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The British Journal of Surgery Apr 2012
Topics: Animals; Antineoplastic Agents; Catheter Ablation; Colorectal Neoplasms; Liver Neoplasms; Male; Prodrugs; Tirapazamine; Triazines
PubMed: 22396055
DOI: 10.1002/bjs.8669 -
FEMS Microbiology Letters Oct 2013Rapidly increasing bacterial resistance to existing therapies creates an urgent need for the development of new antibacterials. Tirapazamine (TPZ,...
Rapidly increasing bacterial resistance to existing therapies creates an urgent need for the development of new antibacterials. Tirapazamine (TPZ, 3-amino-1,2,4-benzotriazine 1,4 dioxide) is a prodrug undergoing clinical trials for various types of cancers. In this study, we showed that TPZ has antibacterial activity, particularly at low oxygen levels. With Escherichia coli, TPZ was bactericidal under both aerobic and anaerobic conditions. Escherichia coli mutants deficient in homologous recombination were hypersusceptible to TPZ, suggesting that drug toxicity may be due to DNA damage. Moreover, E. coli strains deleted for genes encoding putative reductases were resistant to TPZ, implying that these enzymes are responsible for conversion of the prodrug to a toxic compound. Fluoroquinolone-resistant E. coli strains were as susceptible to TPZ as a wild-type strain. Methicillin-resistant Staphylococcus aureus strains were also susceptible to TPZ (MIC = 0.5 μg mL(-1) ), as were pathogenic strains of Clostridium difficile (MIC = 7.5 ng mL(-1) ). TPZ may merit additional study as a broad-spectrum antibacterial, particularly for anaerobes.
Topics: Anti-Bacterial Agents; Clostridioides difficile; Cytochrome P-450 Enzyme System; Drug Resistance, Bacterial; Escherichia coli; Escherichia coli Proteins; Fluoroquinolones; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Microbial Viability; Recombinational DNA Repair; Tirapazamine; Triazines
PubMed: 23888874
DOI: 10.1111/1574-6968.12223 -
International Journal of Gynecological... Jul 2010Hypoxia is an adverse prognostic factor in locoregionally advanced cervical cancer treated with radiation. The aim of this phase I study was to develop a well-tolerated...
INTRODUCTION
Hypoxia is an adverse prognostic factor in locoregionally advanced cervical cancer treated with radiation. The aim of this phase I study was to develop a well-tolerated regimen that added tirapazamine to the standard regimen of radiation and weekly low-dose cisplatin.
METHODS
Eligible patients had previously untreated carcinoma of the cervix, stages IB2 to IVA. The starting schedule was radiotherapy (45-50.4 Gy external beam radiation followed by brachytherapy), with concomitant weekly intravenous cisplatin, 40 mg/m on weeks 1 to 6 and weekly intravenous tirapazamine, 290 mg/m in weeks 1 to 5.
RESULTS
Eleven patients were enrolled. The median age was 52 years (range, 31-65 years). Ten patients had squamous cell carcinoma and 1 patient had adenocarcinoma; 5 patients had stage 1B2 disease, 1 had stage IIA, 3 had stage IIB-3, 1 had stage IIIB, and 1 had stage IVA. The first 2 patients on dose level 1 experienced a dose-limiting toxicity (DLT): 1 experienced grade 3 alanine amino transferase elevation and grade 4 pulmonary embolism, and 1 experienced grade 3 ototoxicity. Doses were decreased to dose level -1 with a 30-mg/m dose of cisplatin and a 260-mg/m dose of tirapazamine. Three patients were treated without any DLTs. Six patients were then treated on dose level -1a: a 35-mg/m dose of cisplatin and a 260-mg/m doses of tirapazamine with 2 DLTs--grade 3 neutropenia with dose omission and grade 4 pulmonary embolism with major hemodynamic compromise. Three of 10 evaluable patients have experienced locoregional failure.
CONCLUSIONS
The combination of weekly tirapazamine and cisplatin with radiation for locally advanced cervical cancer was associated with more toxicity than anticipated with the recommended dose level being tirapazamine 260 mg/m and cisplatin 30 mg/m. Further study of this weekly schedule is not warranted.
Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Female; Humans; Middle Aged; Neoplasms, Squamous Cell; Tirapazamine; Triazines; Uterine Cervical Neoplasms
PubMed: 20606530
DOI: 10.1111/IGC.0b013e3181dc827e -
Clinical Cancer Research : An Official... Oct 2003Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells and has supra-additive toxicity with platinums and... (Clinical Trial)
Clinical Trial
PURPOSE
Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells and has supra-additive toxicity with platinums and taxanes in preclinical studies. We conducted a Phase I study of tirapazamine, carboplatin, and paclitaxel and assessed potential plasma markers of hypoxia as surrogates for response.
