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Biomaterials Science Jul 2021A zinc(ii) phthalocyanine (ZnPc) was conjugated to doxorubicin (Dox) via an acid-labile hydrazone linker. The resulting ZnPc-Dox conjugate was then encapsulated into...
A zinc(ii) phthalocyanine (ZnPc) was conjugated to doxorubicin (Dox) via an acid-labile hydrazone linker. The resulting ZnPc-Dox conjugate was then encapsulated into polymeric micelles formed through self-assembly of a block copolymer of poly(ethylene glycol) and poly(d,l-lactide) both in the absence and presence of the hypoxia-activated prodrug tirapazamine (TPZ) to give ZnPc-Dox@micelles and ZnPc-Dox/TPZ@micelles respectively. These polymeric micelles exhibited an excellent stability in aqueous media, but underwent disassembly in an acidic environment. Upon internalisation into HT29 human colorectal carcinoma cells, fluorescence due to ZnPc and Dox could be observed in the cytoplasm and nucleus respectively for both nanosystems. This observation suggested the disassembly of the polymeric micelles and the cleavage of the hydrazone linker in ZnPc-Dox in the acidic intracellular compartments. These micelles were slightly cytotoxic against HT29 cells in the dark due to the chemotherapeutic effect of Dox and/or TPZ. Upon light irradiation, ZnPc-Dox@micelles showed higher cytotoxicity. The IC50 value under a normoxic condition (0.35 μM based on ZnPc-Dox) was significantly lower than that under hypoxia (>1 μM). With an additional therapeutic component, ZnPc-Dox/TPZ@micelles exhibited higher photocytotoxicity with IC50 values of 0.20 μM and 0.78 μM under normoxia and hypoxia respectively. It is believed that the photodynamic action of this nanosystem consumed the intracellular oxygen and hence triggered the hypoxia-mediated chemotherapeutic action of TPZ. The multimodal antitumor effects of these polymeric micelles were also validated on HT29 tumour-bearing nude mice.
Topics: Animals; Doxorubicin; Hypoxia; Indoles; Isoindoles; Mice; Mice, Nude; Micelles; Neoplasms; Polyethylene Glycols; Tirapazamine
PubMed: 34075948
DOI: 10.1039/d1bm00443c -
British Journal of Cancer Jun 1996Recent data have shown that the in vitro and in vivo cytotoxicity of bioreductive drugs could be significantly increased when combined with chemotherapy drugs such as...
Recent data have shown that the in vitro and in vivo cytotoxicity of bioreductive drugs could be significantly increased when combined with chemotherapy drugs such as cisplatinum, depending on the timing of administration. The aim of this study was to define the toxicity (animal lethality) and the activity (growth delay assay, excision assay) of a bioreductive drug, tirapazamine, alone and combined with chemotherapy agents (5-FU, VP16, bleo, DTIC and c-DDP) on nude mice bearing xenografted human tumours: a rectal carcinoma (HRT18) and a melanoma (Na11+). Animal lethality was markedly increased when tirapazamine at the lethal dose 10% was combined with the other drugs. For the HRT18 tumour the combination of tirapazamine and bleomycin significantly increased the delay of regrowth compared with bleomycin alone (P = 0.04) and was more cytotoxic than tirapazamine alone (P = 0.04). For the Na11+ tumours the combination of tirapazamine with VP16 significantly increased tumour doubling time compared with the controls (P = 0.001) or VP16 alone. The combination of tirapazamine and VP16 was more cytotoxic than VP16 alone (P = 0.0001). When compared with c-DDP or tirapazamine alone, there was a significant decrease in plating efficiency when tirapazamine and c-DDP were given at the same time (P = 0.04), but not when tirapazamine was given 3 h before c-DDP. In conclusion, tirapazamine was shown to be cytotoxic against clonogenic human tumour cells. Its efficacy in vivo may depend on its combination with already active chemotherapy drugs on the tumour model used. The timing of administration may be less important than previously thought.
Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cell Division; Cisplatin; Dacarbazine; Drug Screening Assays, Antitumor; Etoposide; Fluorouracil; Humans; Melanoma; Mice; Mice, Nude; Rectal Neoplasms; Tirapazamine; Transplantation, Heterologous; Triazines
PubMed: 8664116
DOI: 10.1038/bjc.1996.280 -
Cancer Research Apr 1996Tirapazamine (3-amino-1,2,4-benzotriazine-1,4-dioxide, SR 4233) is the lead compound of a new class of hypoxic cell cytotoxins showing considerable antitumor activity....
