scholarly journals Designer Oncolytic Adenovirus: Coming of Age

Cancers ◽  
2018 ◽  
Vol 10 (6) ◽  
pp. 201 ◽  
Author(s):  
Alexander Baker ◽  
Carmen Aguirre-Hernández ◽  
Gunnel Halldén ◽  
Alan Parker
Keyword(s):  
Checkpoint Inhibitors ◽  
Coming Of Age ◽  
Oncolytic Adenovirus ◽  
Detailed Knowledge ◽  
Immunomodulatory Agents ◽  
Double Stranded Dna ◽  
Wide Range ◽  
Anti Cancer ◽  
Targeting Ability

The licensing of talimogene laherparepvec (T-Vec) represented a landmark moment for oncolytic virotherapy, since it provided unequivocal evidence for the long-touted potential of genetically modified replicating viruses as anti-cancer agents. Whilst T-Vec is promising as a locally delivered virotherapy, especially in combination with immune-checkpoint inhibitors, the quest continues for a virus capable of specific tumour cell killing via systemic administration. One candidate is oncolytic adenovirus (Ad); it’s double stranded DNA genome is easily manipulated and a wide range of strategies and technologies have been employed to empower the vector with improved pharmacokinetics and tumour targeting ability. As well characterised clinical and experimental agents, we have detailed knowledge of adenoviruses’ mechanisms of pathogenicity, supported by detailed virological studies and in vivo interactions. In this review we highlight the strides made in the engineering of bespoke adenoviral vectors to specifically infect, replicate within, and destroy tumour cells. We discuss how mutations in genes regulating adenoviral replication after cell entry can be used to restrict replication to the tumour, and summarise how detailed knowledge of viral capsid interactions enable rational modification to eliminate native tropisms, and simultaneously promote active uptake by cancerous tissues. We argue that these designer-viruses, exploiting the viruses natural mechanisms and regulated at every level of replication, represent the ideal platforms for local overexpression of therapeutic transgenes such as immunomodulatory agents. Where T-Vec has paved the way, Ad-based vectors now follow. The era of designer oncolytic virotherapies looks decidedly as though it will soon become a reality.

scholarly journals Designer Oncolytic Adenovirus: Coming of Age

2018 ◽  
Author(s):  
Alexander T. Baker ◽  
Carmen Aguirre-Hernandez ◽  
Gunnel Hallden ◽  
Alan L. Parker
Keyword(s):  
Checkpoint Inhibitors ◽  
Coming Of Age ◽  
Oncolytic Adenovirus ◽  
Detailed Knowledge ◽  
Immunomodulatory Agents ◽  
Double Stranded Dna ◽  
Wide Range ◽  
Anti Cancer ◽  
Targeting Ability

The licensing of Talimogene Laherparepvec (T-Vec) represented a landmark moment for oncolytic virotherapy, since it provided unequivocal evidence for the long-touted potential of genetically modified replicating viruses as anti-cancer agents. Whilst T-Vec is promising as a locally delivered virotherapy, especially in combination with Immune-checkpoint inhibitors, the quest continues for a virus capable of specific tumour cell killing via systemic administration. One candidate is oncolytic Adenovirus; it’s double stranded DNA genome is easily manipulated and a wide range of strategies and technologies have been employed to empower the vector with improved pharmacokinetics and tumour targeting ability. As well characterised clinical and experimental agents we have detailed knowledge of Adenoviruses mechanisms of pathogenicity, supported by detailed virological studies and in vivo interactions. In this review we highlight the strides made in the engineering of bespoke adenoviral vectors to specifically infect, replicate within, and destroy tumour cells. We discuss how mutations in genes regulating adenoviral replication after cell entry can be used to restrict replication to the tumour, and summarise how detailed knowledge of viral capsid interactions enable rational modification to eliminate native tropisms, and simultaneously promote active uptake by cancerous tissues. We argue that these designer-viruses, exploiting the viruses natural mechanisms and regulated at every level of replication, represent the ideal platforms for local overexpression of therapeutic transgenes such as immunomodulatory agents. Where T-Vec has paved the way, Ad based vectors now follow. The era of designer oncolytic virotherapies looks decidedly as though it will soon become a reality.