EXPERIMENTAL DESIGN
Forty-two patients with advanced solid tumors were treated at four dose levels; parallel dose escalations were carried out in chemotherapy-naive and previously treated subjects. Pre and post-therapy plasma levels of the hypoxia-induced proteins plasminogen activator inhibitor-1 and vascular endothelial growth factor were measured.
RESULTS
Three of four chemotherapy-naïve patients developed dose-limiting toxicities at dose level 4 (grade 3 stomatitis/infection, grade 3 emesis, and grade 4 febrile neutropenia). Four of seven previously treated patients developed dose-limiting toxicities at dose level 3, including one death [grade 3 myalgia, grade 3 infection/grade 4 neutropenia, grade 3 infection/grade 4 neutropenia, and grade 5 infection (death)/grade 4 neutropenia]. Of 38 patients assessable for response, 3 had a complete response, 1 a partial response, 1 an unconfirmed partial response, and 23 had stable disease in at least one evaluation; 10 quickly progressed. One complete responder had normalization of vascular endothelial growth factor and plasminogen activator inhibitor-1 levels.
CONCLUSION
Dose levels 3 (carboplatin AUC of 6, 225 mg/m(2) paclitaxel, and 330 mg/m(2) tirapazamine) and 2 (carboplatin AUC 6, 225 mg/m(2) paclitaxel, and 260 mg/m(2) tirapazamine) are the maximum tolerated doses for chemotherapy naive and patients treated previously, respectively. Dose level 3 is the experimental arm of a Phase III Southwest Oncology Group trial (S0003) in advanced non-small cell lung cancer. Potential markers of tumor hypoxia may be useful correlates in studies of hypoxic cytotoxins and are being prospectively investigated in S0003.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cell Hypoxia; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Paclitaxel; Plasminogen Activator Inhibitor 1; Tirapazamine; Triazines; Vascular Endothelial Growth Factor A
PubMed: 14555506
DOI: No ID Found -
Advanced Materials (Deerfield Beach,... Aug 2023Inducing immunogenic cell death (ICD) by sonodynamic therapy (SDT) is promising for cancer immunotherapy, which however is inefficient due to oxygen depletion that...
Inducing immunogenic cell death (ICD) by sonodynamic therapy (SDT) is promising for cancer immunotherapy, which however is inefficient due to oxygen depletion that compromises SDT effect and mediates recruitment of immunosuppressive myeloid-derived suppressor cells (MDSCs). The fabrication of sono-activatable semiconducting polymer nanopartners (SPN ) to simultaneously augment ICD and alleviate MDSCs for immunotherapy is reported. A sonodynamic semiconducting polymer, hydrophobic hypoxia-responsive tirapazamine (TPZ)-conjugate, and MDSC-targeting drug (ibrutinib) are encapsulated inside such SPN with surface shell of a singlet oxygen ( O )-cleavable amphiphilic polymer. TPZ and ibrutinib serve as drug partners to enlarge immunotherapeutic effect. Upon sono-activation, SPN generate O to break O -cleavable polymers for in situ liberations of TPZ-conjugate and ibrutinib in tumor sites, and oxygen is consumed to create severe hypoxic tumor microenvironment, in which, TPZ-conjugate is activated for augmenting ICD action, while ibrutinib alleviates MDSCs for promoting antitumor immunological effect. In a bilateral tumor mouse model, SPN -mediated sono-activatable immunotherapy results in growth restraints of primary and distant tumors and noteworthy precaution of tumor metastases. This study thus provides a sono-activatable immunotherapeutic strategy with high precision and safety for cancer via overcoming post-treatment hypoxia and targeting MDSCs.
Topics: Animals; Mice; Myeloid-Derived Suppressor Cells; Polymers; Immunogenic Cell Death; Neoplasms; Tirapazamine; Immunotherapy; Hypoxia; Oxygen; Tumor Microenvironment; Cell Line, Tumor
PubMed: 37165741
DOI: 10.1002/adma.202302508 -
Biomaterials Science May 2020In the present work, a copper-tirapazamine (TPZ) nanocomplex [Cu(TPZ)] was synthesized for selective hypoxia-targeted therapy. The nanocomplex revealed a crystalline...
Enhanced selectivity, cellular uptake, and in vitro activity of an intrinsically fluorescent copper-tirapazamine nanocomplex for hypoxia targeted therapy in prostate cancer.
