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Article ; Online: Targeting Brain Tumors with Nanomedicines: Overcoming Blood Brain Barrier Challenges.

Khaitan, Divya / Reddy, Polluru L / Ningaraj, Nagendra

2018 Volume 13, Issue 2, Page(s) 110–119

Abstract: Background: This review elucidates ongoing research, which show improved delivery of anticancer drugs alone and/ or enclosed in carriers collectively called nanomedicines to cross the BBB/ BTB to kill tumor cells and impact patient survival. We ... ...

Abstract	Background: This review elucidates ongoing research, which show improved delivery of anticancer drugs alone and/ or enclosed in carriers collectively called nanomedicines to cross the BBB/ BTB to kill tumor cells and impact patient survival. We highlighted various advances in understanding the mechanism of BTB function that has an impact on anticancer therapeutics delivery. We discussed latest breakthroughs in developing pharmaceutical strategies, including nanomedicines and delivering them across BTB for brain tumor management and treatment. Methods: We performed an extensive literature search and highlighted important studies on the regulation of BTB permeability with respect to nanotech-based nanomedicines for targeted treatment of brain tumors. We have reviewed research articles that describe the development of specialized molecules and nanospheres, which carry payload of anticancer agents to brain tumor cells across the BBB/ BTB and avoid drug efflux systems. We highlighted research on the identification and development of targeted anti-cancer drug delivery to brain tumors. In addition, we discussed multimeric molecular therapeutics and nanomedicines that were encapsulated in nanospheres for treatment and monitoring of brain tumors. Results: In this context, we quoted our research on large conductance calcium-activated potassium channels (BKCa) and ATP-dependent potassium channels (KATP) as portals of enhanced antineoplastic drugs delivery. We showed that several innovative drug delivery agents such as liposomes, polymeric nanoparticles, dendrimers and many such tools can be utilized to improve anticancer drugs and nanomedicines across the BTB to reach brain tumor cells. Conclusion: This review might interest both academic and drug company scientists involved in drug delivery to brain tumors. We further seek to present evidence that BTB modulators can be clinically developed as combination drug or/ and as stand-alone anticancer drugs. Eventually, it is expected that unrelenting effort from the scientific community in developing novel drug delivery methods should increase the survival rate of brain tumor patients, which is dismally low presently.
MeSH term(s)	Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/metabolism ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Brain Neoplasms/drug therapy ; Brain Neoplasms/metabolism ; Drug Delivery Systems/methods ; Drug Delivery Systems/trends ; Humans ; Nanomedicine/methods ; Nanomedicine/trends
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2018-04-13
Publishing country	United Arab Emirates
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2250809-0
ISSN	2212-3938 ; 1574-8847
ISSN (online)	2212-3938
ISSN	1574-8847
DOI	10.2174/1574884713666180412150153
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Article: Targeting potassium channels for increasing delivery of imaging agents and therapeutics to brain tumors.

Khaitan, Divya / Ningaraj, Nagendra S

Frontiers in pharmacology

2013 Volume 4, Page(s) 62

Abstract: Every year in the US, 20,000 new primary and nearly 200,000 metastatic brain tumor cases are reported. The cerebral microvessels/capillaries that form the blood-brain barrier not only protect the brain from toxic agents in the blood but also pose a ... ...

Abstract	Every year in the US, 20,000 new primary and nearly 200,000 metastatic brain tumor cases are reported. The cerebral microvessels/capillaries that form the blood-brain barrier not only protect the brain from toxic agents in the blood but also pose a significant hindrance to the delivery of small and large therapeutic molecules. Different strategies have been employed to circumvent the physiological barrier posed by blood-brain tumor barrier (BTB). Studies in our laboratory have identified significant differences in the expression levels of certain genes and proteins between normal and brain tumor capillary endothelial cells (ECs). In this study, we validated the non-invasive and clinically relevant dynamic contrast enhancing-magnetic resonance imaging (DCE-MRI) method with invasive, clinically irrelevant but highly accurate quantitative autoradiography method using rat glioma model. We also showed that DCE-MRI metric of tissue vessel perfusion-permeability is sensitive to changes in blood vessel permeability following administration of calcium-activated potassium (BKCa) channel activator NS-1619. Our results show that human gliomas and brain tumor ECs that overexpress BKCa channels can be targeted for increased BTB permeability for MRI enhancing agents to brain tumors. We conclude that monitoring the outcome of increased MRI enhancing agents' delivery to microsatellites and leading tumor edges in glioma patients would lead to beneficial clinical outcome.
Language	English
Publishing date	2013-05-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2013.00062
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Article ; Online: Successful treatment outcome with itraconazole and potassium iodide in disseminated sporotrichosis.

