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Basic & Clinical Pharmacology &... Sep 2016Tirapazamine is a hypoxia-activated prodrug which was shown to exhibit up to 300 times greater cytotoxicity under anoxic in comparison with aerobic conditions. Thus, the...
Tirapazamine is a hypoxia-activated prodrug which was shown to exhibit up to 300 times greater cytotoxicity under anoxic in comparison with aerobic conditions. Thus, the combined anticancer therapy of tirapazamine with a routinely used anticancer drug seems to be a promising solution. Because tirapazamine undergoes redox cycle transformation in this study, the effect of tirapazamine on redox hepatic equilibrium, lipid status and liver morphology was evaluated in rats exposed to cisplatin, doxorubicin and 5-fluorouracil. Rats were intraperitoneally injected with tirapazamine and a particular cytostatic. The animals were killed, and blood and liver were collected. Hepatic glucose, total cholesterol, triglycerides, NADH, NADPH glutathione and the activity of glucose-6-phosphate dehydrogenase were determined. Liver morphology and the immune expression of HMG-CoA-reductase were also assessed. Glucose, total cholesterol, triglycerides, bilirubin concentrations and the activity of aspartate and alanine aminotransferases were determined in the plasma. Tirapazamine displayed insignificant interactions with cisplatin and 5-fluorouracil referring to hepatic morphology and biochemical parameters. However, tirapazamine interacts with doxorubicin, thus leading to side changes in redox equilibrium and lipid peroxidation, but those effects are not severe enough to exclude that drug combination from further studies. Thus, tirapazamine seems to be a promising agent in successive studies on anticancer activity in similar schedules.
Topics: Alanine Transaminase; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Cholesterol; Cisplatin; Doxorubicin; Drug Interactions; Fluorouracil; Glutathione; Lipid Peroxidation; Liver; Male; Oxidation-Reduction; Rats; Rats, Wistar; Tirapazamine; Triazines; Triglycerides
PubMed: 26990033
DOI: 10.1111/bcpt.12576 -
Nature Communications Apr 2019Hypoxia-based agents (HBAs), such as anaerobic bacteria and bioreductive prodrugs, require both a permeable and hypoxic intratumoural environment to be fully effective....
Hypoxia-based agents (HBAs), such as anaerobic bacteria and bioreductive prodrugs, require both a permeable and hypoxic intratumoural environment to be fully effective. To solve this problem, herein, we report that perfluorocarbon nanoparticles (PNPs) can be used to create a long-lasting, penetrable and hypoxic tumour microenvironment for ensuring both the delivery and activation of subsequently administered HBAs. In addition to the increased permeability and enhanced hypoxia caused by the PNPs, the PNPs can be retained to further achieve the long-term inhibition of intratumoural O reperfusion while enhancing HBA accumulation for over 24 h. Therefore, perfluorocarbon materials may have great potential for reigniting clinical research on hypoxia-based drugs.
Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Cell Line, Tumor; Drug Delivery Systems; Fluorocarbons; Mice; Nanoparticles; Prodrugs; Tirapazamine; Tumor Hypoxia; Tumor Microenvironment
PubMed: 30952842
DOI: 10.1038/s41467-019-09389-2 -
Scientific Reports Feb 2021Tumor tissue contains a continuous distribution of static and dynamically changing oxygen environments with levels ranging from physiologically normal oxygen down to...
Tumor tissue contains a continuous distribution of static and dynamically changing oxygen environments with levels ranging from physiologically normal oxygen down to anoxia. However, in vitro studies are often performed under oxygen levels that are far higher than those found in vivo. A number of devices are available to alter the oxygen environment in cell culture, including designs from our laboratory. However, in our devices and most other designs, changing the media in order to feed or dose cells remains a disruptive factor in maintaining a consistent hypoxic environment. This report presents a novel 96-well plate design that recirculates the local oxygen environment to shield cells during media changes and facilitates toxicity studies of cells cultured under varying oxygen levels. The principle behind the design is presented and the response of human pancreatic cancer PANC-1 cells treated with tirapazamine and doxorubicin under eight different static or cycling oxygen levels was measured. As expected, tirapazamine is progressively more toxic as oxygen levels decrease but retains some toxicity as oxygen is cycled between hypoxic and normoxic levels. Doxorubicin sensitivity is largely unaffected by changing oxygen levels. This technology is ideal for assessing the effects of oxygen as a variable in toxicity screens.