Tirapazamine (3-amino-1,2,4-benzotriazine-1,4-dioxide, SR 4233) is the lead compound of a new class of hypoxic cell cytotoxins showing considerable antitumor activity. Hypoxic cytotoxicity of tirapazamine is believed to be mediated by free radical attack of its one-electron reduced metabolite on DNA, but little is known about the DNA lesions induced by the drug. Using the anoxic xanthine/xanthine oxidase system to effect one-electron reduction of tirapazamine under controlled conditions, we studied the action of the drug toward pUC18 and calf thymus DNA. Agarose gel electrophoresis indicated that tirapazamine causes substantially higher levels of single-strand breakage than double-stand breakage. The 5' DNA termini at the single-strand breaks were shown to be phosphorylated. Little, if any, base damage was observed when the damaged DNA was analyzed by a 32P-postlabeling assay. The major detectable lesion (comprising approximately 32% of the 3' ends of tirapazamine-induced single-strand breaks) was the phosphoglycolate moiety, which is caused by deoxyribose fragmentation. Since phosphoglycolate formation requires the addition of oxygen, we conclude that tirapazamine acts in a dual fashion to produce phosphoglycolates: (a) to generate a free radical in the deoxyribose ring (i.e., .C-4' and (b) then to donate an oxygen atom. The oxygen donation by tirapazamine was confirmed by anoxic irradiation of DNA in the presence of the unmetabolized drug. Increasing the concentration of the drug (up to 50 microM) led to a dramatic increase in the yield of phosphoglycolate.
Topics: Antineoplastic Agents; DNA; DNA Damage; Glycolates; Radiation-Sensitizing Agents; Tirapazamine; Triazines
PubMed: 8603406
DOI: No ID Found -
Biomaterials Oct 2023The efficacy of photodynamic therapy (PDT) is severely limited by the hypoxic tumor microenvironment (TME), while the performance of PDT-aroused antitumor immunity is...
The efficacy of photodynamic therapy (PDT) is severely limited by the hypoxic tumor microenvironment (TME), while the performance of PDT-aroused antitumor immunity is frustrated by the immunosuppressive TME and deficient immunogenic cell death (ICD) induction. To simultaneously tackle these pivotal problems, we herein create an albumin-based nanoplatform co-delivering IR780, NLG919 dimer and a hypoxia-activated prodrug tirapazamine (TPZ) as the dual enhancer for synergistic cancer therapy. Under NIR irradiation, IR780 generates O for PDT, which simultaneously cleaves the ROS-sensitive linker for triggered TPZ release, and activates its chemotherapy via exacerbated tumor hypoxia. Meanwhile, firstly found by us, TPZ-mediated chemotherapy boosts PDT-induced tumor ICD to evoke stronger antitumor immunity including the development of tumor-specific cytotoxic T lymphocytes (CTLs). Eventually, enriched intratumoral GSH triggers the activation of NLG919 to mitigate the immunosuppressive TME via specific indoleamine 2,3-dioxygenase 1 (IDO-1) inhibition, consequently promoting the intratumoral infiltration of CTLs and the killing of both primary and distant tumors, while the resultant memory T cells allows nearly 100% suppression of tumor recurrence and metastasis. This nanoplatform sets up an example for dully enhanced photodynamic immunotherapy of breast cancer via hypoxia-activated chemotherapy, and paves a solid way for the treatment of other hypoxic and immunosuppressive malignant tumors.
Topics: Humans; Photochemotherapy; Neoplasm Recurrence, Local; Tirapazamine; Hypoxia; Neoplasms; Immunotherapy; Cell Line, Tumor; Photosensitizing Agents; Tumor Microenvironment; Nanoparticles
PubMed: 37531778
DOI: 10.1016/j.biomaterials.2023.122257 -
Pretreatment 18F-FAZA PET predicts success of hypoxia-directed radiochemotherapy using tirapazamine.Journal of Nuclear Medicine : Official... Jun 2007We evaluated the predictive value of PET using the hypoxia tracer (18)F-fluoroazomycin arabinoside ((18)F-FAZA) for success of radiotherapy in combination with...
UNLABELLED
We evaluated the predictive value of PET using the hypoxia tracer (18)F-fluoroazomycin arabinoside ((18)F-FAZA) for success of radiotherapy in combination with tirapazamine, a specific cytotoxin for hypoxic cells.
