Docetaxel is used seeing that an effective chemotherapeutic agent in breasts cancer tumor treatment commonly, but the underlying mechanisms of drug level of resistance are not really understood fully. overexpression enhanced MCF-7 and MDA-MB-231 cell level of resistance to docetaxel. Ectopic miR-129 reflection decreased CP110 reflection and the luciferase activity of a CP110 3 untranslated region-based news reporter build in MDA-MB-231 cells, recommending that CP110 is normally a immediate miR-129-3p focus on. We shown that repair of CP110 appearance in MDA-MB-231 and MCF-7 cells by miR-129 overexpression made the cells delicate to docetaxel. In a naked xenograft model, miR-129 up-regulation considerably reduced MDA-MB-231 cells response to docetaxel. Our results recommend that miR-129-3p down-regulation possibly sensitizes breasts tumor cells to docetaxel treatment. Breasts tumor is definitely one of the most common tumor types and the primary trigger of tumor loss of life in ladies ...
TY - JOUR. T1 - Improvement in advanced pancreatic cancer survival with novel chemotherapeutic strategies - experience of a community based hospital. AU - Hann, A. AU - Bohle, W. AU - Egger, Jan. AU - Zoller, W G. N1 - © Georg Thieme Verlag KG Stuttgart · New York.. PY - 2016/10. Y1 - 2016/10. N2 - Background: New chemotherapeutic strategies for locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) have been shown to improve survival in randomized clinical trials. Little is known about the use of such chemotherapies and their benefit in community-based hospitals. This retrospective study analyzes the overall survival of these patients under real life conditions before and after the introduction of FOLFIRINOX in 2011. Methods: We retrospectively identified consecutive patients with PDAC who were treated at our hospital from 2011 to June 2014 (2011+ cohort) and 2004 to 2010 (historical cohort). Patients were included if PDAC was diagnosed in a locally advanced or metastatic ...
TY - JOUR. T1 - A review of the pharmacology and clinical activity of new chemotherapy agents for the treatment of colorectal cancer. AU - Adjei, Alex A.. PY - 1999/9/14. Y1 - 1999/9/14. N2 - Colorectal carcinoma is an important cause of cancer morbidity and mortality. 5-fluorouracil has been the major chemotherapeutic agent for the treatment of colorectal carcinoma for the past four decades. This regimen is noncurative, and its impact on survival is unclear. Attempts at identifying more effective chemotherapeutic agents for colorectal cancer have yielded oral formulations and prodrugs of 5-fluorouracil with apparently equivalent efficacy. Specific thymidylate synthase inhibitors are now available. Platinum analogues with activity in colorectal carcinoma, and no cross-resistance to the antimetabolites have also been developed. The topoisomerase I inhibitors represent a new class of agents with a novel mechanism of action. These agents are in phase II and Phase III clinical trials, others have ...
Pembrolizumab may have a manageable toxicity profile and promising antitumor activity in recurrent or metastatic PD-L1-positive gastric cancer.
Vascularization, oxygenation, and metabolism are important parameters of a tumor, determining its development and treatment response. The overall goals of this thesis were to: 1) describe these parameters in colorectal cancer, both in animal models and in humans; 2) explore the possibility to manipulate vascularization, oxygenation and metabolism for the improvement of cytotoxic treatment; 3) monitor uptake and metabolism of fluorinated cytotoxic drugs in colorectal cancer in an early stage of the treatment. The specific questions were addressed whether vascularization as measured by dynamic contrast enhanced MRI (DCE-MRI) and uptake and metabolism of 5-fluorouracil (FU) as measured by fluorine-19 magnetic resonance spectroscopy (19F MRS) could predict response to cytotoxic treatment. This research shows that nicotinamide and carbogen can decrease tumor hypoxia in murine colon carcinoma, both in subcutaneously implanted tumors and in an orthotopic liver metastases model. Moreover, carbogen ...
The adapters IRS1 and IRS2 link growth factor receptors to downstream signaling pathways that regulate proliferation and survival. Both suppress factor-withdrawal-induced apoptosis and have been implicated in cancer progression. However, recent studi
TY - JOUR. T1 - 2-Aroylquinoline-5,8-diones as potent anticancer agents displaying tubulin and heat shock protein 90 (HSP90) inhibition. AU - Nepali, Kunal. AU - Kumar, Sunil. AU - Huang, Hsiang Ling. AU - Kuo, Fei Chiao. AU - Lee, Cheng Hsin. AU - Kuo, Ching Chuan. AU - Yeh, Teng Kuang. AU - Li, Yu Hsuan. AU - Chang, Jang Yang. AU - Liou, Jing Ping. AU - Lee, Hsueh Yun. PY - 2015. Y1 - 2015. N2 - This study reports the synthesis of a series of 2-aroylquinoline-5,8-diones (11-23) on the basis of scaffold hopping. The presence of a methoxy group at C6 assists the highly regioselective incorporation with various amines, and simplifies the structural identification process. Among the synthetic compounds, 6-dimethylamino-2-(3,4,5-trimethoxybenzoyl)-quinoline-5,8-dione (12) and 7-pyrrolidin-1-yl-2-(3,4,5-trimethoxybenzoyl)-quinoline-5,8-dione (23) exhibit remarkable anti-proliferative activity against the cancer cell lines tested with mean IC50 values of 0.14 and 0.27 μM, respectively. Compound 23 ...