Topics: Cell Culture Techniques; Cell Hypoxia; Cell Line, Tumor; Doxorubicin; High-Throughput Screening Assays; Humans; Neoplasms; Oxygen; Pancreatic Neoplasms; Tirapazamine; Toxicity Tests; Triazines; Tumor Microenvironment
PubMed: 33597640
DOI: 10.1038/s41598-021-83579-1 -
International Journal of Nanomedicine 2016Reductive drug-functionalized gold nanoparticles (AuNPs) have been proposed to enhance the damage of X-rays to cells through improving hydroxyl radical production by...
Reductive drug-functionalized gold nanoparticles (AuNPs) have been proposed to enhance the damage of X-rays to cells through improving hydroxyl radical production by secondary electrons. In this work, polyethylene glycol-capped AuNPs were conjugated with tirapazamine (TPZ) moiety, and then thioctyl TPZ (TPZs)-modified AuNPs (TPZs-AuNPs) were synthesized. The TPZs-AuNPs were characterized by transmission electron microscopy, ultraviolet-visible spectra, dynamic light scattering, and inductively coupled plasma mass spectrometry to have a size of 16.6±2.1 nm in diameter and a TPZs/AuNPs ratio of ~700:1. In contrast with PEGylated AuNPs, the as-synthesized TPZs-AuNPs exhibited 20% increment in hydroxyl radical production in water at 2.0 Gy, and 19% increase in sensitizer enhancement ratio at 10% survival fraction for human hepatoma HepG2 cells under X-ray irradiation. The production of reactive oxygen species in HepG2 cells exposed to X-rays in vitro demonstrated a synergistic radiosensitizing effect of AuNPs and TPZ moiety. Thus, the reductive drug-conjugated TPZs-AuNPs as a kind of AuNP radiosensitizer with low gold loading provide a new strategy for enhancing the efficacy of radiation therapy.
Topics: Gold; Hep G2 Cells; Humans; Hydroxyl Radical; Metal Nanoparticles; Microscopy, Electron, Transmission; Polyethylene Glycols; Radiation-Sensitizing Agents; Tirapazamine; Triazines; Tumor Microenvironment; X-Rays
PubMed: 27555772
DOI: 10.2147/IJN.S105348 -
EBioMedicine Nov 2018Ductal carcinoma in situ (DCIS) is the earliest stage of breast cancer. During DCIS, tumor cells remain inside the mammary duct, growing under a microenvironment...
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.
METHODS
In this work, we have developed a microfluidic model that recapitulates the DCIS microenvironment. In the microdevice, a DCIS model cell line was grown inside a luminal mammary duct model, embedded in a 3D hydrogel with mammary fibroblasts. Cell behavior was monitored by confocal microscopy and optical metabolic imaging. Additionally, metabolite profile was studied by NMR whereas gene expression was analyzed by RT-qPCR.
FINDINGS
DCIS cell metabolism led to hypoxia and nutrient starvation; revealing an altered metabolism focused on glycolysis and other hypoxia-associated pathways. In response to this starvation and hypoxia, DCIS cells modified the expression of multiple genes, and a gradient of different metabolic phenotypes was observed across the mammary duct model. These genetic changes observed in the model were in good agreement with patient genomic profiles; identifying multiple compounds targeting the affected pathways. In this context, the hypoxia-activated prodrug tirapazamine selectively destroyed hypoxic DCIS cells.
INTERPRETATION
The results showed the capacity of the microfluidic model to mimic the DCIS structure, identifying multiple cellular adaptations to endure the hypoxia and nutrient starvation generated within the mammary duct. These findings may suggest new potential therapeutic directions to treat DCIS. In summary, given the lack of in vitro models to study DCIS, this microfluidic device holds great potential to find new DCIS predictors and therapies and translate them to the clinic.
Topics: Breast Neoplasms; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Genomic Instability; Humans; Hydrogels; Microfluidic Analytical Techniques; Models, Biological; Neoplasm Invasiveness; Tumor Microenvironment
PubMed: 30482722
DOI: 10.1016/j.ebiom.2018.10.046 -
Biomicrofluidics Sep 2019In anticancer drug development, it is important to simultaneously evaluate both the effect of drugs on cell proliferation and their ability to penetrate tissues. To...