METHODS
Imaging was performed on EMT6 tumor-bearing nude mice before allocating mice into 4 groups: radiochemotherapy (RCT: 8 fractions of 4.5 Gy within 4 d combined with tirapazamine, 14 mg/kg), radiotherapy alone (RT), chemotherapy alone (tirapazamine) (CHT), or control. Treatment success was assessed by several tumor growth assays, including tumor growth time from 70 to 500 microL and absolute growth delay (aGD). The median pretreatment (18)F-FAZA tumor-to-background ratio served as a discriminator between "hypoxic" and "normoxic" tumors.
RESULTS
The mean tumor growth was significantly accelerated in hypoxic control tumors (growth time from 70 to 500 microL, 11.0 d) compared with normoxic control tumors (growth time from 70 to 500 microL, 15.6 d). Whereas RT delayed tumor growth regardless of the level of hypoxia, an additive beneficial therapeutic effect of tirapazamine to RT was observed only in hypoxic tumors (aGD, 12.9 d) but not in normoxic tumors (aGD, 6.0 d).
CONCLUSION
This study provides compelling evidence that hypoxia imaging using (18)F-FAZA PET is able to predict the success of RCT of tumor-bearing mice using the hypoxia-activated chemotherapeutic agent tirapazamine. Pretreatment (18)F-FAZA PET, therefore, offers a way for the individualization of tumor treatment involving radiation. The data suggest that by reserving hypoxia-directed therapy to tumors with high (18)F-FAZA uptake, improvement of the therapeutic ratio is possible, as the therapeutic effect of tirapazamine seems to be restricted to hypoxic tumors.
Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Cell Line, Tumor; Combined Modality Therapy; Female; Fluorine Radioisotopes; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Neoplasm Transplantation; Nitroimidazoles; Positron-Emission Tomography; Radiation-Sensitizing Agents; Radiopharmaceuticals; Tirapazamine; Transplantation, Heterologous; Triazines; Whole Body Imaging
PubMed: 17536108
DOI: 10.2967/jnumed.106.038570 -
Cancer Chemotherapy and Pharmacology 1999Efficient extravascular penetration is essential for the optimal activity of most anticancer drugs and is particularly relevant to bioreductive cytotoxins which target...
PURPOSE
Efficient extravascular penetration is essential for the optimal activity of most anticancer drugs and is particularly relevant to bioreductive cytotoxins which target hypoxic cells that can be located distal to functional blood vessels within tumours. Tirapazamine (3-amino-1,2,4-benzotriazine-1,4-di-N-oxide; Triazone; SR 259075; formerly SR 4233) is a lead bioreductive cytotoxin currently undergoing clinical evaluation. It exhibits preferential cytotoxicity towards cells at reduced oxygen tension, and could complement existing anticancer therapies where hypoxic cells are believed to constitute a refractory population. We assessed the ability of tirapazamine to penetrate tumour tissue using an in vitro multilayered cell culture (MCC) model.
METHODS
Diffusion of tirapazamine through oxic and hypoxic multilayered cell cultures composed of SiHa. human cervical carcinoma cells, was measured using a dual reservoir diffusion apparatus from which samples were quantified via HPLC. Drug concentration kinetics from both reservoirs were analysed using a mathematical model for diffusion and metabolism within the MCC. Results were then applied to a second mathematical model which described extravascular drug penetration within a tumour cord, the sheath of cells surrounding a blood vessel.
RESULTS
The diffusion coefficient of tirapazamine within SiHa MCCs was determined as 7.0+/-0.5 x 10(-7) cm2/s and the maximal metabolic rate for hypoxic MCCs, Vmax, as 1.5+/-0.4 microM/s. The thickness of individual tissue cultures was determined by diffusion of tritiated water (HTO). A linear relationship was shown to exist between tissue thickness and the inverse of permeability to HTO. Experimental results were used to simulate drug distribution within a tumour cord. These simulations indicate that, when tirapazamine is administered via intravenous infusion, a stable tirapazamine distribution throughout the cord occurs within 15 min with cells most peripheral to the blood vessel exposed to only 10% of the blood drug concentration. Under these conditions, the simulations predict cell kill to be limited to the first 75 microm of tissue surrounding a blood vessel.