Signal transducer and activator of transcription 3 (STAT3) plays critical roles in tumorigenesis and malignant evolution and has been intensively studied as a therapeutic target for cancer. A number of STAT3 inhibitors have been evaluated for their antitumor activity in vitro and in vivo in experimental tumor models and several approved therapeutic agents have been reported to function as STAT3 inhibitors. Nevertheless, most STAT3 inhibitors have yet to be translated to clinical evaluation for cancer treatment, presumably because of pharmacokinetic, efficacy, and safety issues. In fact, a major cause of failure of anticancer drug development is lack of efficacy. Genetic interactions among various cancer-related pathways often provide redundant input from parallel and/or cooperative pathways that drives and maintains survival environments for cancer cells, leading to low efficacy of single-target agents. Exploiting genetic interactions of STAT3 with other cancer-related pathways may provide molecular
Signal transducer and activator of transcription 3 (STAT3) plays critical roles in tumorigenesis and malignant evolution and has been intensively studied as a therapeutic target for cancer. A number of STAT3 inhibitors have been evaluated for their antitumor activity in vitro and in vivo in experimental tumor models and several approved therapeutic agents have been reported to function as STAT3 inhibitors. Nevertheless, most STAT3 inhibitors have yet to be translated to clinical evaluation for cancer treatment, presumably because of pharmacokinetic, efficacy, and safety issues. In fact, a major cause of failure of anticancer drug development is lack of efficacy. Genetic interactions among various cancer-related pathways often provide redundant input from parallel and/or cooperative pathways that drives and maintains survival environments for cancer cells, leading to low efficacy of single-target agents. Exploiting genetic interactions of STAT3 with other cancer-related pathways may provide molecular
A breakthrough international trial of a new cancer drug has given researchers renewed hope in the fight against leukaemia, with one Melbourne doctor suggesting it could end traditional chemotherapy treatments for good.
A multi-center, international, randomized, Phase III study of older untreated patients with chronic lymphocytic leukemia (CLL) demonstrated that ibrutinib, a kinase inhibitor, is significantly more effective than traditional chemotherapy with chlorambucil.
New anti-cancer drugs that are used for treating various kinds of cancer like lung cancer, breast cancer, blood cancer, myeloma, bone cancer and brain cancer have been added to IDM
Download Free eBook:Statins Toxic Side Effects: Evidence from 500 scientific papers (Cholesterol) - Free chm, pdf ebooks download
A mysterious form of cell death, coded in proteins and enzymes, led to a discovery by UNC researchers uncovering a prime suspect for new cancer drug development.
BACKGROUND: TNBC is an aggressive breast cancer subtype defined by lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2), and for which no approved targeted therapies have shown benefit to date. Inhibition of PARP1, a key regulator of DNA repair, has been associated with antitumor activity in both clinical and preclinical settings. Iniparib, a PARP inhibitor, has demonstrated promising efficacy and safety for treatment of patients with metastatic TNBC when combined with gemcitabine (G) and carboplatin (C), two standard chemotherapeutic agents that synergize to induce DNA damage (OShaughnessy et al. SABCS 2009). We hypothesized that by inhibiting DNA repair, iniparib potentiates antiproliferative effects and cell cycle arrest induced by G+C. METHODS: Triple-negative MDA-MB-468(-) cells were selected by fluorescence-activated cell sorting (FACS) of HER2-negative cells. Cells confirmed negative for ER, PR, and HER2 were ...
Drug resistance represents a major obstacle towards the cure of different tumor types including non‐small cell lung cancer (NSCLC), being one of the main causes of failure of antitumor therapy. Tumor cells frequently exhibit simultaneous resistance to multiple structurally unrelated drugs, a phenotype known as multidrug resistance (MDR). A major cause of the MDR phenotype is the over‐expression of members of a conserved family of transmembrane proteins (ABC transporters). Different structurally unrelated compounds, including conventional cytotoxic and target‐specific agents are substrates for ABC transporters. Cancer stem cells (CSC) refer to a subset of tumor cells with the ability to self‐renew and generate the diverse cells that comprise tumors. At present, the mechanisms contributing to the drug‐resistant phenotype of CSC are poorly understood. Some lines of evidence support that specific ABC transporters may be expressed in CSC and may be relevant therapeutic targets. The aim of ...
TY - JOUR. T1 - PD-L1 targeting high-affinity NK (t-haNK) cells induce direct antitumor effects and target suppressive MDSC populations. AU - Fabian, Kellsye P.. AU - Padget, Michelle R.. AU - Donahue, Renee N.. AU - Solocinski, Kristen. AU - Robbins, Yvette. AU - Allen, Clint T.. AU - Lee, John H.. AU - Rabizadeh, Shahrooz. AU - Soon-Shiong, Patrick. AU - Schlom, Jeffrey. AU - Hodge, James W.. PY - 2020/5/20. Y1 - 2020/5/20. N2 - Background Although immune checkpoint inhibitors have revolutionized cancer treatment, clinical benefit with this class of agents has been limited to a subset of patients. Hence, more effective means to target tumor cells that express immune checkpoint molecules should be developed. For the first time, we report a novel natural killer (NK) cell line, programmed death-ligand 1 (PD-L1) targeting high-affinity natural killer (t-haNK), which was derived from NK-92 and was engineered to express high-affinity CD16, endoplasmic reticulum-retained interleukin (IL)-2, and a ...
A team of scientists is combining sophisticated chemistry and experiments in zebrafish to develop a new cancer drug that shows early potential against melanoma and metastatic breast cancer.
Gastric and Esophageal Cancer Drug Development Pipeline Review, 2017This report provides an overview of the Gastric and Esophageal Cancer pipeline landscape. The report provides comprehensive information on the therapeutics under
Anticancer drugs are also called anti-neoplastic agents or chemotherapeutic agents. They act upon rapidly dividing cancer cells and destroy them.
Anticancer drugs are also called anti-neoplastic agents or chemotherapeutic agents. They act upon rapidly dividing cancer cells and destroy them.
