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hypoxia activated prodrug

Linda Spiegelberg, Ruud Houben, Raymon Niemans, Dirk de Ruysscher, Ala Yaromina, Jan Theys, Christopher P Guise, Jeffrey B Smaill, Adam V Patterson, Philippe Lambin, Ludwig J Dubois
Hypoxia-activated prodrugs (HAPs) are designed to specifically target the hypoxic cells of tumors, which are an important cause of treatment resistance to conventional therapies. Despite promising preclinical and clinical phase I and II results, the most important of which are described in this review, the implementation of hypoxia-activated prodrugs in the clinic has, so far, not been successful. The lack of stratification of patients based on tumor hypoxia status, which can vary widely, is sufficient to account for the failure of phase III trials...
February 2019: Clinical and Translational Radiation Oncology
Shengcai Yang, Zhaohui Tang, Chenyang Hu, Dawei Zhang, Na Shen, Haiyang Yu, Xuesi Chen
Hypoxia-activated prodrugs (HAPs) have the potential to selectively kill hypoxic cells and convert tumor hypoxia from a problem to a selective treatment advantage. However, HAPs are unsuccessful in most clinical trials owing to inadequate hypoxia within the treated tumors, as implied by a further substudy of a phase II clinical trial. Here, a novel strategy for the combination of HAPs plus vascular disrupting agent (VDA) nanomedicine for efficacious solid tumor therapy is developed. An effective VDA nanomedicine of poly(l-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4 (CA4-NPs) is prepared and can selectively enhance tumor hypoxia and boost a typical HAP tirapazamine (TPZ) therapy against metastatic 4T1 breast tumors...
January 24, 2019: Advanced Materials
Haiyang Guo, Xinpei Ci, Musaddeque Ahmed, Junjie Tony Hua, Fraser Soares, Dong Lin, Loredana Puca, Aram Vosoughi, Hui Xue, Estelle Li, Peiran Su, Sujun Chen, Tran Nguyen, Yi Liang, Yuzhe Zhang, Xin Xu, Jing Xu, Anjali V Sheahan, Wail Ba-Alawi, Si Zhang, Osman Mahamud, Ravi N Vellanki, Martin Gleave, Robert G Bristow, Benjamin Haibe-Kains, John T Poirier, Charles M Rudin, Ming-Sound Tsao, Bradly G Wouters, Ladan Fazli, Felix Y Feng, Leigh Ellis, Theo van der Kwast, Alejandro Berlin, Marianne Koritzinsky, Paul C Boutros, Amina Zoubeidi, Himisha Beltran, Yuzhuo Wang, Housheng Hansen He
Neuroendocrine prostate cancer (NEPC), a lethal form of the disease, is characterized by loss of androgen receptor (AR) signaling during neuroendocrine transdifferentiation, which results in resistance to AR-targeted therapy. Clinically, genomically and epigenetically, NEPC resembles other types of poorly differentiated neuroendocrine tumors (NETs). Through pan-NET analyses, we identified ONECUT2 as a candidate master transcriptional regulator of poorly differentiated NETs. ONECUT2 ectopic expression in prostate adenocarcinoma synergizes with hypoxia to suppress androgen signaling and induce neuroendocrine plasticity...
January 17, 2019: Nature Communications
Lydia P Liew, Dean C Singleton, Way W Wong, Gary J Cheng, Stephen M F Jamieson, Michael Hay
Tumour hypoxia plays an important role in tumour progression and resistance to therapy. Under hypoxia unfolded proteins accumulate in the endoplasmic reticulum (ER) and this stress is relieved through the protein kinase R-like ER kinase (PERK) signalling arm of the unfolded protein response (UPR). Targeting the UPR through PERK kinase inhibitors provides tumour growth inhibition, but also elicits on-mechanism normal tissue toxicity. Hypoxia presents a target for tumour-selective drug delivery using hypoxia-activated prodrugs...