Khaitan, Binod K / Gupta, Vishal / Asati, Dinesh P / Seshadri, Divya / Ramam, M

Indian journal of dermatology, venereology and leprology

2017 Volume 84, Issue 1, Page(s) 101–104

MeSH term(s)	Antifungal Agents/administration & dosage ; Back/pathology ; Drug Therapy, Combination ; Humans ; Itraconazole/administration & dosage ; Male ; Middle Aged ; Potassium Iodide/administration & dosage ; Sporotrichosis/diagnosis ; Sporotrichosis/drug therapy ; Treatment Outcome
Chemical Substances	Antifungal Agents ; Potassium Iodide (1C4QK22F9J) ; Itraconazole (304NUG5GF4)
Language	English
Publishing date	2017-12-15
Publishing country	India
Document type	Case Reports ; Letter
ZDB-ID	416068-x
ISSN	0973-3922 ; 0019-5162 ; 0378-6323
ISSN (online)	0973-3922
ISSN	0019-5162 ; 0378-6323
DOI	10.4103/ijdvl.IJDVL_958_16
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Article: Dehabilitation in the era of elimination and rehabilitation: a study of 100 leprosy patients from a tertiary care hospital in India.

Seshadri, Divya / Khaitan, Binod K / Khanna, Neena / Sagar, Rajesh

Leprosy review

2015 Volume 86, Issue 1, Page(s) 62–74

Abstract: Objectives: To study the clinical profile of leprosy patients; to assess dehabilitation in leprosy patients and to study the factors affecting dehabilitation.: Design: A cross-sectional questionnaire-based study was carried out on 100 leprosy ... ...

Abstract	Objectives: To study the clinical profile of leprosy patients; to assess dehabilitation in leprosy patients and to study the factors affecting dehabilitation. Design: A cross-sectional questionnaire-based study was carried out on 100 leprosy patients visiting the All India Institute of Medical Sciences (AIIMS), New Delhi between February 2009 and February 2010. Demographic and clinical data were collected and subjects were administered the 52-item Anandaraj Dehabilitation scale which measures the negative impact of leprosy on family relationships, vocational condition, social interaction and self-esteem. Results: The mean patient age was 30.9 years, 81% were males, 51% were at the lepromatous end of the spectrum, 87% had multibacillary leprosy, 22% each had Type 1 and Type 2 reactions, 22% had Grade 1 disability and 39% had Grade 2 disability. The mean duration of symptoms before diagnosis was 20 months. On the Anandaraj scale, 23% had high levels of dehabilitation; on an average, scores were in the range of medium level dehabilitation. Nearly 80% of patients avoided meeting friends, one-third hid the diagnosis from their families and worried about losing their jobs due to the disease, while around a quarter avoided sexual relations, used separate utensils and avoided touching children. Over 40% of unmarried patients faced matrimonial difficulty due to leprosy. Anxiety and guilt were common and incidence of suicidal ideas was much higher than the lifetime incidence in general population. Lack of education, Type 2 reactions, Grade 2 disability and lower age were predictors of greater dehabilitation. Conclusions: Dehabilitation of leprosy patients continues in this post-elimination era of rehabilitation. A large segment of preventable disability and resultant dehabilitation is likely being missed. There is an urgent need for corrective and preventive measures.
MeSH term(s)	Adolescent ; Adult ; Cross-Sectional Studies ; Disabled Persons/psychology ; Disabled Persons/rehabilitation ; Female ; Humans ; India ; Leprosy/prevention & control ; Leprosy/psychology ; Leprosy/rehabilitation ; Male ; Middle Aged ; Patients/psychology ; Surveys and Questionnaires ; Tertiary Healthcare/statistics & numerical data ; Young Adult
Language	English
Publishing date	2015-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	415137-9
ISSN	0305-7518 ; 0024-1032
ISSN	0305-7518 ; 0024-1032
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Article: Endogenous and induced oxidative stress in multi-cellular tumour spheroids: implications for improving tumour therapy.