TY - JOUR. T1 - Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers. T2 - American society of clinical oncology clinical practice guideline. AU - Hershman, Dawn L.. AU - Lacchetti, Christina. AU - Dworkin, Robert H.. AU - Lavoie Smith, Ellen M.. AU - Bleeker, Jonathan. AU - Cavaletti, Guido. AU - Chauhan, Cynthia. AU - Gavin, Patrick. AU - Lavino, Antoinette. AU - Lustberg, Maryam B.. AU - Paice, Judith. AU - Schneider, Bryan. AU - Smith, Mary Lou. AU - Smith, Tom. AU - Terstriep, Shelby. AU - Wagner-Johnston, Nina. AU - Bak, Kate. AU - Loprinzi, Charles L.. PY - 2014/6/20. Y1 - 2014/6/20. N2 - Purpose: To provide evidence-based guidance on the optimum prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathies (CIPN) in adult cancer survivors. Methods: A systematic literature search identified relevant, randomized controlled trials (RCTs) for the treatment of CIPN. Primary outcomes included incidence and ...
Chemotherapy-induced peripheral neuropathy (CIPN) is a progressive, enduring, and often irreversible condition featuring pain, numbness, tingling and sensitivity to cold in the hands and feet (sometimes progressing to the arms and legs) that afflicts between 30% and 40% of patients undergoing chemotherapy. Chemotherapy drugs associated with CIPN include thalidomide, the epothilones such as ixabepilone, the vinca alkaloids vincristine and vinblastine, the taxanes paclitaxel and docetaxel, the proteasome inhibitors such as bortezomib, and the platinum-based drugs cisplatin, oxaliplatin and carboplatin. Whether CIPN arises, and to what degree, is determined by the choice of drug, duration of use, the total amount consumed and whether the patient already has peripheral neuropathy. Though the symptoms are mainly sensory - pain, tingling, numbness and temperature sensitivity - in some cases motor nerves are affected, and occasionally, also, the autonomic nervous system. CIPN often follows the first ...
ASCO has released a clinical practice guideline on prevention and treatment of chemotherapy-induced peripheral neuropathy in adult cancer patients, published in the Journal of Clinical Oncology.1. The guidelines resulted from the efforts of an expert panel, with representation from the fields of medical oncology, community oncology, nursing, pain research, genetics, neurology, pharmacology, patient representation, and guideline methodology. Charles Loprinzi, MD, of the Mayo Clinic, Rochester, Minnesota, and Dawn Hershman, MD, of Columbia University Medical Center, New York, were the panel co-chairs.. The overall incidence of the condition is estimated at close to 40% in patients treated with multiple agents, with reported rates varying according to chemotherapy regimens, duration of exposure, and assessment methods. Regimens associated with higher risk are those including platinum drugs, vinca alkaloids, bortezomib (Velcade), and taxanes.. Clinical Question. The clinical question addressed by ...
Huang, S, et al. (2011) Inhibition of mTOR kinase by AZD8055 can antagonize chemotherapy-induced cell death through autophagy induction and down-regulation of p62/sequestosome 1. J. Biol. Chem.. 2011 Nov 18; 286(46):40002-12. PM ID: ...
To update the ASCO guideline on the recommended prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathy (CIPN) in adult cancer survivors.An Expert Panel conducted targeted systematic literature reviews to identify new studies.The search strategy identified 257 new references, which led to a full-text review of 87 manuscripts. A total of 3 systematic reviews, 2 with meta-analyses, and 28 primary trials for prevention of CIPN in addition to 14 primary trials related to treatment of established CIPN, are included in this update.The identified data reconfirmed that no agents are recommended for the prevention of CIPN. The use of acetyl-l-carnitine for the prevention of CIPN in patients with cancer should be discouraged. Furthermore, clinicians should assess the appropriateness of dose delaying, dose reduction, substitutions, or stopping chemotherapy in patients who develop intolerable neuropathy and/or functional impairment. Duloxetine is the only agent ...
Rapid advances have been made in the diagnosis and treatment of neurological disease over the last two decades. Over that period, major developments have also occurred in other fields of medicine, most notably in the management of cancer. Two-thirds of all cancer patients now survive at 5-years post-diagnosis, with over 28 million cancer survivors worldwide.1 As cancer outcomes improve, there has been increased focus on the long-term quality of life in cancer survivors. Not unexpectedly, neurological complications are a prevalent and potentially disabling long-term side effect of cancer treatment. Chemotherapy-induced peripheral neuropathy (CIPN), in particular, is the dose-limiting toxicity of many chemotherapeutic agents, … ...
cansSAR 3D Structure of 6BA5_P | POTENT AND SELECTIVE ANTITUMOR ACTIVITY OF A T-CELL ENGAGING BISPECIFIC ANTIBODY TARGETING A MEMBRANE-PROXIMAL EPITOPE OF ROR1 | 6BA5
The primary objective for this study is to establish if any side effects or toxicity issues occur, that will prevent further clinical development of the autologous cell based immunotherapy ALECSAT in Glioblastoma (GBM) or to establish if there are side effects or toxicity issues, that will suggest that the further clinical development planned, has to change course significantly. It is a primary objective to show safety and tolerability for administration of ALECSAT, thus not meeting this endpoint, may stop further clinical development of ALECSAT.. The secondary objective for this study is to establish if any indications of a positive therapeutic or palliative effect may be observed. As this is a secondary objective, no observed significant positive clinical effect, will not prevent further clinical development or in itself, trigger changes in the further clinical development planned.. The overall endpoint of the study is to develop a new therapeutic approach that may slow down or stop disease ...