January 7, 2019: Chemistry, An Asian Journal
Cho Rong Hong, William R Wilson, Kevin O Hicks
Tumor hypoxia contributes to resistance to anticancer therapies. Hypoxia-activated prodrugs (HAPs) selectively target hypoxic cells and their activity can extend to well-oxygenated areas of tumors via diffusion of active metabolites. This type of bystander effect has been suggested to be responsible for the single agent activity of the clinical-stage HAP evofosfamide (TH-302) but direct evidence is lacking. To dissect the contribution of bystander effects to TH-302 activity, we implemented a Green's function pharmacokinetic (PK) model to simulate the spatial distribution of O2 , TH-302 and its cytotoxic metabolites, bromo-isophosphoramide mustard (Br-IPM) and its dichloro derivative isophosphoramide mustard (IPM), in two digitized tumor microvascular networks...
December 23, 2018: Neoplasia: An International Journal for Oncology Research
Fabia de Oliveira Andrade, Kelly Silva Furtado, Renato Heidor, Silvana Sandri, Cristina Bichels Hebeda, Mayara Lilian Paulino Miranda, Laura Helena Gasparini Fernandes, Roberto Carvalho Yamamoto, Maria Aderuza Horst, Sandra Helena Poliselli Farsky, Fernando Salvador Moreno
Agents that inhibit angiogenic factors may prevent the development of hepatocellular carcinoma. Thus, the objective of this study was to kinetically evaluate the anti-angiogenic activity of tributyrin (TB), a butyric acid prodrug, in the promotion stage of hepatocarcinogenesis. For this purpose, the resistant hepatocyte model was used for induction of preneoplastic lesions in Wistar rats. During the promotion phase, the animals received TB or maltodextrin (MD) as control daily. The rats were euthanized at three different time-points (P1, P2, P3)...
December 24, 2018: Carcinogenesis
Amit Sharma, Jonathan F Arambula, Seyoung Koo, Rajesh Kumar, Hardev Singh, Jonathan L Sessler, Jong Seung Kim
Hypoxia is a state of low oxygen tension found in numerous solid tumours. It is typically associated with abnormal vasculature, which results in a reduced supply of oxygen and nutrients, as well as impaired delivery of drugs. The hypoxic nature of tumours often leads to the development of localized heterogeneous environments characterized by variable oxygen concentrations, relatively low pH, and increased levels of reactive oxygen species (ROS). The hypoxic heterogeneity promotes tumour invasiveness, metastasis, angiogenesis, and an increase in multidrug-resistant proteins...
December 21, 2018: Chemical Society Reviews
Zhimei He, Yunlu Dai, Xiangli Li, Dan Guo, Yijing Liu, Xiaolin Huang, Jingjing Jiang, Sheng Wang, Guizhi Zhu, Fuwu Zhang, Lisen Lin, Jun-Jie Zhu, Guocan Yu, Xiaoyuan Chen
During photodynamic therapy (PDT), severe hypoxia often occurs as an undesirable limitation of PDT owing to the O2 -consuming photodynamic process, compromising the effectiveness of PDT. To overcome this problem, several strategies aiming to improve tumor oxygenation are developed. Unlike these traditional approaches, an opposite method combining hypoxia-activated prodrug and PDT may provide a promising strategy for cancer synergistic therapy. In light of this, azido-/photosensitizer-terminated UiO-66 nanoscale metal-organic frameworks (UiO-66-H/N3 NMOFs) which serve as nanocarriers for the bioreductive prodrug banoxantrone (AQ4N) are engineered...
December 19, 2018: Small
Yao Ge, Xinxin Lai, Jintao Li, Ran Yu, Zhuochen Zhuang, Guohui Sun, Xin Cui, Na Zhang, Lijiao Zhao, Pramod Upadhyaya, Rugang Zhong
AIM: A hypoxia-activated combi-nitrosourea prodrug, N-(2-chloroethyl)-N'-2-(2-(4-nitrobenzylcarbamate)-O 6 -benzyl-9-guanine)ethyl-N-nitrosourea (NBGNU), was synthesized and evaluated for its hypoxic selectivity and anticancer activity in vitro. RESULTS: The prodrug was designed as a tripartite molecule consisting of a chloroethylnitrosourea pharmacophore to induce DNA interstrand crosslinks (ICLs) and an O 6 -benzylguanine analog moiety masked by a 4-nitrobenzylcarbamate group to induce hypoxia-activated inhibition of O 6 -alkylguanine-DNA alkyltransferase...
