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British Journal of Cancer Jun 1993SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide, WIN 59075, tirapazamine) is the lead compound in a new class of bioreductive anticancer drugs, the benzotriazine... (Review)
Review
SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide, WIN 59075, tirapazamine) is the lead compound in a new class of bioreductive anticancer drugs, the benzotriazine di-N-oxides. It is currently undergoing Phase I clinical testing. The preferential tumour cell killing of SR 4233 is a result of its high specific toxicity to cells at low oxygen tensions. Such hypoxic cells are a common feature of solid tumours, but not normal tissues, and are resistant to cancer therapies including radiation and some anticancer drugs. The killing of these tumour cells by SR 4233, particularly when given on multiple occasions, can increase total tumour cell killing by fractionated irradiation by several orders of magnitude without increasing toxicity to surrounding normal tissues. Topics covered in this review include the rationale for developing a hypoxic cytotoxic agent, the cytotoxicity of SR 4233 as a function of oxygen concentration, the mechanism of action of the drug and its intracellular target and the in vivo evidence that the drug may be useful as an adjunct both to radiotherapy and chemotherapy. Finally, the major unanswered questions on the drug are outlined.
Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Humans; Mice; Neoplasms, Experimental; Tirapazamine; Triazines
PubMed: 8512801
DOI: 10.1038/bjc.1993.220 -
International Journal of Molecular... Apr 20233-Amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ) and other heteroaromatic -oxides (ArN→O) exhibit tumoricidal, antibacterial, and antiprotozoal activities....
3-Amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ) and other heteroaromatic -oxides (ArN→O) exhibit tumoricidal, antibacterial, and antiprotozoal activities. Their action is attributed to the enzymatic single-electron reduction to free radicals that initiate the prooxidant processes. In order to clarify the mechanisms of aerobic mammalian cytotoxicity of ArN→O, we derived a TPZ-resistant subline of murine hepatoma MH22a cells (resistance index, 5.64). The quantitative proteomic of wild-type and TPZ-resistant cells revealed 5818 proteins, of which 237 were up- and 184 down-regulated. The expression of the antioxidant enzymes aldehyde- and alcohol dehydrogenases, carbonyl reductases, catalase, and glutathione reductase was increased 1.6-5.2 times, whereas the changes in the expression of glutathione peroxidase, superoxide dismutase, thioredoxin reductase, and peroxiredoxins were less pronounced. The expression of xenobiotics conjugating glutathione-S-transferases was increased by 1.6-2.6 times. On the other hand, the expression of NADPH:cytochrome P450 reductase was responsible for the single-electron reduction in TPZ and for the 2.1-fold decrease. These data support the fact that the main mechanism of action of TPZ under aerobic conditions is oxidative stress. The unchanged expression of intranuclear antioxidant proteins peroxiredoxin, glutaredoxin, and glutathione peroxidase, and a modest increase in the expression of DNA damage repair proteins, tend to support non-site-specific but not intranuclear oxidative stress as a main factor of TPZ aerobic cytotoxicity.
Topics: Animals; Mice; Tirapazamine; Triazines; Antineoplastic Agents; Antioxidants; Carcinoma, Hepatocellular; Proteomics; Oxidation-Reduction; Liver Neoplasms; Glutathione Peroxidase; Mammals
PubMed: 37047836
DOI: 10.3390/ijms24076863 -
Journal of Molecular Modeling Mar 2022New data on 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine) fluorescence has been obtained using the Perkin-Elmer Lambda 950 UV-Vis-NIR spectrophotometer...
New data on 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine) fluorescence has been obtained using the Perkin-Elmer Lambda 950 UV-Vis-NIR spectrophotometer experimental technique in combination with the extensive DFT-theory approach. Based on the results obtained, we revealed that the optical properties of the molecule under study remain significantly unchanged when the number of oxygen substitutions decreases from 2 to 0. Here we also present the results of the study of the influence of acetonitrile and ethyl acetate on the fluorescence of tirapazamine with the different number of oxygen atoms. Results of our investigation indicate the formation of anion in the case of 3-amino-1,2,4-benzotriazine 1,4-dioxide with two oxygen atoms and their transformation to tirapazamine with one oxygen atom.