CONCLUSION
This study indicates that extravascular penetration of tirapazamine to peripheral cells existing at low oxygen tension may be limited by the metabolism of tirapazamine by more proximal cells existing at moderate oxygen tension. Simulations found that tirapazamine reached only 10% of the blood concentration at cells most peripheral to blood vessels. These results indicate that tirapazamine would be significantly cytotoxic only to cells located within approximately 75 microm of blood vessels. Further MCC-based modelling of extravascular drug penetration would serve as a means of identifying new antitumour agents with location-specific activity.
Topics: Algorithms; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Survival; Chromatography, High Pressure Liquid; Diffusion; Female; Humans; Membranes, Artificial; Models, Biological; Polytetrafluoroethylene; Tirapazamine; Tissue Distribution; Triazines; Tumor Cells, Cultured; Uterine Cervical Neoplasms
PubMed: 9923551
DOI: 10.1007/s002800050886 -
Journal of Clinical Oncology : Official... Mar 2000A phase III trial, Cisplatin and Tirapazamine in Subjects with Advanced Previously Untreated Non-Small-Cell Lung Tumors (CATAPULT I), was designed to determine the... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
Tirapazamine plus cisplatin versus cisplatin in advanced non-small-cell lung cancer: A report of the international CATAPULT I study group. Cisplatin and Tirapazamine in Subjects with Advanced Previously Untreated Non-Small-Cell Lung Tumors.
PURPOSE
A phase III trial, Cisplatin and Tirapazamine in Subjects with Advanced Previously Untreated Non-Small-Cell Lung Tumors (CATAPULT I), was designed to determine the efficacy and safety of tirapazamine plus cisplatin for the treatment of non-small-cell lung cancer (NSCLC).
PATIENTS AND METHODS
Patients with previously untreated NSCLC were randomized to receive either tirapazamine (390 mg/m(2) infused over 2 hours) followed 1 hour later by cisplatin (75 mg/m(2) over 1 hour) or 75 mg/m(2) of cisplatin alone, every 3 weeks for a maximum of eight cycles.
RESULTS
A total of 446 patients with NSCLC (17% with stage IIIB disease and pleural effusions; 83% with stage IV disease) were entered onto the study. Karnofsky performance status (KPS) was >/= 60 for all patients (for 10%, KPS = 60; for 90%, KPS = 70 to 100). Sixty patients (14%) had clinically stable brain metastases. The median survival was significantly longer (34.6 v 27. 7 weeks; P =.0078) and the response rate was significantly greater (27.5% v 13.7%; P <.001) for patients who received tirapazamine plus cisplatin (n = 218) than for those who received cisplatin alone (n = 219). The tirapazamine-plus-cisplatin regimen was associated with mild to moderate adverse events, including acute, reversible hearing loss, reversible, intermittent muscle cramping, diarrhea, skin rash, nausea, and vomiting. There were no incremental increases in myelosuppression, peripheral neuropathy, or renal, hepatic, or cardiac toxicity and no deaths related to tirapazamine.
CONCLUSION
The CATAPULT I study shows that tirapazamine enhances the activity of cisplatin in patients with advanced NSCLC and confirms that hypoxia is an exploitable therapeutic target in human malignancies.
Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cell Hypoxia; Cisplatin; Drug Synergism; Female; Humans; Lung Neoplasms; Male; Middle Aged; Survival Analysis; Tirapazamine; Triazines
PubMed: 10715308
DOI: 10.1200/JCO.2000.18.6.1351 -
Anti-cancer Agents in Medicinal... Jul 2006Solid tumours contain regions of very low oxygen concentrations that are said to be hypoxic. Hypoxia is a natural phenotype of solid tumours resulting from an imperfect... (Review)
Review
Solid tumours contain regions of very low oxygen concentrations that are said to be hypoxic. Hypoxia is a natural phenotype of solid tumours resulting from an imperfect vascular network. There are a number of consequences associated with tumour hypoxia including: resistance to ionising radiation, resistance to chemotherapy and the magnification of mutated p53. In addition tissue hypoxia has been regarded as a key factor for tumour aggressiveness and metastasis by activation of signal transduction pathways and gene regulatory mechanisms. It is clear that hypoxia in solid tumours promotes a strong oncogenic phenotype and is a phenomenon that occurs in all solid tumours. As such this provides a significant target for drug discovery particularly for tumour-targeting agents. A range of chemical classes (N-oxides, quinones, nitro-aromatics) have been explored as bioreductive agents that target tumour hypoxia. The most advanced agent, tirapazamine, is in phase III clinical trials in combination with cis-platin. The aim of this review is to give a brief overview of the current molecules and strategies being explored for targeting tumour hypoxia.
