The Hypoxia-Activated Prodrug TH-302: Exploiting Hypoxia in Cancer Therapy

Li, Yue; Zhao, Long; Li, Xiaofeng

doi:10.3389/fphar.2021.636892

Cited by 38 publications

(27 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Reducing the accumulation of fatty acids in cells can reduce the migration and invasion of tumor cells ( 45 ). Hypoxia also participates in the formation of a protumor microenvironment ( 46 ). Glycolysis is regarded as one of the key metabolic characteristics of malignant tumor ( 47 ).…”

Section: Discussionmentioning

confidence: 99%

Development and Validation of Epigenetic Modification-Related Signals for the Diagnosis and Prognosis of Hepatocellular Carcinoma

Sheng

Jiang

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

BackgroundIncreasing evidence has indicated that abnormal epigenetic factors such as RNA m6A modification, histone modification, DNA methylation, RNA binding proteins and transcription factors are correlated with hepatocarcinogenesis. However, it is unknown how epigenetic modification-associated genes contribute to the occurrence and clinical outcome of hepatocellular carcinoma (HCC). Thus, we constructed the epigenetic modification-associated models that may enhance the diagnosis and prognosis of HCC.MethodsIn this study, we focused on the clinical value of epigenetic modification-associated genes for HCC. Our gene expression data were collected from TCGA and HCC data sets from the GEO database to ensure the reliability of the data. Their functions were analyzed by bioinformatics methods. We used lasso regression, Support vector machine (SVM), logistic regression and Cox regression to construct the diagnostic and prognostic models. We also constructed a nomogram of the practicability of the above-mentioned prognostic model. The above results were verified in an independent liver cancer data set from the ICGC database and clinical samples. Furthermore, we carried out pan-cancer analysis to verify the specificity of the above model and screened a wide range of drug candidates.ResultsMany epigenetic modification-associated genes were significantly different in HCC and normal liver tissues. The gene signatures showed a good ability to predict the occurrence and survival of HCC patients, as verified by DCA and ROC curve analysis.ConclusionGene signatures based on epigenetic modification-associated genes can be used to identify the occurrence and prognosis of liver cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

Development and Validation of Epigenetic Modification-Related Signals for the Diagnosis and Prognosis of Hepatocellular Carcinoma

Sheng

Jiang

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

show abstract

“…It showed limited efficacy in the treatment of leukemia and failed in two phase 3 clinical trials ( 179 – 181 ). Researchers analyzed the possible reasons, including the lack of patient screening based on tumor hypoxia status ( 182 , 183 ), antagonism between drugs ( 184 ), and drug formulation changes ( 185 ). Further research is still in progress.…”

Section: Th-302 (Evofosfamide)mentioning

confidence: 99%

Targeting Hypoxia: Hypoxia-Activated Prodrugs in Cancer Therapy

Zhao

2021

Front. Oncol.

Self Cite

View full text Add to dashboard Cite

Hypoxia is an important characteristic of most solid malignancies, and is closely related to tumor prognosis and therapeutic resistance. Hypoxia is one of the most important factors associated with resistance to conventional radiotherapy and chemotherapy. Therapies targeting tumor hypoxia have attracted considerable attention. Hypoxia-activated prodrugs (HAPs) are bioreductive drugs that are selectively activated under hypoxic conditions and that can accurately target the hypoxic regions of solid tumors. Both single-agent and combined use with other drugs have shown promising antitumor effects. In this review, we discuss the mechanism of action and the current preclinical and clinical progress of several of the most widely used HAPs, summarize their existing problems and shortcomings, and discuss future research prospects.

show abstract

“…The localization of the hypoxic target cells and the relative degree of effector redistribution (known as the bystander effect) determine the resultant cell killing. The limited success of earlier clinical candidates reflects, in part, the complexity of this design criteria ( Marcu and Olver, 2006 ; Spiegelberg et al, 2019 ; Li et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Tissue Pharmacokinetic Properties and Bystander Potential of Hypoxia-Activated Prodrug CP-506 by Agent-Based Modelling

et al. 2022

View full text Add to dashboard Cite

Hypoxia-activated prodrugs are bioactivated in oxygen-deficient tumour regions and represent a novel strategy to exploit this pharmacological sanctuary for therapeutic gain. The approach relies on the selective metabolism of the prodrug under pathological hypoxia to generate active metabolites with the potential to diffuse throughout the tumour microenvironment and potentiate cell killing by means of a “bystander effect”. In the present study, we investigate the pharmacological properties of the nitrogen mustard prodrug CP-506 in tumour tissues using in silico spatially-resolved pharmacokinetic/pharmacodynamic (SR-PK/PD) modelling. The approach employs a number of experimental model systems to define parameters for the cellular uptake, metabolism and diffusion of both the prodrug and its metabolites. The model predicts rapid uptake of CP-506 to high intracellular concentrations with its long plasma half-life driving tissue diffusion to a penetration depth of 190 µm, deep within hypoxic activating regions. While bioreductive metabolism is restricted to regions of severe pathological hypoxia (<1 µM O2), its active metabolites show substantial bystander potential with release from the cell of origin into the extracellular space. Model predictions of bystander efficiency were validated using spheroid co-cultures, where the clonogenic killing of metabolically defective “target” cells increased with the proportion of metabolically competent “activator” cells. Our simulations predict a striking bystander efficiency at tissue-like densities with the bis-chloro-mustard amine metabolite (CP-506M-Cl2) identified as a major diffusible metabolite. Overall, this study shows that CP-506 has favourable pharmacological properties in tumour tissue and supports its ongoing development for use in the treatment of patients with advanced solid malignancies.

show abstract

The Hypoxia-Activated Prodrug TH-302: Exploiting Hypoxia in Cancer Therapy

Cited by 38 publications

References 76 publications

Development and Validation of Epigenetic Modification-Related Signals for the Diagnosis and Prognosis of Hepatocellular Carcinoma

Development and Validation of Epigenetic Modification-Related Signals for the Diagnosis and Prognosis of Hepatocellular Carcinoma

Targeting Hypoxia: Hypoxia-Activated Prodrugs in Cancer Therapy

Tissue Pharmacokinetic Properties and Bystander Potential of Hypoxia-Activated Prodrug CP-506 by Agent-Based Modelling

Contact Info

Product

Resources

About