Topics: Antineoplastic Agents; Oxygen; Tirapazamine; Triazines
PubMed: 35320419
DOI: 10.1007/s00894-022-05085-z -
Hypoxia-targeted cupric-tirapazamine liposomes potentiate radiotherapy in prostate cancer spheroids.International Journal of Pharmaceutics Sep 2021In this study, novel cupric-tirapazamine [Cu(TPZ)]-liposomes were developed as an effective hypoxia-targeted therapeutic, which potentiated radiotherapy in a three...
In this study, novel cupric-tirapazamine [Cu(TPZ)]-liposomes were developed as an effective hypoxia-targeted therapeutic, which potentiated radiotherapy in a three dimensional (3D) prostate cancer (PCa) model. To overcome the low water solubility of the Cu(TPZ), a remote loading method was developed to efficiently load the lipophilic complex into different liposomal formulations. The effect of pH, temperature, PEGylation, lipid composition, liposome size, lipid: complex ratio on the liposome properties, and drug loading was evaluated. The highest loading efficiency was obtained at neutral pH, which was independent of lipid composition and incubation time. In addition, enhanced drug loading was achieved upon decreasing the lipid:complex molar ratio with minimal effects on liposomes' morphology. Interestingly, the in vitro potency of the developed liposomes was easily manipulated by changing the lipid composition. The hydrophilic nature of our liposomal formulations improved the complex's solubility, leading to enhanced cellular uptake and toxicity, both in PCa monolayers and tumour spheroids. Moreover, Cu(TPZ)-loaded liposomes combined with radiation, showed a significant reduction in PCa spheroids growth rate, compared to the free complex or radiation alone, which could potentiate radiotherapy in patients with localised advanced PCa.
Topics: Humans; Hypoxia; Liposomes; Male; Prostatic Neoplasms; Solubility; Tirapazamine
PubMed: 34416329
DOI: 10.1016/j.ijpharm.2021.121018 -
Anti-cancer Drug Design Sep 1998The enzymology of triapazamine (TPZ, SR 4233, WIN 59075, 3-amino-1,2,4-benzotriazene 1,4-dioxide, Tirazone) has been extensively studied in rodents and to a lesser... (Review)
Review
The enzymology of triapazamine (TPZ, SR 4233, WIN 59075, 3-amino-1,2,4-benzotriazene 1,4-dioxide, Tirazone) has been extensively studied in rodents and to a lesser extent in human systems. While it is clear that the initial reductive step in TPZ activation is enzyme-mediated, there is limited consensus in the published literature as to the relative contributions of the cellular reductases involved. Moreover, not only is the importance of subcellular localization for these putative activating reductase(s) far from clear, but their activity profiles in vivo are poorly defined. The same might also be said of the potential detoxifying enzymes. This review will attempt to establish what common ground exists regarding the enzymology of TPZ metabolism, and will relate the available evidence to the enzyme profiles found in human cell lines in vitro, as well as in xenograft models and human solid tumours.
Topics: Animals; Antineoplastic Agents; Cytochrome P-450 Enzyme System; Cytochrome Reductases; Cytochrome-B(5) Reductase; Humans; Microsomes, Liver; Mitochondria, Liver; NADPH-Ferrihemoprotein Reductase; Oxidoreductases; Tirapazamine; Triazines
PubMed: 9755718
DOI: No ID Found -
Journal of Photochemistry and... Nov 2023Photodynamic therapy (PDT) has a promising application prospect in Echinococcus granulosus (Egs), however, the hypoxic environment of Egs and the hypoxia associated with...
BACKGROUND
Photodynamic therapy (PDT) has a promising application prospect in Echinococcus granulosus (Egs), however, the hypoxic environment of Egs and the hypoxia associated with PDT will greatly limit its effects. As a hypoxic-activated pre-chemotherapeutic drug, tirapazamine (TPZ) can be only activated and produce cytotoxicity under hypoxia environment. Albendazole sulfoxide (ABZSO) is the first choice for the treatment of Egs. This study aimed to explore the effects of ABZSO nanoparticles (ABZSO NPs), TPZ combined with PDT on the activity of Egs in vitro and in vivo.
METHODS
The Egs were divided into control, ABZSO NPs, ABZSO NPs + PDT, and ABZSO NPs + TPZ + PDT groups, and the viability of Egs was determined using methylene blue staining. Then, the ROS, LDH and ATP levels were measured using their corresponding assay kit, and H2AX and TopoI protein expression was detected by western blot. The morphology of Egs with different treatments was observed using hematoxylin eosin (HE) staining and scanning electron microscopy (SEM). After that, the in vivo efficacy of ABZSO NPs, TPZ and PDT on Egs was determined in a Egs infected mouse model.