Khaitan, Divya / Dwarakanath, B S

Indian journal of biochemistry & biophysics

2009 Volume 46, Issue 1, Page(s) 16–24

Abstract: The endogenous oxidative stress in tumours is determined by the status of mitochondrial, metabolic, oxygen (hypoxia) and inherent enzymatic as well as non-enzymatic antioxidant defense systems, which influence tumour growth and respond to anticancer ... ...

Abstract	The endogenous oxidative stress in tumours is determined by the status of mitochondrial, metabolic, oxygen (hypoxia) and inherent enzymatic as well as non-enzymatic antioxidant defense systems, which influence tumour growth and respond to anticancer therapeutics. Induced oxidative stress is one of the important determinants of the outcome of treatment with certain chemotherapeutic drugs and ionizing radiation. The mild to moderate levels of reactive oxygen species (ROS) have often been found to trigger prosurvival responses, thereby contributing to the resistance against therapy. The higher levels of ROS stimulate multiple death pathways viz. typical and atypical apoptosis, necrosis etc, thereby enhancing the therapeutic efficiency. Therefore, approaches employing therapeutic agents that generate ROS efficiently in the tumour cells and enhance the antioxidant defense system in the normal cells could significantly enhance the therapeutic gain. Multi-cellular tumour spheroids (MCTS) offer an excellent in vitro system that mimics endogenous oxidative stress often observed in tumours, arising due to a number of factors (gradients of oxygen and nutrients, altered intercellular interaction and tumour necrosis factor), besides antioxidant defense systems similar to tumours in vivo. More importantly, MCTS resemble tumours in vivo with reference to the induced oxidative stress related responses, particularly following combinations of certain chemotherapeutic drugs and metabolic inhibitors and differs significantly from the responses in monolayer cultures. Therefore, MCTS appear to be excellent in vitro models, ideally suited for developing novel therapies that are based on the generation of oxidative stress in tumours. The present review provides a modest account on the utility of MCTS in understanding the role of oxidative stress in treatment-induced responses of tumours for designing therapies and therapeutics.
MeSH term(s)	ATP-Binding Cassette, Sub-Family B, Member 1/metabolism ; Antineoplastic Agents/therapeutic use ; Cell Death ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Neoplasms/pathology ; Neoplasms/physiopathology ; Neoplasms/therapy ; Neovascularization, Pathologic ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Spheroids, Cellular/drug effects ; Spheroids, Cellular/physiology ; Tumor Cells, Cultured
Chemical Substances	ATP-Binding Cassette, Sub-Family B, Member 1 ; Antineoplastic Agents ; HIF1A protein, human ; Hypoxia-Inducible Factor 1, alpha Subunit ; Reactive Oxygen Species
Language	English
Publishing date	2009-02
Publishing country	India
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	121689-2
ISSN	0975-0959 ; 0301-1208
ISSN (online)	0975-0959
ISSN	0301-1208
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Article ; Online: Peripheral T-cell lymphoma, not otherwise specified presenting with multiple tender cutaneous nodules and plaques.

Gupta, Vishal / Seshadri, Divya / Khaitan, Binod K / Nath, Debojit / Mridha, Asit R

Indian journal of dermatology, venereology and leprology

2015 Volume 81, Issue 3, Page(s) 313–315

MeSH term(s)	Adult ; Humans ; Lymphoma, T-Cell, Cutaneous/diagnosis ; Lymphoma, T-Cell, Cutaneous/therapy ; Lymphoma, T-Cell, Peripheral/diagnosis ; Lymphoma, T-Cell, Peripheral/therapy ; Male ; Skin Neoplasms/diagnosis ; Skin Neoplasms/therapy
Language	English
Publishing date	2015-05
Publishing country	India
Document type	Case Reports ; Letter
ZDB-ID	416068-x
ISSN	0973-3922 ; 0019-5162 ; 0378-6323
ISSN (online)	0973-3922
ISSN	0019-5162 ; 0378-6323
DOI	10.4103/0378-6323.152742
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Article ; Online: Peripheral T-cell lymphoma, not otherwise specified presenting with multiple tender cutaneous nodules and plaques

Vishal Gupta / Divya Seshadri / Binod K Khaitan / Debojit Nath / Asit R Mridha

Indian Journal of Dermatology, Venereology and Leprology, Vol 81, Iss 3, Pp 313-

2015 Volume 315

Keywords	Dermatology ; RL1-803 ; Medicine ; R
Language	English
Publishing date	2015-01-01T00:00:00Z
Publisher	Medknow Publications
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Multicellular spheroids as an in vitro model in experimental oncology: applications in translational medicine.