Topics: Anthraquinones; Antineoplastic Agents; Aziridines; Benzoquinones; Cell Hypoxia; Clinical Trials, Phase III as Topic; Drug Screening Assays, Antitumor; Humans; Imidazoles; Indolequinones; Neoplasms; Prodrugs; Quinolines; Radiation-Sensitizing Agents; Tirapazamine; Triazines
PubMed: 16842231
DOI: 10.2174/187152006777698169 -
Advanced Science (Weinheim,... Aug 2023As a currently common strategy to treat cancer, surgical resection may cause tumor recurrence and metastasis due to residual postoperative tumors. Herein, an implantable...
Sandwich-Structured Implants to Obstruct Multipath Energy Supply and Trigger Self-Enhanced Hypoxia-Initiated Chemotherapy Against Postsurgical Tumor Recurrence and Metastasis.
As a currently common strategy to treat cancer, surgical resection may cause tumor recurrence and metastasis due to residual postoperative tumors. Herein, an implantable sandwich-structured dual-drug depot is developed to trigger a self-intensified starvation therapy and hypoxia-induced chemotherapy sequentially. The two outer layers are 3D-printed using a calcium-crosslinked mixture ink containing soy protein isolate, polyvinyl alcohol, sodium alginate, and combretastatin A4 phosphate (CA4P). The inner layer is one patch of poly (lactic-co-glycolic acid)-based electrospun fibers loaded with tirapazamine (TPZ). The preferentially released CA4P destroys the preexisting blood vessels and prevents neovascularization, which obstructs the external energy supply to cancer cells but aggravates hypoxic condition. The subsequently released TPZ is bioreduced to cytotoxic benzotriazinyl under hypoxia, further damaging DNA, generating reactive oxygen species, disrupting mitochondria, and downregulating hypoxia-inducible factor 1α, vascular endothelial growth factor, and matrix metalloproteinase 9. Together these processes induce apoptosis, block the intracellular energy supply, counteract the disadvantage of CA4P in favoring intratumor angiogenesis, and suppress tumor metastasis. The in vivo and in vitro results and the transcriptome analysis demonstrate that the postsurgical adjuvant treatment with the dual-drug-loaded sandwich-like implants efficiently inhibits tumor recurrence and metastasis, showing great potential for clinical translation.
Topics: Humans; Neoplasm Recurrence, Local; Vascular Endothelial Growth Factor A; Cell Line, Tumor; Antineoplastic Agents; Tirapazamine; Hypoxia
PubMed: 37156756
DOI: 10.1002/advs.202300899 -
International Journal of Radiation... Feb 2007To examine the effects of fluctuating oxygen levels on the hypoxic cytotoxin tirapazamine (TPZ) using theoretical predictions.
PURPOSE
To examine the effects of fluctuating oxygen levels on the hypoxic cytotoxin tirapazamine (TPZ) using theoretical predictions.
METHODS AND MATERIALS
Tirapazamine's pharmacokinetic and pharmacodynamic oxygen dependence has previously been characterized in vitro. Here, a one-dimensional theoretical model was used to examine the effects of fluctuating hypoxia on metabolized TPZ concentration, assuming sinusoidally fluctuating oxygen levels. TPZ concentration is changing according to published experimental data. Simulations of experimentally observed time-courses of perivascular pO2 were also conducted.
RESULTS
The predicted pharmacodynamic effect of TPZ was increased with fluctuating (vs. constant) hypoxia at all frequencies (1-30 min period) and all amplitudes (1-15 mm Hg). Additionally, fluctuating oxygen resulted in more metabolized TPZ near the oxygen source as compared with the steady-state condition of the same overall average pO2.
CONCLUSIONS
Fluctuating pO2 reduced the concentration of metabolized TPZ at distances farther from the source, thereby limiting its ability to reach and kill the most hypoxic cells. These results suggest that the kinetics of fluctuating oxygenation should be taken into account when considering drug designs that involve oxygen-sensitive agents.
Topics: Antineoplastic Agents; Cell Hypoxia; Cell Survival; Models, Biological; Oxygen; Partial Pressure; Time Factors; Tirapazamine; Triazines
PubMed: 17236974
DOI: 10.1016/j.ijrobp.2006.10.002