scholarly journals Designer Oncolytic Adenovirus: Coming of Age

2018 ◽  
Author(s):  
Alexander T. Baker ◽  
Carmen Aguirre-Hernández ◽  
Gunnel Halldén ◽  
Alan L. Parker
Keyword(s):  
Checkpoint Inhibitors ◽  
Coming Of Age ◽  
Oncolytic Adenovirus ◽  
Detailed Knowledge ◽  
Immunomodulatory Agents ◽  
Double Stranded Dna ◽  
Wide Range ◽  
Anti Cancer ◽  
Targeting Ability

The licensing of talimogene laherparepvec (T-Vec) represented a landmark moment for oncolytic virotherapy, since it provided unequivocal evidence for the long-touted potential of genetically modified replicating viruses as anti-cancer agents. Whilst T-Vec is promising as a locally delivered virotherapy, especially in combination with immune-checkpoint inhibitors, the quest continues for a virus capable of specific tumour cell killing via systemic administration. One candidate is oncolytic adenovirus (Ad); it’s double stranded DNA genome is easily manipulated and a wide range of strategies and technologies have been employed to empower the vector with improved pharmacokinetics and tumour targeting ability. As well characterised clinical and experimental agents, we have detailed knowledge of adenoviruses’ mechanisms of pathogenicity, supported by detailed virological studies and in vivo interactions. In this review we highlight the strides made in the engineering of bespoke adenoviral vectors to specifically infect, replicate within, and destroy tumour cells. We discuss how mutations in genes regulating adenoviral replication after cell entry can be used to restrict replication to the tumour, and summarise how detailed knowledge of viral capsid interactions enable rational modification to eliminate native tropisms, and simultaneously promote active uptake by cancerous tissues. We argue that these designer-viruses, exploiting the viruses natural mechanisms and regulated at every level of replication, represent the ideal platforms for local overexpression of therapeutic transgenes such as immunomodulatory agents. Where T-Vec has paved the way, Ad-based vectors now follow. The era of designer oncolytic virotherapies looks decidedly as though it will soon become a reality.

Ethnomedicinal uses, Phytochemistry and Pharmacological Aspects of the Genus Berberis Linn: A Comprehensive Review

2020 ◽  
Vol 23 ◽  
Author(s):  
Roohi Mohi-ud-din ◽  
Reyaz Hassan Mir ◽  
Prince Ahad Mir ◽  
Saeema Farooq ◽  
Syed Naiem Raza ◽  
...  
Keyword(s):  
Chemical Constituents ◽  
Pharmacological Activities ◽  
Traditional Use ◽  
Comprehensive Review ◽  
Wide Range ◽  
Anti Cancer ◽  
Comprehensive Survey ◽  
Ethnomedicinal Uses

Background: Genus Berberis (family Berberidaceae), which contains about 650 species and 17 genera worldwide, has been used in folklore and various traditional medicine systems. Berberis Linn. is the most established group among genera with around 450-500 species across the world. This comprehensive review will not only help researchers for further evaluation but also provide substantial information for future exploitation of species to develop novel herbal formulations. Objective: The present review is focussed to summarize and collect the updated review of information of Genus Berberis species reported to date regarding their ethnomedicinal information, chemical constituents, traditional/folklore use, and reported pharmacological activities on more than 40 species of Berberis. Conclusion: A comprehensive survey of the literature reveals that various species of the genus possess various phytoconstituents mainly alkaloids, flavonoid based compounds isolated from different parts of a plant with a wide range of pharmacological activities. So far, many pharmacological activities like anti-cancer, anti-hyperlipidemic, hepatoprotective, immunomodulatory, anti-inflammatory both in vitro & in vivo and clinical study of different extracts/isolated compounds of different species of Berberis have been reported, proving their importance as a medicinal plant and claiming their traditional use.