December 18, 2018: Future Medicinal Chemistry
Jose M Ayuso, Amani Gillette, Karina Lugo-Cintrón, Suehelay Acevedo-Acevedo, Ismael Gomez, Molly Morgan, Tiffany Heaster, Kari B Wisinski, Sean P Palecek, Melissa C Skala, David J Beebe
BACKGROUND: Ductal carcinoma in situ (DCIS) is the earliest stage of breast cancer. During DCIS, tumor cells remain inside the mammary duct, growing under a microenvironment characterized by hypoxia, nutrient starvation, and waste product accumulation; this harsh microenvironment promotes genomic instability and eventually cell invasion. However, there is a lack of biomarkers to predict what patients will transition to a more invasive tumor or how DCIS cells manage to survive in this harsh microenvironment...
October 25, 2018: EBioMedicine
Min-Xia Su, Le-Le Zhang, Zhang-Jian Huang, Jia-Jie Shi, Jin-Jian Lu
Hypoxia, which occurs in most cancer cases, disrupts the efficacy of anticarcinogens. Fortunately, hypoxia can become a potential target for cancer treatment. Hypoxia-activated prodrugs (HAPs) can be selectively activated by reductase under hypoxia. Some promising HAPs have been already achieved, and many clinical trials of HAPs in different cancers are ongoing. However, none of them has been approved for clinical applications to date. Studies on HAPs have been conducted for many years, presenting some achievements and challenges...
November 23, 2018: Current Drug Targets
Silvia Alonso-de Castro, Alessio Terenzi, Sonja Hager, Bernhard Englinger, Adriana Faraone, Javier Calvo Martínez, Markus Galanski, Bernhard K Keppler, Walter Berger, Luca Salassa
We have recently demonstrated that riboflavin (Rf) functions as unconventional bioorthogonal photocatalyst for the activation of PtIV prodrugs. In this study, we show how the combination of light and Rf with two PtIV prodrugs is a feasible strategy for light-mediated pancreatic cancer cell death induction. In Capan-1 cells, which have high tolerance against photodynamic therapy, Rf-mediated activation of the cisplatin and carboplatin prodrugs cis,cis,trans-[Pt(NH3 )2 (Cl)2 (O2 CCH2 CH2 CO2 H)2 ] (1) and cis,cis,trans-[Pt(NH3 )2 (CBDCA)(O2 CCH2 CH2 CO2 H)2 ] (2, where CBDCA = cyclobutane dicarboxylate) resulted in pronounced reduction of the cell viability, including under hypoxia conditions...
November 21, 2018: Scientific Reports
Sarah L Collins, Jaideep Saha, Laure C Bouchez, Ester M Hammond, Stuart J Conway
Hypoxia, conditions of reduced oxygen, occur in a wide variety of biological contexts, including solid tumours and bacterial biofilms, which are relevant to human health. Consequently, the development of chemical tools to study hypoxia is vital. Here we report a hypoxia-activated small molecule-mediated gene expression system using a bioreductive prodrug of the inducer isopropyl 1-thio-β-D-galactopyranoside (IPTG). As a proof-of-concept we have placed the production of a green fluorescent protein under the control of hypoxia...
November 19, 2018: ACS Chemical Biology
Alessio Nocentini, Elena Trallori, Srishti Singh, Carrie L Lomelino, Gianluca Bartolucci, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Robert McKenna, Paola Gratteri, Claudiu T Supuran
Human carbonic anhydrases (CA, EC, IX and XII are overexpressed in cancer cells as adaptive response to hypoxia and acidic conditions characteristic of many tumors. In addition, hypoxia facilitates the activity of specific oxido-reductases that may be exploited to selectively activate bioreductive prodrugs. Here, new selective CA IX/XII inhibitors, as analogues of the antitumor phase II drug SLC-0111 are described, namely ureido-substituted benzenesulfonamides appended with a nitro-aromatic moiety to yield an antiproliferative action increased by hypoxia...