TY - JOUR. T1 - erbB-2 Signaling Enhances Cisplatin-induced Cytotoxicity in Human Breast Carcinoma Cells. T2 - Association between an Oncogenic Receptor Tyrosine Kinase and Drug-induced DNA Repair. AU - Arteaga, Carlos L.. AU - Winnier, Angela R.. AU - Hurd, Stephen D.. AU - Stewart, Stanford J.. PY - 1994/7/15. Y1 - 1994/7/15. N2 - The c-erbB-2 (HER-2/neu) protooncogene encodes an Mr 185,000 transmembrane glycoprotein with intrinsic tyrosine kinase activity. Agonistic antibodies against pl85c-erbB-2 enhance the cytotoxic effect of the DNA alkylator, cisplatin, against c-erB-2-overexpressing human carcinoma cells (Hancock et al., Cancer Res., 51: 4575-4580,1991). We have studied the possible association between receptor signal transduction and cispla-tin-mediated cytotoxicity utilizing the SKBR-3 human breast cancer cell line and the anti-pl85 TAb 250 IgGl. TAb 250 induced tyrosine phosphorylation of pl85 and the receptor substrate phospholipase C-yl, as well as rapid association of these ...
TY - JOUR. T1 - Inhibition of PKCδ reduces cisplatin-induced nephrotoxicity without blocking chemotherapeutic efficacy in mouse models of cancer. AU - Pabla, Navjotsingh. AU - Dong, Guie. AU - Jiang, Man. AU - Huang, Shuang. AU - Kumar, M. Vijay. AU - Messing, Robert O.. AU - Dong, Zheng. PY - 2011/7. Y1 - 2011/7. N2 - Cisplatin is a widely used cancer therapy drug that unfortunately has major side effects in normal tissues, notably nephrotoxicity in kidneys. Despite intensive research, the mechanism of cisplatin-induced nephrotoxicity remains unclear, and renoprotective approaches during cisplatin-based chemotherapy are lacking. Here we have identified PKCδ as a critical regulator of cisplatin nephrotoxicity, which can be effectively targeted for reno-protection during chemotherapy. We showed that early during cisplatin nephrotoxicity, Src interacted with, phosphorylated, and activated PKCδ in mouse kidney lysates. After activation, PKCδ regulated MAPKs, but not p53, to induce renal cell ...
ROCKVILLE, Md., June 2 /PRNewswire-FirstCall/ -- ENMD-2076 Demonstrates Preclinical Antitumor Activity in Colorectal Cancer. Data Published in Clinical...
Cancer is one of the leading causes of death worldwide. According to the WHO, cancer accounted for 7.4 million deaths world wide in 2004. The metallo-compound cisplatin has been used for years as an effective antitumor agent for treating solid tumours such as breast, bladder, lung, oesophageal, and head and neck carcinomas. However, the use of cisplatin as an antitumor agent has been limited because of its association with problems such as lack of selectivity for cancer cells over normal cells, development of resistance to cisplatin treatment, and side effects such as nephrotoxicity. Recent studies on anticancer drugs have focussed on alternative anticancer agents such as gold compounds in both Au(I) and (III) oxidation states, which have shown to be potential anticancer drug agents because of their ability to induce apoptosis in several human cancer cells. Some gold complexes have shown to be able to selectively kill cancer cells over normal cells ...
Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect of many chemotherapeutic agents including vincristine, paclitaxel, cisplatin, oxaliplatin, bortezomib and ixabepilone. Chemotherapy-induced peripheral neuropathy commonly occurs in greater than 40% of patients. To improve the peripheral neuropathy, the chemotherapy dosing is often either decreased or discontinued potentially affecting tumor responsiveness, prognosis, and survival.. There is an unmet medical need for treatment of cancer patients with chemotherapy induced neuropathic pain (CINP) and the proposed study will investigate the efficacy and safety of multiple dose levels of tetrodotoxin (TTX) versus placebo in moderate to severe neuropathic pain caused by chemotherapy. ...
Colorectal cancer (CRC) the third leading causes of cancer-related death worldwide with an estimated 639,000 deaths each year. In the United States, CRC is the second leading cause of cancer-related death, resulting in approximately 49,920 deaths in 2009. Despite significant advances in research and development in CRC and gastric cancer, the current response rate for 1st line treatment of mCRC remains ~50% and dramatically decreases for 2nd line therapy. In addition, the five-year survival rate for patients diagnosed with mCRC is approximately 10%. While, molecularly targeted therapies have improved treatment outcomes for patients with cancer, these benefits are modest and in only select patient populations. It is clear that the new chemotherapeutic options and novel drug combinations must be developed to provide benefit for the approximately half of patients that fail to response to current chemotherapeutic options that are available. We hypothesize that combining novel agents that target ...
The present study was designed to determine the effects of artemisinin (ARS) and its derivatives on human ovarian cancer cells, to evaluate their potential as novel chemotherapeutic agents used alone or in combination with a conventional cancer chemotherapeutic agent, and to investigate their underlying mechanisms of action. Human ovarian cancer cells (A2780 and OVCAR-3), and immortalized non-tumourigenic human ovarian surface epithelial cells (IOSE144), were exposed to four ARS compounds for cytotoxicity testing. The in vitro and in vivo antitumour effects and possible underlying mechanisms of action of dihydroartemisinin (DHA), the most effective compound, were further determined in ovarian cancer cells. ...These effects were also observed in in vivo ovarian A2780 and OVCAR-3 xenograft tumour models. In conclusion, ARS derivatives, particularly DHA, exhibit significant anticancer activity against ovarian cancer cells in vitro and in vivo, with minimal toxicity to non-tumourigenic human OSE ...