scholarly journals Characterization of the phototoxicity, chemigenetic profile, and mutational signatures of the chemotherapeutic CX-5461 in Caenorhabditis elegans

2019 ◽  
Author(s):  
Frank B. Ye ◽  
Akil Hamza ◽  
Tejomayee Singh ◽  
Stephane Flibotte ◽  
Philip Hieter ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Cancer Therapeutics ◽  
Copy Number Variations ◽  
Factors Affecting ◽  
C Elegans ◽  
Dna Damaging Agents ◽  
Wide Range ◽  
Anti Cancer ◽  
Exogenous Factors

ABSTRACTNew anti-cancer therapeutics require extensive in vivo characterization to identify endogenous and exogenous factors affecting efficacy, to measure toxicity and mutagenicity, and to determine genotypes resulting in therapeutic sensitivity or resistance. We used Caenorhabditis elegans as a platform with which to characterize properties of anti-cancer therapeutic agents in vivo. We generated a map of chemigenetic interactions between DNA damage response mutants and common DNA damaging agents. We used this map to investigate the properties of the new anti-cancer therapeutic CX-5461. We phenocopied the photoreactivity observed in CX-5461 clinical trials and found that CX-5461 generates reactive oxygen species when exposed to UVA radiation. We demonstrated that CX-5461 is a mutator, resulting in both large copy number variations and a high frequency of single nucleotide variations (SNVs). CX-5461-induced SNVs exhibited a distinct mutational signature. Consistent with the wide range of CX-5461-induced mutation types, we found that multiple repair pathways were needed for CX-5461 tolerance. Together, the data from C. elegans demonstrate that CX-5461 is a multimodal DNA damaging agent with strong similarity to ellipticines, a class of antineoplastic agents, and to anthracycline-based chemotherapeutics.

Versatile and Valuable Utilization of Amidohydrolase L-glutaminase in Pharma and Food industries: A Review

2020 ◽  
Vol 21 (1) ◽  
pp. 11-24
Author(s):  
Chandrasai Potla Durthi ◽  
Madhuri Pola ◽  
Satish Babu Rajulapati ◽  
Anand Kishore Kola ◽  
Mohammad Amjad Kamal
Keyword(s):  
Enzyme Engineering ◽  
Soy Sauce ◽  
Acute Lymphocytic Leukaemia ◽  
Food Industries ◽  
In Silico Studies ◽  
Wide Range ◽  
Anti Cancer ◽  
Cancer Agent

L-glutaminase has versatile applications in pharma and food industries. In pharmaceutical industry, L-glutaminase can be used as anti-oxidant and anti-cancer agent to treat Acute Lymphocytic Leukaemia (ALL). Whereas, in the food industry, L-glutaminase is used for acrylamide degradation, theanine production, flavour enhancer, soy sauce and many. The other applications include nitrogen metabolism and its use as biosensor in hybridoma technology. Both intra-cellular and extra-cellular L-glutaminases from wide range of sources were identified. Because of its diverse applications, there is a need to improve the production of L-glutaminase by enzyme engineering technology. Effect of recombination on L-glutaminase production was also reported. Researchers also confirmed the antitumor properties of L-glutaminase by conducting in vitro, in vivo and in silico studies. Bacillus sps. and Aspergillus sps. are the commercial producers of L-glutaminase. In this review, the applications, different sources of Lglutaminase, anti-cancer properties were discussed.

The Potential of T Cell Immunoglobulin and Mucin-Domain containing-3 (Tim-3) in Designing Novel Immunotherapy for Bladder Cancer

2021 ◽  
Vol 21 ◽  
Author(s):  
Monireh Mohsenzadegan ◽  
Parizad Bavandpour ◽  
Mohammad Reza Nowroozi ◽  
Erfan Amini ◽  
Masoumeh Kourosh-Arami ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Immunity ◽  
Checkpoint Inhibitors ◽  
Number Of Patients ◽  
Anti Cancer ◽  
Domain 3