Khaitan, Divya / Dwarakanath, B S

Expert opinion on drug discovery

2006 Volume 1, Issue 7, Page(s) 663–675

Abstract: Multicellular tumour spheroids (MCTS), the best-described three-dimensional tumour model, offers an excellent in vitro screening system, which to a great extent mimics the microenvironment prevailing in the tumour tissue, supporting studies on such ... ...

Abstract	Multicellular tumour spheroids (MCTS), the best-described three-dimensional tumour model, offers an excellent in vitro screening system, which to a great extent mimics the microenvironment prevailing in the tumour tissue, supporting studies on such tumour specific processes such as angiogenesis, invasion and metastasis and the assessment of responses to various therapies as well as their underlying mechanisms. Developed as an alternative in vitro model to monolayer cultures, nearly 30 years ago, their role as part of high-throughput cell-based assay system in drug discovery is gaining considerable importance. The distinct possibility of establishing MCTS from primary tumour cells and co-culturing with different normal cells, namely stromal fibroblasts, endothelial cells and cells of hemopoietic as well as immune system lineage, enhance the value of MCTS in cancer research and drug development. Here, the authors present a brief overview on the present status on the application of multicellular spheroids in experimental oncology, particularly from the view point of cancer therapy and drug development.
Language	English
Publishing date	2006-12
Publishing country	England
Document type	Journal Article
ZDB-ID	2259618-5
ISSN	1746-0441
ISSN	1746-0441
DOI	10.1517/17460441.1.7.663
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Article ; Online: Short-term exposure of multicellular tumor spheroids of a human glioma cell line to the glycolytic inhibitor 2-deoxy-D-glucose is more toxic than continuous exposure.

Khaitan, Divya / Chandna, Sudhir / Dwarakanath, S Bilikere

Journal of cancer research and therapeutics

2009 Volume 5 Suppl 1, Page(s) S67–73

Abstract: The glycolytic inhibitor 2-deoxy-D-glucose (2-DG) has been used as a therapeutic agent and as an adjuvant in cancer therapy with either weekly fractions of the treatment or daily administration. While the weekly fraction has often been found to be ... ...

Abstract	The glycolytic inhibitor 2-deoxy-D-glucose (2-DG) has been used as a therapeutic agent and as an adjuvant in cancer therapy with either weekly fractions of the treatment or daily administration. While the weekly fraction has often been found to be nontoxic and effective, other treatment regimes are tolerated to a relatively lesser extent. It was therefore, considered worthwhile to investigate the efficacy of short- and long-term exposure of tumor cells to 2-DG under the controlled conditions. Seven-day-old MTS were exposed to 2-DG (5 mM, equimolar to glucose concentration in media) for different time intervals (30 min to 24 h) trypsinized and plated for clonogenicity. Alternatively, spheroids were grown either continuously in the presence of 2-DG or were treated with 2-DG for 2 h (short-term exposure) and grown in 2-DG-free media for 21 days and assessed for spheroid growth, cell viability, apoptosis, cytogenetic damage, mitochondrial status, and oxidative stress. Exposure of spheroids to 2-DG for 2-4 h induced 30% cell death (SF 0.70) while, a 24-h exposure resulted in only a marginal decrease in clonogenicity (SF 0.95). Furthermore, the spheroids disintegrated completely by 28 days in the case of 2-h exposure to 2-DG, while spheroids grown continuously in the presence of 2-DG repopulated. The cytotoxicity following short-term exposure of MTS to 2-DG was primarily due to the induction of apoptosis revealed by morphological features as well as flow cytometric analysis of the DNA content. Interestingly however, cytogenetic damage (micronuclei induction) was observed in spheroids that were continuously exposed to 2-DG. Short-term exposure to 2-DG resulted in a significant increase in ROS levels and a reduction in the levels of unoxidized cardiolipin as measured by NAO suggesting the involvement of mitochondria leakiness leading to oxidative stress which, could be responsible for apoptotic cell death observed under these conditions. However, continuous exposure to 2-DG resulted in a moderate level of oxidative stress leading to the genomic instability. Preliminary studies also show that spheroids exposed continuously to 2-DG result in the development of resistance to certain chemotherapeutic drugs which could be correlated with elevated levels of mdr1. The present results suggest that a persistent down-regulation of glycolysis (as seen here with continuous exposure to 2-DG) could activate prosurvival responses besides inducing moderate levels of oxidative stress resulting in the development of resistance against therapeutic agents.
MeSH term(s)	Antineoplastic Agents/administration & dosage ; Apoptosis/drug effects ; Brain Neoplasms/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Separation ; Cell Survival/drug effects ; Deoxyglucose/administration & dosage ; Drug Resistance, Neoplasm/drug effects ; Flow Cytometry ; Glioma/metabolism ; Glycolysis/drug effects ; Humans ; Oxidative Stress/drug effects ; Spheroids, Cellular ; Time
Chemical Substances	Antineoplastic Agents ; Deoxyglucose (9G2MP84A8W)
Language	English
Publishing date	2009-09
Publishing country	India
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2187633-2
ISSN	1998-4138 ; 0973-1482
ISSN (online)	1998-4138
ISSN	0973-1482
DOI	10.4103/0973-1482.55147
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Short-term exposure of multicellular tumor spheroids of a human glioma cell line to the glycolytic inhibitor 2-deoxy-D-glucose is more toxic than continuous exposure