SHIRLEY, NOV 30TH,2017 - Researchers from the Albert Einstein College of Medicine found a compound that can directly contribute to the suicide of cancer cells for the first time by inducing cell apoptosis, moreover, it will not affect specific compounds in healthy cells of the body. The study results was published in the Journal of Cancer. As a new type of therapy which can directly resist Acute Myeloid Leukemia (AML) cells, it also can help offer effectively supply for other types of cancer cells.. Professor Evripidis Gavathiotis, one of the researchers for this study, claimed that this new targeting compounds they developed were more effective than the current anticancer therapies, which promote cancer cells to self-destruct. Ideally, this new type of compounds will work with other therapies to kill cancer cells more quickly and efficiently but with fewer side effects, while the traditional chemotherapy often causes some side effects to patients.. AML, which accounts for almost a third of ...
Chemotherapy can impact or damage the bodys peripheral nerves. Peripheral nerves carry sensations (or neurological messages) to and from the brain and spine, to control feeling and movement in different parts of the body including arms, legs, hands and feet. They also control the bowel and bladder. Damage to peripheral nerves that is caused by chemotherapy is called
Conventional cytotoxic chemotherapy plays a major role in cancer therapy. Development of intensified regimen improved the outcome of several diseases [45, 46, 49, 66, 67] but is limited by toxic side effects. A major dose-limiting side effect is general haematotoxicity which is routinely treated with growth factors EPO and G-CSF. Different pharmaceutical derivatives of these factors are available, which differ greatly in pharmacokinetic and -dynamic properties. Furthermore, outcome of growth factor treatment depends on many factors such as chemotherapy drugs used, drug doses, growth-factor derivatives and individual risk factors [68, 69]. Due to this variety of variable therapy parameters, identification of optimal growth-factor schedules cannot be performed solely on the basis of clinical trials. We showed in the past that mathematical models of haematopoiesis under chemotherapy can facilitate the development of optimised and individualised growth-factor schedules [6].. Efforts to model ...
Cisplatin is a widely used cancer therapy drug that unfortunately has major side effects in normal tissues, notably nephrotoxicity in kidneys. Despite intensive research, the mechanism of cisplatin-induced nephrotoxicity remains unclear, and renoprotective approaches during cisplatin-based chemotherapy are lacking. Here we have identified PKCδ as a critical regulator of cisplatin nephrotoxicity, which can be effectively targeted for renoprotection during chemotherapy. We showed that early during cisplatin nephrotoxicity, Src interacted with, phosphorylated, and activated PKCδ in mouse kidney lysates. After activation, PKCδ regulated MAPKs, but not p53, to induce renal cell apoptosis. Thus, inhibition of PKCδ pharmacologically or genetically attenuated kidney cell apoptosis and tissue damage, preserving renal function during cisplatin treatment. Conversely, inhibition of PKCδ enhanced cisplatin-induced cell death in multiple cancer cell lines and, remarkably, enhanced the chemotherapeutic ...
Cisplatin is a widely used cancer therapy drug that unfortunately has major side effects in normal tissues, notably nephrotoxicity in kidneys. Despite intensive research, the mechanism of cisplatin-induced nephrotoxicity remains unclear, and renoprotective approaches during cisplatin-based chemotherapy are lacking. Here we have identified PKCδ as a critical regulator of cisplatin nephrotoxicity, which can be effectively targeted for renoprotection during chemotherapy. We showed that early during cisplatin nephrotoxicity, Src interacted with, phosphorylated, and activated PKCδ in mouse kidney lysates. After activation, PKCδ regulated MAPKs, but not p53, to induce renal cell apoptosis. Thus, inhibition of PKCδ pharmacologically or genetically attenuated kidney cell apoptosis and tissue damage, preserving renal function during cisplatin treatment. Conversely, inhibition of PKCδ enhanced cisplatin-induced cell death in multiple cancer cell lines and, remarkably, enhanced the chemotherapeutic ...
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Treatment of multifunctional diseases such as cancer typically cannot be achieved by therapeutic agents that inhibit a single target.1 Single agent therapeutics often lead to development of drug resistance as well as limited accessibility of drug to tumour tissue due to intra-tumour heterogeneity.2 Moreover, in order to achieve therapeutically relevant concentrations within the tumour, high systemic doses of chemotherapy agents need to be administered, often resulting in severe toxic side effects.3 This is the case with drugs such as cisplatin and other platinum derivative drugs that are widely used in the treatment of ovarian cancer and head and neck squamous cell carcinoma (HNSCC).4,5 The primary mechanism of action of cisplatin is through DNA damage.6 However, several cellular pathways are activated by cisplatin exposure, including DNA repair pathways that remove the damage and result in the emergence of drug resistance.7 It has been shown that a combination of multiple anticancer drugs can ...
Multidrug resistance is a major barrier against successful chemotherapy, and this has been shown in vitro to be often caused by ATP-binding cassette (ABC) transporters. These transporters are frequently overexpressed in human cancers and confer an adverse prognosis in many common malignancies. The genetic factors, however, that initiate their expression in cancer are largely unknown. Here we report that the major multidrug transporter ABCG2 (BCRP/MXR) is directly and specifically activated by the transcription factor E2F1-a factor perturbed in the majority of human cancers. E2F1 regulates ABCG2 expression in multiple cell systems, and, importantly, we have identified a significant correlation between elevated E2F1 and ABCG2 expression in human lung cancers. We show that E2F1 causes chemotherapeutic drug efflux both in vitro and in vivo via ABCG2. Furthermore, the E2F1-ABCG2 axis suppresses chemotherapy-induced cell death that can be restored by the inhibition of ABCG2. These findings therefore ...