: Targeting inhibitory receptors on T cells in the tumor sites can promote effective anti-tumor immunity in bladder cancer. Unfortunately, the main dilemma is that a large number of patients remain refractory to CTLA-4, PD-1, and PD-L1 blockade therapies. T-cell immunoglobulin and mucin domain 3 (Tim-3) is an inhibitory receptor expressed on T cells and innate immune cells. Both in vivo and in vitro data from patients with advanced cancers support the role of Tim-3 inhibition in satisfactory anti-tumor immunity. In bladder cancer, the expression level of Tim-3 significantly increases with advanced pathological grade and T stage. Therefore, rationality implies that designing novel monoclonal antibodies reactive with Tim-3 alone or in combination with other checkpoint inhibitors may indicate a favorable response in bladder cancer. Here, we aimed to investigate the possibility of targeting Tim-3 as a novel anti-cancer treatment for bladder cancer.

scholarly journals Combination Therapy of Novel Oncolytic Adenovirus with Anti-PD1 Resulted in Enhanced Anti-Cancer Effect in Syngeneic Immunocompetent Melanoma Mouse Model

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 547
Author(s):  
Mariangela Garofalo ◽  
Laura Bertinato ◽  
Monika Staniszewska ◽  
Magdalena Wieczorek ◽  
Stefano Salmaso ◽  
...  
Keyword(s):  
Mouse Model ◽  
Enzyme Assay ◽  
Survival Rates ◽  
Oncolytic Adenovirus ◽  
The Novel ◽  
Anti Cancer ◽  
Check Point Inhibitors ◽  
Melanoma Therapy

Malignant melanoma, an aggressive form of skin cancer, has a low five-year survival rate in patients with advanced disease. Immunotherapy represents a promising approach to improve survival rates among patients at advanced stage. Herein, the aim of the study was to design and produce, by using engineering tools, a novel oncolytic adenovirus AdV-D24- inducible co-stimulator ligand (ICOSL)-CD40L expressing potent co-stimulatory molecules enhancing clinical efficacy through the modulation of anti-cancer immune responses. Firstly, we demonstrated the vector’s identity and genetic stability by restriction enzyme assay and sequencing, then, by performing in vitro and in vivo pre-clinical studies we explored the anti-cancer efficacy of the virus alone or in combination with anti PD-1 inhibitor in human melanoma cell lines, i.e., MUG Mel-1 and MUG Mel-2, and in immunocompetent C57BL/6 melanoma B16V mouse model. We showed that both monotherapy and combination approaches exhibit enhanced anti-cancer ability and immunogenic cell death in in vitro settings. Furthermore, AdV-D24-ICOSL-CD40L combined with anti PD-1 revealed a fall in tumor volume and 100% survival in in vivo context, thus suggesting enhanced efficacy and survival via complementary anti-cancer properties of those agents in melanoma therapy. Collectively, the novel oncolytic vector AdV-D24-ICOSL-CD40L alone or in combination with anticancer drugs, such as check point inhibitors, may open novel therapeutic perspectives for the treatment of melanoma.

scholarly journals Preclinical small molecule WEHI-7326 overcomes drug resistance and elicits response in patient-derived xenograft models of human treatment-refractory tumors

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Christoph Grohmann ◽  
Francesca Walker ◽  
Mark Devlin ◽  
Meng-Xiao Luo ◽  
Anderly C. Chüeh ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Death ◽  
Cell Division ◽  
Side Effects ◽  
Small Molecule ◽  
Standard Of Care ◽  
Wide Range ◽  
Anti Cancer ◽  
Treatment Refractory