In the present work, a copper-tirapazamine (TPZ) nanocomplex [Cu(TPZ)] was synthesized for selective hypoxia-targeted therapy. The nanocomplex revealed a crystalline form, and exhibited higher lipophilicity, compared to TPZ. Furthermore, its stability was confirmed in different media, with minimum dissociation in serum (∼20% up to 72 h). In contrast to other hypoxia-targeted agents, our intrinsically fluorescent nanocomplex offered an invaluable tool to monitor its cellular uptake and intracellular distribution under both normoxia and hypoxia. The conferred higher cellular uptake of the nanocomplex, especially under hypoxia, and its biocompatible reductive potential resulted in superior hypoxia selectivity in two prostate cancer (PC) cell lines. More promisingly, the nanocomplex showed higher potency in three-dimensional tumor spheroids, compared to TPZ, due to its slower metabolism, and probably deeper penetration in tumor spheroids. Interestingly, the nuclear localization of the intact nanocomplex, combined with its higher DNA binding affinity, as evidenced by the DNA binding assay, resulted in significant S-phase cell-cycle arrest, followed by apoptosis in the three-dimensional spheroid model. In conclusion, the presented findings suggested that the Cu(TPZ) nanocomplex can be a promising hypoxia-targeted therapeutic, which could potentiate the efficacy of the existing chemo- and radiotherapy in PC.
Topics: Antineoplastic Agents; Biological Transport; Copper; DNA; Humans; Hypoxia; Male; Nanoparticles; Prostatic Neoplasms; Radiation-Sensitizing Agents; Spheroids, Cellular; Tirapazamine; Tumor Cells, Cultured
PubMed: 32236169
DOI: 10.1039/c9bm01905g -
International Journal of Radiation... Nov 1998To evaluate the efficacy and toxicity of tirapazamine, a hypoxic cytotoxin, combined with conventional radiotherapy (RT) for advanced head and neck carcinomas. (Clinical Trial)
Clinical Trial
PURPOSE
To evaluate the efficacy and toxicity of tirapazamine, a hypoxic cytotoxin, combined with conventional radiotherapy (RT) for advanced head and neck carcinomas.
MATERIALS AND METHODS
From Oct. 1994 to Nov. 1996, 40 patients with stage III or IV carcinomas of the head and neck were enrolled in a Phase II trial to receive conventional RT (70 Gy in 7 weeks) with concurrent tirapazamine (159 mg/m2 intravenously, 3 times per week for 12 doses). One patient subsequently withdrew from the protocol treatment, and was excluded from analyses. Among the 39 cases, the primary sites were located in the oropharynx (n = 28), supraglottic larynx (n = 6), or hypopharynx (n = 5). Twenty-seven patients had T3 or T4, and 27 had N2 or N3 disease.
RESULTS
Thirty-two (82%) patients received full 12 drug doses. Thirty-two patients (82%) received full 70 Gy of RT. The most frequent drug toxicities were muscle cramps (77%) and nausea/vomiting (62%), usually grade 1 or 2. Overall, 13 patients (33%) experienced grade 3 or 4 drug-related toxicities. No excessive RT-associated acute normal tissue reactions were observed. With a median follow-up of 13 months, the 1-year and 2-year local control rate was 64% and 59% respectively.
CONCLUSION
The tirapazamine regimen was well tolerated with a compliance rate of 82%. The toxicity of RT with concurrent tirapazamine was acceptable in treating advanced head and neck carcinomas. The disease control trend was encouraging. Further clinical studies are warranted.
Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Follow-Up Studies; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neoplasm Staging; Radiation-Sensitizing Agents; Radiotherapy Dosage; Tirapazamine; Triazines
PubMed: 9845102
DOI: 10.1016/s0360-3016(98)00310-1 -
Radiation Oncology Investigations 1997Tirapazamine, a new bioreductive agent currently advancing through clinical trials, may have a valuable role to play in cancer therapy. In vitro, the drug shows markedly...
Tirapazamine, a new bioreductive agent currently advancing through clinical trials, may have a valuable role to play in cancer therapy. In vitro, the drug shows markedly more toxicity to hypoxic cells than to aerobic cells, and preferential activity against hypoxic cells of solid tumors in vivo also can be inferred in many investigations. However, we have previously reported that tirapazamine has minimal activity against cells in the center of hypoxic spheroids, raising concerns with regard to whether the drug may be bioreductively inactivated before reaching chronically hypoxic tumor cells. We consequently examined the oxygen-dependent differential activity of tirapazamine in solid tumors in vivo by using fluorescence-activated cell sorting with clonogenicity assays for cell viability or with the comet assay for DNA damage. The preferential activity of tirapazamine against hypoxic vs. aerobic tumor cells in vivo was approximately threefold, much less than the factors of 50-500 typically seen in vitro. Interestingly, we also found that tirapazamine administration often modified tumor blood flow in the murine models, an effect that could be of clinical utility in sufficiently sensitive tumor cells. Taken together, our observations suggest that sequencing of tirapazamine with other agents requires careful consideration in the clinic.