The establishment of new treatment options for chemo- and radiation-resistant NETs is essential because of the inefficacy of conventional chemotherapy. Medicinal herbs have come increasingly into the spotlight as complementary medicines. In the present study, we provide a first report of the antitumor activity of plant extracts from Christia vespertilionis, in which the ethylacetate fraction CV-45 showed significant antiproliferative and pro-apoptotic effects in MTC-SK as well as in KRJ-I cells.. It is known that many chemotherapeutic agents are able to induce apoptosis in cancer cells, as with sorafenib or 5-fluorouracil for human hepatoma cells (18,19). One goal in the establishment of new therapies against NETs is to define substances that have the ability to trigger anticancer effects and to induce apoptosis specifically in tumor cells, but not in normal cells.. In the human fibroblasts (HF-SAR) tested, the same concentration of CV-45 (10 μg/ml) as used for tumor cells did not inhibit ...
Paclitaxel is a standard chemotherapeutic agent for ovarian cancer. Resistance of ovarian cancer cells to the drug has been a major obstacle in clinical practice. Thus, alternative approaches are needed to conquer the resistance. PEA-15 (phosphoprotein enriched in astrocytes-15 kDa) regulates cell proliferation and apoptosis. It is phosphorylated at S104 and S116 by Akt, PKC and CaMKII. PEA-15s functions are phosphorylation dependent. Although PEA-15 is known to mediate chemoresistance in breast cancer, the effect of PEA-15 phosphorylation status on chemosensitivity remains unknown. We hypothesized that phospho-PEA-15 (pPEA-15) enhances sensitivity of ovarian cancer cells to paclitaxel. To test our hypothesis, we silenced PEA-15 expression in HEY and OVTOKO cells using siRNA and observed a 14% reduction in apoptosis after paclitaxel exposure. To further determine if PEA-15 phosphorylation contributes to chemosensitivity, we generated SKOV3.ip1-vector (control), SKOV3.ip1-AA (AA, ...
The natural product (-)-dictyostatin is a microtubule stabilizing agent that potently inhibits the growth of human cancer cells including paclitaxel-resistant clones. Extensive structure-activity relationship studies have revealed several regions of the molecule that could be altered without loss of activity. The most potent synthetic dictyostatin analog described to date, 6-epi-dictyostatin, has in vivo antitumor activity against human breast cancer xenografts superior to paclitaxel. Despite their encouraging preclinical activities, the complex chemical structure of the dictyostatins presents a major obstacle in their development into novel antineoplastic therapies. We recently reported a streamlined synthesis of 16-desmethyl-25,26 dihydrodictyostatins and found several agents that compared with 6-epi-dictyostatin retained nanomolar activity in cellular microtubule bundling assays but showed cross-resistance to paclitaxel in cells with mutations in beta-tubulin. Extending these studies, we ...
The development of new anti-cancer treatments with greater efficacy and fewer side effects remains a significant challenge of modern scientific and medical research. Curcumin, a natural polyphenol found in the dietary spice turmeric, has been demonstrated to inhibit cancer cell survival and proliferation, and to in Chemistry for Medicine: Special Collection for RSC Advances Bioconvergence for food function
Abstract Purpose Subsequent to chemotherapy treatment, breast cancer patients often report a decline in cognitive functioning that can adversely impact many aspects of their lives. Evidence has mounted in recent years indicating that a portion of breast cancer survivors who have undergone chemotherapy display reduced performance on objective measures of cognitive functioning relative to comparison groups. Neurophysiological support for chemotherapy-related cognitive impairment has been accumulating due to an increase in neuroimaging studies in this field; however, longitudinal studies are limited and have not examined the relationship between structural grey matter alterations and neuropsychological performance. The aim of this study was to extend the cancer-cognition literature by investigating the association between grey matter attenuation and objectively measured cognitive functioning in chemotherapy-treated breast cancer patients. Methods Female breast cancer patients (n = 19) underwent ...
The mechanisms underlying the proapoptotic effect of the chemotherapeutic agent, cisplatin, are undefined largely. MAPK-dependent system. Cisplatin treatment coupled with particular inhibitors to each MAPK pathway (c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38) led to reduced ATF3 induction on the proteins level. MAPK pathway inhibition resulted in reduced ATF3 messenger RNA appearance and decreased cytotoxic ramifications of cisplatin as assessed with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell viability assay. In A549 lung carcinoma cells, concentrating on ATF3 with specific little hairpin RNA attenuated the cytotoxic ramifications of cisplatin also. Likewise, ATF3-/- murine embryonic fibroblasts (MEFs) had been been shown to be much less delicate to cisplatin-induced cytotoxicity weighed against ATF3+/+ MEFs. This research recognizes cisplatin being a MAPK pathway-dependent inducer of ATF3, whose expression influences cisplatins cytotoxic ...
The antiangiogenic effects need to be fine-tuned and adapted over time to obtain the best antitumor response possible because suboptimal antiangiogenic therapy might, in some cases, lead to potentially more aggressive tumor progression (23). Combined with conventional cytotoxic drugs, the extent of the antiangiogenic activity might determine whether the combination is synergistic, for instance, by transient normalization of the tumor vasculature resulting in temporarily better oxygenation and drug deposition (24), otherwise, the combination could be antagonistic. A further layer of complexity derives from the finding that most conventional, and many targeted antitumor agents, exert accidental antiangiogenic effects (25). Indeed, if given in a metronomic fashion (i.e., administered frequently in comparatively low doses over prolonged periods with no prolonged breaks), traditional cytotoxic drugs might act primarily via antiangiogenic mechanisms that are accompanied by only low-grade toxicity ...