AbstractTargeting cell division by chemotherapy is a highly effective strategy to treat a wide range of cancers. However, there are limitations of many standard-of-care chemotherapies: undesirable drug toxicity, side-effects, resistance and high cost. New small molecules which kill a wide range of cancer subtypes, with good therapeutic window in vivo, have the potential to complement the current arsenal of anti-cancer agents and deliver improved safety profiles for cancer patients. We describe results with a new anti-cancer small molecule, WEHI-7326, which causes cell cycle arrest in G2/M, cell death in vitro, and displays efficacious anti-tumor activity in vivo. WEHI-7326 induces cell death in a broad range of cancer cell lines, including taxane-resistant cells, and inhibits growth of human colon, brain, lung, prostate and breast tumors in mice xenografts. Importantly, the compound elicits tumor responses as a single agent in patient-derived xenografts of clinically aggressive, treatment-refractory neuroblastoma, breast, lung and ovarian cancer. In combination with standard-of-care, WEHI-7326 induces a remarkable complete response in a mouse model of high-risk neuroblastoma. WEHI-7326 is mechanistically distinct from known microtubule-targeting agents and blocks cells early in mitosis to inhibit cell division, ultimately leading to apoptotic cell death. The compound is simple to produce and possesses favorable pharmacokinetic and toxicity profiles in rodents. It represents a novel class of anti-cancer therapeutics with excellent potential for further development due to the ease of synthesis, simple formulation, moderate side effects and potent in vivo activity. WEHI-7326 has the potential to complement current frontline anti-cancer drugs and to overcome drug resistance in a wide range of cancers.

scholarly journals Bioorthogonal Photo-Catalytic Activation of an Anti-Cancer Prodrug by Riboflavin

2021 ◽  
Author(s):  
Xin Yang ◽  
Limin Ma ◽  
Hongwei Shao ◽  
Xia Ling ◽  
Mengyu Yao ◽  
...  
Keyword(s):  
Side Effects ◽  
Cancer Treatment ◽  
Cancer Drug ◽  
Spatiotemporal Resolution ◽  
Precise Control ◽  
Catalytic Activation ◽  
Anti Cancer ◽  
Targeting Ability

Chemotherapies for cancer treatment usually suffer from poor targeting ability and serious side-effects. To improve the treatment efficiency and reduce side effects, photoactivatable chemotherapy has been recently proposed for precise cancer treatment with high spatiotemporal resolution. However, most photoactivatable prodrugs require decoration by stoichiometric photo-cleavable groups, which are only responsive to ultraviolet irradiation and suffer from low reaction efficiency. To tackle these challenges, we herein propose a bioorthogonal photo-catalytic activation strategy with riboflavin as the catalyst for in situ transformation of prodrug dihydrochelerythrine (DHCHE) prodrug into anti-cancer drug chelerythrine (CHE), which can efficiently kill cancer cells and inhibit in vivo tumor growth under light irradiation. Meanwhile, the photo-catalytic transformation from DHCHE into CHE can be in situ monitored by green-to-red fluorescence conversion, which can be used for precise control of the therapeutic dose. We believe this imaging-guided bioorthogonal photo-catalytic strategy is promising for cancer treatment in clinical applications.

In Vitro and In Vivo Approaches for Screening the Potential of Anti Cancer Agents: A Review

2022 ◽  
Vol 19 ◽  
Author(s):  
Rakhi Mishra ◽  
Prem Shankar Mishra ◽  
Shruti Varshney ◽  
Rupa Mazumder ◽  
Avijit Mazumder
Keyword(s):  
In Vivo Studies ◽  
Chemical Toxicity ◽  
Vitro Assay ◽  
Wide Range ◽  
Anti Cancer ◽  
Assay Methods ◽  
New Anticancer Drugs ◽  
Hallmark Feature

Background: Anticancer drug development is a tedious process, requiring several in vitro, in vivo, and clinical studies. To avoid chemical toxicity in animals during an experiment, it is necessary to envisage toxic doses of screened drugs in vivo at different concentrations. Several in vitro and in vivo studies have been reported to discover the management of cancer. Materials and Methods: This study has focused on bringing together a wide range of in vivo and in vitro assay methods, developed to evaluate each hallmark feature of cancer. Result: This review provides elaborated information about target-based and cell-based screening of new anticancer drugs in the molecular targeting period. This would help to incite an alteration from the preclinical screening of pragmatic compound-orientated to target-orientated drug selection. Conclusion: Selection methodologies for finding anticancer activity have importance for tumor-specific agents. In this study, advanced rationalization of the cell-based assay is explored along with broad applications of the cell-based methodologies considering other opportunities also.

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