November 28, 2018: Journal of Medicinal Chemistry
Yun Zeng, Jingwen Ma, Yonghua Zhan, Xinyi Xu, Qi Zeng, Jimin Liang, Xueli Chen
Hypoxia is one of the marked features of malignant tumors, which is associated with several adaptation changes in the microenvironment of tumor cells. Therefore, targeting tumor hypoxia is a research hotspot for cancer therapy. In this review, we summarize the developing chemotherapeutic drugs for targeting hypoxia, including quinones, nitroaromatic/nitroimidazole, N-oxides, and transition metal complexes. In addition, redox-responsive bonds, such as nitroimidazole groups, azogroups, and disulfide bonds, are frequently used in drug delivery systems for targeting the redox environment of tumors...
2018: International Journal of Nanomedicine
Ming-Kang Zhang, Chu-Xin Li, Shi-Bo Wang, Tao Liu, Xian-Lin Song, Xiao-Quan Yang, Jun Feng, Xian-Zheng Zhang
By integrating the characteristics of each therapy modality and material chemistry, a multitherapy modality is put forward: tumor starvation triggered synergism with sensitized chemotherapy. Following starvation-induced amplification of pathological abnormalities in tumors, chemotherapy is arranged to be locally activated and accurately reinforced to perfect multitherapy synergism from spatial and temporal perspectives. To this end, glucose oxidase (GOD) and a hypoxic prodrug of tirapazamine (TPZ) are loaded in acidity-decomposable calcium carbonate (CaCO3 ) nanoparticles concurrently tethered by hyaluronic acid...
October 29, 2018: Small
Xinjian Mao, Sarah McManaway, Jagdish K Jaiswal, Priyanka B Patel, William R Wilson, Kevin O Hicks, Gib Bogle
Multicellular tumour spheroids capture many characteristics of human tumour microenvironments, including hypoxia, and represent an experimentally tractable in vitro model for studying interactions between radiotherapy and anticancer drugs. However, interpreting spheroid data is challenging because of limited ability to observe cell fate within spheroids dynamically. To overcome this limitation, we have developed a hybrid continuum/agent-based model (ABM) for HCT116 tumour spheroids, parameterised using experimental models (monolayers and multilayers) in which reaction and diffusion can be measured directly...
October 2018: PLoS Computational Biology
Vidhi M Shah, Duc X Nguyen, Adel Al Fatease, Pragnesh Patel, Brianna Cote, Yeonhee Woo, Rohi Gheewala, Yvonne Pham, Man Gia Huynh, Christen Gannett, Deepa A Rao, Adam W G Alani
In this work, a new sphingomyelin-cholesterol liposomal formulation (CPD100Li) for the delivery of a hypoxia activated prodrug of vinblastine, mon-N-oxide (CPD100), is developed. The optimized liposomal formulation uses an ionophore (A23187) mediated pH-gradient method. Optimized CPD100Li is characterized for size, drug loading, and stability. The in vitro toxicity of CPD100Li is assessed on different aspects of cell proliferation and apoptosis of ES2 ovarian cancer under normoxic and hypoxic conditions. The pharmacokinetics of CPD100Li in mice as well as the influence of A23187 on the retention of CPD100 are assessed...
December 10, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Kaitlin Graham, Evan Unger
Hypoxia exists to some degree in most solid tumors due to inadequate oxygen delivery of the abnormal vasculature which cannot meet the demands of the rapidly proliferating cancer cells. The levels of oxygenation within the same tumor are highly variable from one area to another and can change over time. Tumor hypoxia is an important impediment to effective cancer therapy. In radiotherapy, the primary mechanism is the creation of reactive oxygen species; hypoxic tumors are therefore radiation resistant. A number of chemotherapeutic drugs have been shown to be less effective when exposed to a hypoxic environment which can lead to further disease progression...
2018: International Journal of Nanomedicine
Kunal Nepali, Hsueh-Yun Lee, Jing-Ping Liou
The nitro group is considered to be a versatile and unique functional group in medicinal chemistry. Despite a long history of use in therapeutics, the nitro group has toxicity issues and is often categorized as a structural alert or a toxicophore, and evidence related to drugs containing nitro groups is rather contradictory. In general, drugs containing nitro groups have been extensively associated with mutagenicity and genotoxicity. In this context, efforts toward the structure-mutagenicity or structure-genotoxicity relationships have been undertaken...
November 1, 2018: Journal of Medicinal Chemistry
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