Sulfonamides are the first effective chemotherapeutic agents used for several years to cure or prevent systemic bacterial infections. In addition, this agents showed anti-carbonic anhydrase and cause cell cycle perturbation in the G1 phase, disruption of microtubule assembly, suppression of the transcription activator Nf-Y, angiogenesis and matrix metalloproteinase (MMP). In recent years, novel synthesized sulfonamides have been introduced as antitumor, antiviral and anti-inflammatory agents. In this paper, the cytotoxic effects of 8 synthesized sulfonamides were investigated by MTT assay on HeLa, MDA-MD-468 and MCF-7 cancer cell lines. Human cancer cells were cultured and passaged in RPMI-1640 medium. Cells incubated in 96-well plates in a concentration of 1 × 105 cells/mL for 24 h, and then logarithmic concentrations (0.1 µm, 1 µm, 10 µm, 100 µm, 1mM) of each drug were prepared, added to the plates and incubated for 72 h. Cell survival was then determined using ELISA plate reader in 540 nm
TY - JOUR. T1 - Continuing challenges and current issues in acute lymphoblastic leukemia. AU - Kansagra, Ankit. AU - Dahiya, Saurabh. AU - Litzow, Mark. PY - 2017/6/12. Y1 - 2017/6/12. N2 - Conventional cytotoxic chemotherapy used to treat acute lymphoblastic leukemia (ALL) has resulted into high cure rates for pediatric patients, however outcomes for adult patients remain suboptimal. The 5-year overall survival is only 30-40% in adults and elderly patients with ALL compared to 90% in children. We have seen major advances in our understanding and management of ALL related to identification of new cytogenetic and molecular abnormalities and development of novel targeted agents for the treatment of ALL. The addition of tyrosine kinase inhibitors, monoclonal antibodies and novel immune therapies (e.g. bispecific T cell engager [BiTE] and chimeric antigen receptor [CAR] T cells) has resulted in improved outcomes. These new developments are changing the treatment paradigm of adults ALL from a one ...
Multi-drug resistance is the biggest threat to long-term survival of cancer patients. Despite treatment, some tumor cells survive chemotherapy and become resistant to the drugs, causing follow-up treatments to fail. These drug-resistant tumors become untreatable and continue to flourish, ultimately killing the patient. Multi-drug resistance proteins expressed by tumor cells are a major source of resistance to conventional chemotherapeutic drugs. Small interfering RNAs (siRNAs) can silence these messenger RNAs that make multi-drug resistance proteins and EnGeneIC has discovered that EDVs can effectively load up to 10,000 copies of siRNA and deliver them directly to cancer cells. This process silences the respective messenger RNAs and makes the tumor cells sensitive to chemotherapeutic drugs which are subsequently delivered via the EDVs to eradicate the formerly drug resistant tumor. EnGeneIC has demonstrated in mouse studies carrying human drug resistant tumors and the data has been published in ...
Conventional cytotoxic chemotherapy has not provided clinical benefit or prolonged survival for patients with advanced HCC. This review summarizes the results of prospective clinical trials of several categories of systemic therapy, with emphasis on the more promising results from recent trials of biologically targeted therapeutic agents in HCC.
Abstract Background Cisplatin is a platinum-based chemotherapeutic that damages genomic DNA leading to cell death. It also damages mitochondrial DNA and...
This thesis describes bioanalysis of small and large molecules in biological matrices and includes screening of illegal drugs in urine with high resolution mass spectrometer, bioanalysis of MTH1 inhibitors in mice plasma and quantification of proteins in plasma and cell lysates.. Screening of illegal drugs was based on high resolving power mass spectrometer (QTOF) and the results were compared to immunoassays. For the study, the nine most commonly abused drugs were selected for screening of a large number of authentic urine samples. Evaluation of the screening results showed that the QTOF generated a low rate of false positive and false negative results and can be used as an alternative or a complementary to immunoassays.. In another study, a bioanalytical method for the two new anticancer targets TH588 and TH287 was developed and validated. The compounds inhibit the MTH1 protein that is required for cancer cell survival. To study the pharmacokinetic properties of the substances, a bioanalytical ...
TY - JOUR. T1 - Synthesis and evaluation of Taxol-folic acid conjugates as targeted antineoplastics. AU - Lee, Jae Wook. AU - Lu, June Y.. AU - Low, Philip. AU - Fuchs, P. L.. PY - 2002/5/8. Y1 - 2002/5/8. N2 - A series of Taxol derivatives tethered at C2′ and C-7 to glutamate and folate have been synthesized for evaluation as prodrugs which release Taxol via hydrolytic lability of their α-alkoxy and α-amino esters. The half-time for hydrolysis of these materials was determined in pH 7 and pH 5 buffer. The in vitro cytotoxicity has been assessed in cell culture against A-549 lung cancer, MCF-7 breast cancer, and HT-29 colon cancer. Selected agents were further screened for folate binding and competitive binding with free folic acid. One agent (54), further evaluated in animal studies was found to increase the lifespan in mice, but was less effective than Taxol itself.. AB - A series of Taxol derivatives tethered at C2′ and C-7 to glutamate and folate have been synthesized for evaluation as ...
Chemotherapy is one of the most important therapeutic options used to treat human cancers, either alone or in combination with radiation therapy and surgery. Recent studies have indicated that intra-tumoural heterogeneity has a significant role in driving resistance to chemotherapy in many human malignancies. Multiple factors including the internal cell-cycle dynamics and the external microenvironement contribute to the intra-tumoural heterogeneity. In this paper we present a hybrid, multiscale, individual-based mathematical model, incorporating internal cell-cycle dynamics and changes in oxygen concentration, to study the effects of delivery of several different chemotherapeutic drugs on the heterogeneous subpopulations of cancer cells with varying cell-cycle dynamics. The computational simulation results from the multiscale model are in good agreement with available experimental data and support the hypothesis that slow-cycling sub-populations of tumour cells within a growing tumour mass can ...
