in enzyme-inhibitor interactions of the most potent compounds (2 and 22) and they were found to be reversible, slow, tight binding inhibitors of cathepsin L. These data support formation of a transient covalent intermediate between thiosemicarbazone inhibitors and the cathepsin L active site thiolate. Ten of the most promising lead compounds were also tested for cytotoxicity in HEK-293 cells and generated no toxicity after 24 hours. Exposure of the prostate cancer cell line DU-145 to the most promising lead compounds successfully decreased the invasiveness and mobility properties of these cells in vitro. The non-peptidic nature of these inhibitors, coupled with their cell-based activity, makes these compounds very promising leads for the development of selective cathepsin L inhibitors. A separate research project consisted of recombinant cruzain purification and evaluation of thiosemicarbazone derivatives as potential inhibitors of this parasitic cysteine protease. Cruzain is the major cysteine protease of Trypanosoma cruzi organism and is a validated therapeutic target for the development of new chemotherapy. Chagas disease, a result of Trypanosoma cruzi infection, is the third largest parasitic disease challenge worldwide after malaria and leishmania and there is an urgent need for development of new therapeutic agents against Chagas disease. From the same library of thiosemicarbazone derivatives evaluated against cathepsin L, 25 compounds were evaluated against cruzain from which six compounds were in the nanomolar range with IC50 values ranging from 170 nM to 622 nM.Item Inhibitors of tubulin, nitric oxide synthase, and HIF-1 alpha; synthesis, biological, and biochemical evaluation.(2008-06-16T13:10:55Z) Hall, John Jacobs.; Pinney, Kevin G.; Trawick, Mary Lynn.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.Vascular disruption is an innovative method for treating cancer. By selectively altering the endothelial cells of tumor vasculature, the tumor can be destroyed by oxygen deprivation and starvation. The combretastatin (CA) family of small molecules has shown great effectiveness as vascular disrupting agents (VDAs). Structure activity relationship (SAR) studies were continued for the combretastatin family by placement of a 3,4,5-trifluoro substituted A-ring, and 2- or 3-nitro/amine substitutions on the B-ring. Indole scaffolds that are similar to the CA analogues and Oxi8006 were also prepared. The VDAs were tested for cancer cytotoxicity and their ability to inhibit tubulin polymerization. The 3′-amino stilbene 15 was the most effective of the fluoro-nitro stilbenes synthesized, having a tubulin IC50 of 2.9 µM, and a cell cytotoxicity of 0.0093 µg/mL against NCI H460 lung cancer carcinoma. Though VDAs have been effective against a variety of tumor cells, there are cancers, such as human oral squamous cell (SaS), that are resistant to combretastatin A4 phosphate (CA4P). It is believed the SaS resistance results from an increase in nitric oxide (NO) production, which can increase tumor blood supply and vascular tone. CA4P co-salts with the nitric oxide synthase (NOS) inhibitors L-NMMA and L-NAME have been shown to increase drug sensitivity. As such, L-NMMA and L-NAME co-salt formulations with Oxi8007 were prepared to increase drug sensitivity CA4 and CA1 were coupled with aromatic bioreductive triggers to increase drug response in hypoxic areas that are resistant to chemotherapeutics. These nitro-aromatic triggers are expected to only release upon reduction within the hypoxic environment, and increase drug specificity to these areas. The transcription factor HIF-1α has been labeled as a primary target in treating the hypoxic areas of tumors. Drugs that are effective at inhibiting HIF-1α may be better suited for treating hypoxic tumor cells. Approximately 20 compounds were analyzed for their ability to inhibit HIF-1α preservation. Benzosuberene 96 and benzophenone 37 were the most effective at inhibiting HIF-1α preservation. The tubulin IC50 activity of compound 96 is > 40 µM, suggesting that it is inhibiting HIF-1α preservation by a means other than microtubule disruption.