In anticancer drug development, it is important to simultaneously evaluate both the effect of drugs on cell proliferation and their ability to penetrate tissues. To realize such an evaluation process, here, we present a compartmentalized tumor spheroid culture system utilizing a thin membrane with a through-hole to conduct localized anticancer treatment of tumor spheroids and monitor spheroid dimensions as an indicator of cell proliferation. The system is based on a commercialized Boyden chamber plate; a through-hole was bored through a porous membrane of the chamber, and the pre-existing 0.4 m membrane pores were filled with parylene C. A HepG2 spheroid was immobilized onto the through-hole, separating the upper and lower compartments. Fluorescein (to verify the isolation between the compartments) and tirapazamine (TPZ; to treat only the lower part of the spheroid) were added to the upper and lower compartments, respectively. Since the transportation of fluorescein was blocked during treatment, i.e., the upper and lower compartments were isolated, it was confirmed that localized TPZ treatment was successfully conducted using the developed system. The effect of localized TPZ treatment on cell proliferation was estimated by measuring the maximum horizontal cross-sectional areas in the upper and lower parts of the spheroid by microscopic observations. This system can, thus, be used to perform localized anticancer drug treatment of tumor spheroids and evaluate the effect of drugs on cell proliferation.
PubMed: 31893010
DOI: 10.1063/1.5125650 -
Journal of Nanobiotechnology Nov 2022Carbon monoxide (CO) is an important signaling molecule participating in multiple biological functions. Previous studies have confirmed the valuable roles of CO in...
BACKGROUND
Carbon monoxide (CO) is an important signaling molecule participating in multiple biological functions. Previous studies have confirmed the valuable roles of CO in cancer therapies. If the CO concentration and distribution can be controlled in tumors, new cancer therapeutic strategy may be developed to benefit the patient survival.
RESULTS
In this study, a UiO-67 type metal-organic framework (MOF) nanoplatform was produced with cobalt and ruthenium ions incorporated into its structure (Co/Ru-UiO-67). Co/Ru-UiO-67 had a size range of 70-90 nm and maintained the porous structure, with cobalt and ruthenium distributed uniformly inside. Co/Ru-UiO-67 was able to catalyze carbon dioxide into CO upon light irradiation in an efficient manner with a catalysis speed of 5.6 nmol/min per 1 mg Co/Ru-UiO-67. Due to abnormal metabolic properties of tumor cells, tumor microenvironment usually contains abundant amount of CO. Co/Ru-UiO-67 can transform tumor CO into CO at both cellular level and living tissues, which consequently interacts with relevant signaling pathways (e.g. Notch-1, MMPs etc.) to adjust tumor microenvironment. With proper PEGylation (pyrene-polyacrylic acid-polyethylene glycol, Py-PAA-PEG) and attachment of a tumor-homing peptide (F3), functionalized Co/Ru-UiO-67 could accumulate strongly in triple-negative MDA-MB-231 breast tumors, witnessed by positron emission tomography (PET) imaging after the addition of radioactive zirconium-89 (Zr) into Co-UiO-67. When applied in vivo, Co/Ru-UiO-67 could alter the local hypoxic condition of MDA-MB-231 tumors, and work synergistically with tirapazamine (TPZ).
CONCLUSION
This nanoscale UiO-67 MOF platform can further our understanding of CO functions while produce CO in a controllable manner during cancer therapeutic administration.
Topics: Humans; Metal-Organic Frameworks; Carbon Monoxide; Ruthenium; Triple Negative Breast Neoplasms; Carbon Dioxide; Cobalt; Tumor Microenvironment
PubMed: 36424645
DOI: 10.1186/s12951-022-01704-2 -
PloS One 2015Quinoxaline 1,4-di-N-oxides (QdNOs) are widely known as potent antibacterial agents, but their antibacterial mechanisms are incompletely understood. In this study, the...
Quinoxaline 1,4-di-N-oxides (QdNOs) are widely known as potent antibacterial agents, but their antibacterial mechanisms are incompletely understood. In this study, the transcriptomic and proteomic profiles of Escherichia coli exposed to QdNOs were integratively investigated, and the results demonstrated that QdNOs mainly induced an SOS response and oxidative stress. Moreover, genes and proteins involved in the bacterial metabolism, cellular structure maintenance, resistance and virulence were also found to be changed, conferring bacterial survival strategies. Biochemical assays showed that reactive oxygen species were induced in the QdNO-treated bacteria and that free radical scavengers attenuated the antibacterial action of QdNOs and DNA damage, suggesting an oxidative-DNA-damage action of QdNOs. The QdNO radical intermediates, likely carbon-centered and aryl-type radicals, as identified by electron paramagnetic resonance, were the major radicals induced by QdNOs, and xanthine oxidase was one of the QdNO-activating enzymes. This study provides new insights into the action of QdNOs in a systematic manner and increases the current knowledge of bacterial physiology under antibiotic stresses, which may be of great value in the development of new antibiotic-potentiating strategies.