Chemotherapy is one of the most important therapeutic options used to treat human cancers, either alone or in combination with radiation therapy and surgery. Recent studies have indicated that intra-tumoural heterogeneity has a significant role in driving resistance to chemotherapy in many human malignancies. Multiple factors including the internal cell-cycle dynamics and the external microenvironement contribute to the intra-tumoural heterogeneity. In this paper we present a hybrid, multiscale, individual-based mathematical model, incorporating internal cell-cycle dynamics and changes in oxygen concentration, to study the effects of delivery of several different chemotherapeutic drugs on the heterogeneous subpopulations of cancer cells with varying cell-cycle dynamics. The computational simulation results from the multiscale model are in good agreement with available experimental data and support the hypothesis that slow-cycling sub-populations of tumour cells within a growing tumour mass can ...
Cancer research is an area of biology where growth curve analysis plays an important role. In many types of cancer, the rate at which tumors shrink following chemotherapy is related to the rate of tumor growth before treatment. Tumors that grow rapidly are generally more sensitive to the toxic effects that conventional anticancer drugs have on the cancer cells. Many conventional anticancer drugs (for example, 5-Fluorouracil) interfere with DNA replication and can cause the death of cells that attempt to replicate their DNA and divide. A rapidly growing tumor will have more actively dividing cells and more cell death upon exposure to such anticancer drugs. ...
DESCRIPTION (provided by applicant): We will conduct Phase I clinical trials of new anticancer agents or combinations of anticancer agents to characterize drug toxicity, determine the maximum tolerated dose, evaluate the pharmacokinetics, perform pharmacogenetic analysis, and relating clinical endpoints to pharmacokinetics, pharmacogenetics, and/or biologic endpoints. A major focus of this proposal is the study agents that interact with novel targets such as signal transduction pathways, cell cycle checkpoint components, DNA repair pathways and apoptosis regulators, either alone or in combination with standard chemotherapy. The endpoints for the evaluation of such treatments will be clinical effect (toxicity and antineoplasti response) as well as alterations in biochemical pathways affected in preclinical model systems. The specific aims of these studies are: to determine as efficiently as compatible with patient safety the appropriate dose of new anticancer agents selected by the National ...
Purpose: Ridaforolimus (MK-8669, AP23573) is a potent and selective mTOR inhibitor. Preclinically, ridaforolimus displays antiproliferative activity against a variety of human tumors in vitro and tumor xenograft models in vivo, with additive or synergistic activity when combined with other anticancer agents. Anti-tumor activity has been confirmed in adults. This phase I study determined the safety, pharmacological, biologic, and toxicity profiles of ridaforolimus in pediatric patients with refractory malignancies. Experimental Design: Eligible children ages 1-18 years with advanced solid tumors were enrolled in a 3+3 dose escalation design, to determine the safety, tolerability, and maximum tolerated dose (MTD)/dose limiting toxicity (DLT) of ridaforolimus. Toxicities, pharmacokinetics and pharmacodynamics were characterized. Results: Fifteen patients were treated. No dose-limiting toxicity was observed at any dose level tested; therefore, an MTD was not identified. Most adverse events were mild ...
Amgen, a drug company, stopped studies of a pancreatic cancer drug just shy of the studys end due to results that did not live up to expected standards.. The drug was not found to affect patients longevity, and the study was stopped during the final step of the human trial process. According to Bloomberg.com, the addition of ganitumab to the pancreatic cancer drug, gemcitabine, is meant to target the type 1 insulin growth factor receptor. The other name of the pancreatic cancer drug is AMG 479.. The main goal of this ingredient in the pancreatic cancer drug is to regulate cell growth.. Previous test trials for colorectal and small-cell lung cancer are currently being reviewed, as they too involved the pancreatic cancer drug.. Sean Harper, executive vice president of research and development at Amgen, said, These disappointing results underscore the difficulty of treating pancreatic cancer, which remains a major unmet medical need.. According to Reuters, while the pancreatic cancer drug ...
Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting and disabling side effect of taxane anticancer agents. We prospectively evaluated the efficacy of cryotherapy for CIPN prevention. Methods: Breast cancer patients treated weekly with paclitaxel (80 mg/m2 for one hour) wore frozen gloves and socks on the dominant side for 90 minutes, including the entire duration of drug infusion. Symptoms on the treated sides were compared with those on the untreated (nondominant) sides. The primary end point was CIPN incidence assessed by changes in tactile sensitivity from pretreatment baseline in a monofilament test at a cumulative dose of 960 mg/m2. We also assessed thermosensory deficits, subjective symptoms (Patient Neuropathy Questionnaire [PNQ]), manipulative dexterity, and the time to events and hazard ratio by PNQ. All statistical tests were two-sided. Results: Among the 40 patients, four did not reach the cumulative dose (due to the occurrence of pneumonia, severe ...
Great strides are being made in understanding the signaling pathways involved in initiation and growth of cancers, as well as their abilities to evade treatment. Some of this research is being driven by the development of new chemotherapeutics. Accordingly, there is a broadening spectrum of potential drugs in various stages of clinical trials that can be used to treat this highly invasive disease. The continued development of new chemotherapeutic agents and the identification of novel cellular targets are imperative for the successful treatment of cancer, as well as to gain a more complete understanding of how cells work. Such efforts will bring us closer to the goal of personalizing medicine by targeting specific weaknesses in certain types of cancer. The overarching theme of the work contained herein has been the identification of potential chemotherapeutic agents. Multiple strategies have been employed, from assessment of a compound selective for white blood cell cancers to analysis of ...