Khaitan Divya / Chandna Sudhir / Dwarakanath S

Journal of Cancer Research and Therapeutics, Vol 5, Iss 9, Pp 67-

2009 Volume 73

Abstract	The glycolytic inhibitor 2-deoxy-D-glucose (2-DG) has been used as a therapeutic agent and as an adjuvant in cancer therapy with either weekly fractions of the treatment or daily administration. While the weekly fraction has often been found to be nontoxic and effective, other treatment regimes are tolerated to a relatively lesser extent. It was therefore, considered worthwhile to investigate the efficacy of short- and long-term exposure of tumor cells to 2-DG under the controlled conditions. Seven-day-old MTS were exposed to 2-DG (5 mM, equimolar to glucose concentration in media) for different time intervals (30 min to 24 h) trypsinized and plated for clonogenecity. Alternatively, spheroids were grown either continuously in the presence of 2-DG or were treated with 2-DG for 2 h (short-term exposure) and grown in 2-DG-free media for 21 days and assessed for spheroid growth, cell viability, apoptosis, cytogenetic damage, mitochondrial status, and oxidative stress. Exposure of spheroids to 2-DG for 2-4 h induced 30% cell death (SF 0.70) while, a 24-h exposure resulted in only a marginal decrease in clonogenecity (SF 0.95). Furthermore, the spheroids disintegrated completely by 28 days in the case of 2-h exposure to 2-DG, while spheroids grown continuously in the presence of 2-DG repopulated. The cytotoxicity following short-term exposure of MTS to 2-DG was primarily due to the induction of apoptosis revealed by morphological features as well as flow cytometric analysis of the DNA content. Interestingly however, cytogenetic damage (micronuclei induction) was observed in spheroids that were continuously exposed to 2-DG. Short-term exposure to 2-DG resulted in a significant increase in ROS levels and a reduction in the levels of unoxidized cardiolipin as measured by NAO suggesting the involvement of mitochondria leakiness leading to oxidative stress which, could be responsible for apoptotic cell death observed under these conditions. However, continuous exposure to 2-DG resulted in a moderate level of oxidative stress leading to the genomic instability. Preliminary studies also show that spheroids exposed continuously to 2-DG result in the development of resistance to certain chemotherapeutic drugs which could be correlated with elevated levels of mdr1. The present results suggest that a persistent down-regulation of glycolysis (as seen here with continuous exposure to 2-DG) could activate prosurvival responses besides inducing moderate levels of oxidative stress resulting in the development of resistance against therapeutic agents.
Keywords	Glioma cell line ; spheroids ; 2-deoxy-D-glucose ; cytotoxicity ; apoptosis ; necrosis ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Oncology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	610
Language	English
Publishing date	2009-09-01T00:00:00Z
Publisher	Medknow Publications
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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