Topics: Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Hypoxia; Cell Separation; Cell Survival; Drug Screening Assays, Antitumor; Flow Cytometry; Mice; Mice, SCID; Neoplasm Transplantation; Tirapazamine; Triazines
PubMed: 9372543
DOI: 10.1002/(SICI)1520-6823(1997)5:5<213::AID-ROI1>3.0.CO;2-0 -
International Journal of Radiation... Jan 2001To determine if the observed tirapazamine (TPZ)-cisplatin synergistic cell kill was mediated at the cellular level by impairment of upregulation of key proteins involved...
PURPOSE
To determine if the observed tirapazamine (TPZ)-cisplatin synergistic cell kill was mediated at the cellular level by impairment of upregulation of key proteins involved in repair of DNA interstrand crosslinks. Cisplatin sensitivity has been shown to be dependent on the expression of the two DNA repair proteins ERCC1 and XPA. ERCC1 expression has also been shown to be upregulated by cisplatin exposure. Therefore, these studies were undertaken to determine if hypoxia-activated TPZ pretreatment inhibited the cells' normal protective response to cisplatin via inhibiting the upregulation of ERCC1 and/or XPA expression.
METHODS AND MATERIALS
Two different cell lines, one cisplatin sensitive and one cisplatin resistant, were treated with TPZ, cisplatin, both drugs together (which results in additive cytotoxicity), or TPZ followed by cisplatin (which results in synergistic cytotoxicity). All cells were exposed to 1 h of hypoxia to bioactivate the TPZ. Expression of ERCC1 and XPA were evaluated at the mRNA and protein level at 24 or 48 h after drug exposure.
RESULTS
In the cisplatin-sensitive non-small-cell lung cancer cell line, ERCC1 expression at the mRNA or protein level was not significantly altered in any of the treatment groups. In the cisplatin-resistant ovarian cancer cell line, ERCC1 expression was upregulated by TPZ, but not by cisplatin alone. The change in protein expression was less pronounced than the change in mRNA level. XPA expression was not significantly changed from baseline in either cell line at the mRNA or protein level.
CONCLUSION
In contrast to reports in the literature, this study did not demonstrate cisplatin inducing its own repair by upregulating the DNA crosslink repair proteins ERCC1 or XPA. Therefore, the TPZ-cisplatin synergism cannot be mediated through hypoxia-activated TPZ inhibiting this cellular protective response. TPZ alone, however, was able to alter repair protein expression, which may play a role in mediating its cytotoxicity.
Topics: Antineoplastic Agents; Cell Hypoxia; Cisplatin; DNA Repair; DNA-Binding Proteins; Drug Synergism; Endonucleases; Humans; Proteins; RNA, Messenger; Radiation-Sensitizing Agents; Tirapazamine; Triazines; Tumor Cells, Cultured; Up-Regulation; Xeroderma Pigmentosum Group A Protein
PubMed: 11163512
DOI: 10.1016/s0360-3016(00)01379-1 -
Proceedings of the National Academy of... Oct 2016Transarterial chemoembolization (TACE) is the main treatment for intermediate stage hepatocellular carcinoma (HCC) with Barcelona Clinic Liver Cancer classification...
Transarterial chemoembolization (TACE) is the main treatment for intermediate stage hepatocellular carcinoma (HCC) with Barcelona Clinic Liver Cancer classification because of its exclusive arterial blood supply. Although TACE achieves substantial necrosis of the tumor, complete tumor necrosis is uncommon, and the residual tumor generally rapidly recurs. We combined tirapazamine (TPZ), a hypoxia-activated cytotoxic agent, with hepatic artery ligation (HAL), which recapitulates transarterial embolization in mouse models, to enhance the efficacy of TACE. The effectiveness of this combination treatment was examined in HCC that spontaneously developed in hepatitis B virus X protein (HBx) transgenic mice. We proved that the tumor blood flow in this model was exclusively supplied by the hepatic artery, in contrast to conventional orthotopic HCC xenografts that receive both arterial and venous blood supplies. At levels below the threshold oxygen levels created by HAL, TPZ was activated and killed the hypoxic cells, but spared the normoxic cells. This combination treatment clearly limited the toxicity of TPZ to HCC, which caused the rapid and near-complete necrosis of HCC. In conclusion, the combination of TPZ and HAL showed a synergistic tumor killing activity that was specific for HCC in HBx transgenic mice. This preclinical study forms the basis for the ongoing clinical program for the TPZ-TACE regimen in HCC treatment.
Topics: Animals; Antineoplastic Agents; Biomarkers; Carcinoma, Hepatocellular; Cell Line, Tumor; Combined Modality Therapy; Disease Models, Animal; Dose-Response Relationship, Drug; Hepatic Artery; Humans; Immunohistochemistry; Ligation; Liver Neoplasms; Magnetic Resonance Imaging; Mice; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; Necrosis; Recurrence; Tirapazamine; Trans-Activators; Triazines; Tumor Burden; Viral Regulatory and Accessory Proteins; Xenograft Model Antitumor Assays
PubMed: 27702890
DOI: 10.1073/pnas.1613466113