RESULTS
In vitro experiments showed that the combined treatment of TPZ, ABZSO NPs and PDT significantly inhibited Egs viability; and significantly increased ROS levels and LDH contents, while decreased ATP contents in Egs; as well as up-regulated H2AX and down-regulated TopoI protein expression. HE staining and SEM results showed that breaking-then-curing treatment seriously damaged the Egs wall. Additionally, in vivo experiments found that the combination of ABZSO NPs, PDT and TPZ had more serious calcification and damage of the wall structure of cysts.
CONCLUSIONS
ABZSO NPs combined with TPZ and PDT has a better inhibitory effect on the growth of Egs in vitro and in vivo based on the strategy of "breaking-then-curing".
Topics: Animals; Mice; Tirapazamine; Echinococcus granulosus; Reactive Oxygen Species; Hypoxia; Photochemotherapy; Echinococcosis; Nanoparticles; Adenosine Triphosphate
PubMed: 37820499
DOI: 10.1016/j.jphotobiol.2023.112798 -
International Journal of Molecular... Mar 2021We investigate dissociative electron attachment to tirapazamine through a crossed electron-molecule beam experiment and quantum chemical calculations. After the electron...
We investigate dissociative electron attachment to tirapazamine through a crossed electron-molecule beam experiment and quantum chemical calculations. After the electron is attached and the resulting anion reaches the first excited state, D, we suggest a fast transition into the ground electronic state through a conical intersection with a distorted triazine ring that almost coincides with the minimum in the D state. Through analysis of all observed dissociative pathways producing heavier ions (90-161 u), we consider the predissociation of an OH radical with possible roaming mechanism to be the common first step. This destabilizes the triazine ring and leads to dissociation of highly stable nitrogen-containing species. The benzene ring is not altered during the process. Dissociation of small anionic fragments (NO, CN, CN, NH, O) cannot be conclusively linked to the OH predissociation mechanism; however, they again do not require dissociation of the benzene ring.
Topics: Algorithms; Anions; Electrons; Models, Chemical; Radiation-Sensitizing Agents; Tirapazamine
PubMed: 33808887
DOI: 10.3390/ijms22063159 -
Biomedicine & Pharmacotherapy =... Jul 2022Tirapazamine (TPZ) is a promising hypoxia-selective cytotoxic agent that may exert synergistic tumor-killing activity with transcatheter arterial embolization (TAE) for...
Tirapazamine (TPZ) is a promising hypoxia-selective cytotoxic agent that may exert synergistic tumor-killing activity with transcatheter arterial embolization (TAE) for liver cancer. To investigated whether TPZ-loaded microspheres enhance the synergy between TPZ and TAE in liver cancer, we prepared TPZ-loaded CalliSpheres microspheres (CSMTPZs) and characterized their properties as a chemoembolization agent in vitro. Tumor hypoxia after TAE was detected in the rabbit VX2 model of liver cancer using a modified Clark-type microelectrode research system. CSMTPZ therapy was performed in the animal model. The plasma and tumor concentrations of TPZ and its metabolites were measured, and the efficacy and safety of CSMTPZ therapy were evaluated and compared with those of the conventional combination of intraarterial TPZ injection and embolization. The results showed that CSMTPZs displayed favorable in vitro properties including drug loading and release and microsphere size, shape, and surface profiles. TAE induced acute tumor hypoxia, but residual tumor cells responded to hypoxia through hypoxia-inducible factor 1α. CSMTPZ therapy improved TPZ delivery into tumor tissue with minimal systemic exposure. Accordingly, CSMTPZ therapy exhibited advantages in terms of hypoxia-selected cytotoxicity, tumor apoptosis and necrosis, animal survival, and safety over the conventional combination of TPZ and TAE. We revealed the improved synergistic anti-tumor effects of CSMTPZ therapy in the rabbit VX2 liver cancer model. Our data support the clinical evaluation of CSMTPZs in the treatment of hepatocellular carcinoma, and CSMTPZ administration might serve as a successful therapeutic strategy for this malignancy.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Disease Models, Animal; Embolization, Therapeutic; Hypoxia; Liver Neoplasms; Microspheres; Rabbits; Tirapazamine
PubMed: 35594702
DOI: 10.1016/j.biopha.2022.113123 -
Radiotherapy and Oncology : Journal of... Feb 2006Tirapazamine is a hypoxic cytotoxin currently undergoing Phase II/III clinical evaluation in combination with radiation and chemotherapeutics for the treatment of...