Topics: Anti-Bacterial Agents; Cell Survival; DNA Damage; Dose-Response Relationship, Drug; Escherichia coli; Gene Expression Regulation, Bacterial; Microbial Sensitivity Tests; Molecular Sequence Annotation; Oxidation-Reduction; Oxidative Stress; Protein Biosynthesis; Proteomics; Quinoxalines; Reactive Oxygen Species; SOS Response, Genetics; Structure-Activity Relationship; Tirapazamine; Triazines
PubMed: 26296207
DOI: 10.1371/journal.pone.0136450 -
Journal of Hepatocellular Carcinoma 2021Tirapazamine (TPZ) is a hypoxia activated drug that may be synergistic with transarterial embolization (TAE). The primary objective was to evaluate the safety of... (Clinical Trial)
Clinical Trial
BACKGROUND
Tirapazamine (TPZ) is a hypoxia activated drug that may be synergistic with transarterial embolization (TAE). The primary objective was to evaluate the safety of combining TPZ and TAE in patients with unresectable HCC and determine the optimal dose for Phase II.
METHODS
This was a Phase 1 multicenter, open-label, non-randomized trial with a classic 3+3 dose escalation and an expansion cohort in patients with unresectable HCC, Child Pugh A, ECOG 0 or 1. Two initial cohorts consisted of I.V. administration of Tirapazamine followed by superselective TAE while the remaining three cohorts underwent intraarterial administration of Tirapazamine with superselective TAE. Safety and tolerability were assessed using NCI CTCAE 4.0 with clinical, imaging and laboratory examinations including pharmacokinetic (PK) analysis and an electrocardiogram 1 day pre-dose, at 1, 2, 4, 6, 10, and 24 hours post-TPZ infusion and an additional PK at 15- and 30-minutes post-TPZ. Tumor responses were evaluated using mRECIST criteria.
RESULTS
Twenty-seven patients (mean [range] age of 66.4 [37-79] years) with unresectable HCC were enrolled between July 2015 and January 2018. Two patients were lost to follow-up. Mean tumor size was 6.53 cm ± 2.60 cm with a median of two lesions per patient. Dose limiting toxicity and maximum tolerated dose were not reached. The maximal TPZ dose was 10 mg/m I.V. and 20 mg/m I.A. One adverse event (AE) was reported in all patients with fatigue, decreased appetite or pain being most common. Grade 3-5 AE were hypertension and transient elevation of AST/ALT in 70.4% of patients. No serious AE were drug related. Sixty percent (95% CI=38.7-78.9) achieved complete response (CR), and 84% (95% CI=63.9-95.5) had complete and partial response per mRECIST for target lesions.
DISCUSSION
TAE with TPZ was safe and tolerable with encouraging results justifying pursuit of a Phase II trial.
PubMed: 34041204
DOI: 10.2147/JHC.S304275 -
International Journal of Nanomedicine 2024Photodynamic therapy (PDT) has been an attractive strategy for skin tumor treatment. However, the hypoxic microenvironment of solid tumors and further O consumption...
PURPOSE
Photodynamic therapy (PDT) has been an attractive strategy for skin tumor treatment. However, the hypoxic microenvironment of solid tumors and further O consumption during PDT would diminish its therapeutic effect. Herein, we developed a strategy using the combination of PDT and hypoxia-activated bioreductive drug tirapazamine (TPZ).
METHODS
TPZ was linked to DSPE-PEG-NHS forming DSPE-PEG-TPZ to solve leakage of water-soluble TPZ and serve as an antitumor agent and monomer molecule further forming the micellar. Chlorin e6 (Ce6) was loaded in DSPE-PEG-TPZ forming DSPE-PEG-TPZ@Ce6 (DPTC). To further improve tumor infiltration and accumulation, hyaluronic acid was adopted to make DPTC-containing microneedles (DPTC-MNs).
RESULTS
Both in vitro and in vivo studies consistently demonstrated the synergistic antitumor effect of photodynamic therapy and TPZ achieved by DPTC-MNs. With laser irradiation, overexpressions of PDT tolerance factors NQO1 and HIF-1α were inhibited by this PDT process.
CONCLUSION
The synergistic effect of PDT and TPZ significantly improved the performance of DPTC-MNs in the treatment of melanoma and cutaneous squamous cell carcinoma and has good biocompatibility.
Topics: Humans; Photochemotherapy; Carcinoma, Squamous Cell; Skin Neoplasms; Tirapazamine; Hypoxia; Cell Line, Tumor; Photosensitizing Agents; Nanoparticles; Tumor Microenvironment; Organometallic Compounds; Phenanthrolines
PubMed: 38482522
DOI: 10.2147/IJN.S443835