BACKGROUND AND PURPOSE
Tirapazamine is a hypoxic cytotoxin currently undergoing Phase II/III clinical evaluation in combination with radiation and chemotherapeutics for the treatment of non-hematological cancers. Tissue penetration studies using multicellular models have suggested that tirapazamine exposure may be limited to cells close to blood vessels. However, animal studies show tirapazamine enhances the anti-tumour activity of radiation and chemotherapy and clinical studies with tirapazamine, so far, are promising. To investigate this apparent paradox we examined the microregional effects of tirapazamine in vivo by mapping drug effects with respect to the position of blood vessels in tumour cryosections.
PATIENTS AND METHODS
Tirapazamine was administered i.p. to mice bearing HCT-116 tumours, which were excised at various times after treatment. Images of multiple-stained cryosections were overlaid to provide microregional information on the relative position of proliferating cells, hypoxia, perfusion and vasculature.
RESULTS
We observed extensive and permanent vascular dysfunction in a large proportion of tumours from mice treated with tirapazamine. In the affected tumours, blood flow ceased in the centrally located tumour vessels, leaving a rim of functional vessels around the periphery of the tumour. This vascular dysfunction commenced within 24 h after tirapazamine administration and the areas affected appeared to be replaced by necrosis over the following 24-48 h.
CONCLUSIONS
Because the majority of hypoxic cells are located in the center of tumours we propose that the activity of tirapazamine in vivo may be related to its effects on tumour vasculature and that its activity against hypoxic cells located distal to functional blood vessels may not be as important as previously believed.
Topics: Animals; Antimetabolites; Antineoplastic Agents; Blood Vessels; Bromodeoxyuridine; Cell Hypoxia; Cell Proliferation; Coloring Agents; Female; HCT116 Cells; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Mice; Mice, Inbred NOD; Mice, SCID; Necrosis; Platelet Endothelial Cell Adhesion Molecule-1; Regional Blood Flow; Skin Neoplasms; Tirapazamine; Transplantation, Heterologous; Triazines
PubMed: 16455148
DOI: 10.1016/j.radonc.2006.01.002 -
Journal of Vascular and Interventional... Aug 2022To investigate the safety of replacing doxorubicin with tirapazamine in conventional transarterial chemoembolization (TACE) in an Asian population with hepatocellular...
PURPOSE
To investigate the safety of replacing doxorubicin with tirapazamine in conventional transarterial chemoembolization (TACE) in an Asian population with hepatocellular carcinoma (HCC), and to determine the optimal tirapazamine dose for phase II studies.
MATERIALS AND METHODS
This was a phase I, 3 + 3 dose-escalation study for patients with unresectable early- and intermediate-stage HCC who received 5, 10, or 20 mg/m of intra-arterial (IA) tirapazamine followed by ethiodized oil/gelatin sponge-based embolization. Key eligibilities included HCCs no more than 10 cm in diameter, prior embolization allowed, Eastern Cooperative Oncology Group performance status of 0 or 1, Child-Pugh score of 5-7, and platelet count of ≥60,000 μL. Dose-limiting toxicity (DLT) was defined as any grade 3 nonhematological or grade 4 hematological toxicity, with the exception of transient elevation of aminotransferase levels after the procedure.
RESULTS
Seventeen patients were enrolled, 59% of whom had progression from a prior HCC therapy and 35% of whom had progression or recurrence after TACE. All patients tolerated the tirapazamine TACE well without any DLT or serious adverse event. Using the modified Response Evaluation Criteria in Solid Tumors, the complete response (CR) rate was 47%, and the CR + partial response rate was 65%. The median duration of response was not reached. The median time to progression was 12.6 months (95% confidence interval, 5.1-not reached). The median overall survival was 29.3 months. The selected phase II dose was set at a fixed dose of 35 mg of IA tirapazamine.
CONCLUSIONS
IA tirapazamine with transarterial embolization was well tolerated and showed promising efficacy signals in intermediate-stage HCC, justifying pursuit of a phase II study.
Topics: Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Ethiodized Oil; Humans; Liver Neoplasms; Tirapazamine; Treatment Outcome
PubMed: 35504436
DOI: 10.1016/j.jvir.2022.04.031