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Journal of Clinical Oncology : Official... Nov 1998A phase II study was conducted to evaluate the safety and efficacy of tirapazamine combined with cisplatin for the treatment of patients with advanced non-small-cell... (Clinical Trial)
Clinical Trial
PURPOSE
A phase II study was conducted to evaluate the safety and efficacy of tirapazamine combined with cisplatin for the treatment of patients with advanced non-small-cell lung cancer (NSCLC).
PATIENTS AND METHODS
Forty-four patients with stage IIIB/IV NSCLC were treated with a combination of tirapazamine and cisplatin. Patients received tirapazamine 260 mg/m2 administered intravenously over 2 hours, followed 1 hour later by cisplatin 75 mg/m2 administered over an additional hour, repeated every 21 days. The duration of therapy was meant to be limited to four cycles for nonresponders and eight cycles for responders.
RESULTS
Ten of 44 patients (23%) showed a partial response. The estimated median survival for all patients was 37 weeks. Toxicities were treatable and included grade 3 nausea or vomiting (25%), fatigue (27.3%), and muscle cramps (4.5%). No dose reductions were necessary.
CONCLUSION
The results show that tirapazamine can safely be added to cisplatin. Both the median survival and response rate observed strongly suggest that tirapazamine with cisplatin is more active than cisplatin alone.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Drug Administration Schedule; Female; Humans; Lung Neoplasms; Male; Middle Aged; Survival Analysis; Tirapazamine; Treatment Outcome; Triazines
PubMed: 9817270
DOI: 10.1200/JCO.1998.16.11.3524 -
Biomaterials Sep 2024It is imperative to optimize chemotherapy for heightened anti-tumor therapeutic efficacy. Unrestrained tumor cell proliferation and sustained angiogenesis are pivotal...
It is imperative to optimize chemotherapy for heightened anti-tumor therapeutic efficacy. Unrestrained tumor cell proliferation and sustained angiogenesis are pivotal for cancer progression. Plinabulin, a vascular disrupting agent, selectively destroys tumor blood vessels. Tirapazamine (TPZ), a hypoxia-activated prodrug, intensifies cytotoxicity in diminishing oxygen levels within tumor cells. Despite completing Phase III clinical trials, both agents exhibited modest treatment efficiency due to dose-limiting toxicity. In this study, we employed methoxy poly(ethylene glycol)-b-poly(-lactide) (mPEG-b-PDLLA) to co-deliver Plinabulin and TPZ to the tumor site, concurrently disrupting blood vessels and eliminating tumor cells, addressing both symptoms and the root cause of tumor progression. Plinabulin was converted into a prodrug with esterase response (PSM), and TPZ was synthesized into a hexyl chain-containing derivative (TPZHex) for effective co-delivery. PSM and TPZHex were co-encapsulated with mPEG-b-PDLLA, forming nanodrugs (PT-NPs). At the tumor site, PT-NPs responded to esterase overexpression, releasing Plinabulin, disrupting blood vessels, and causing nutritional and oxygen deficiency. TPZHex was activated in response to increased hypoxia, killing tumor cells. In treating 4T1 tumors, PT-NPs demonstrated enhanced therapeutic efficacy, achieving a 92.9 % tumor suppression rate and a 20 % cure rate. This research presented an innovative strategy to enhance synergistic efficacy and reduce toxicity in combination chemotherapy.
Topics: Tirapazamine; Animals; Cell Line, Tumor; Humans; Polyethylene Glycols; Antineoplastic Agents; Female; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; Triazines; Diketopiperazines
PubMed: 38718615
DOI: 10.1016/j.biomaterials.2024.122586 -
International Journal of Antimicrobial... Sep 2023Escherichia coli is an important pathogen responsible for numerous cases of diarrhoea worldwide. The bioreductive agent tirapazamine (TPZ), which was clinically used to...
OBJECTIVES
Escherichia coli is an important pathogen responsible for numerous cases of diarrhoea worldwide. The bioreductive agent tirapazamine (TPZ), which was clinically used to treat various types of cancers, has obvious antibacterial activity against E. coli strains. In the present study, we aimed to evaluate the protective therapeutic effects of TPZ in E. coli-infected mice and provide insights into its antimicrobial action mechanism.
METHODS
The MIC and MBC tests, drug sensitivity test, crystal violet assay and proteomic analysis were used to detect the in vitro antibacterial activity of TPZ. The clinical symptoms of infected mice, tissue bacteria load, histopathological features and gut microbiota changes were regarded as indicators to evaluation the efficacy of TPZ in vivo.
RESULTS
Interestingly, TPZ-induced the reversal of drug resistance in E. coli by regulating the expression of resistance-related genes, which may have an auxiliary role in the clinical treatment of drug-resistant bacterial infections. More importantly, the proteomics analysis showed that TPZ upregulated 53 proteins and downregulated 47 proteins in E. coli. Among these, the bacterial defence response-related proteins colicin M and colicin B, SOS response-related proteins RecA, UvrABC system protein A, and Holliday junction ATP-dependent DNA helicase RuvB were all significantly upregulated. The quorum sensing-related protein glutamate decarboxylase, ABC transporter-related protein glycerol-3-phosphate transporter polar-binding protein, and ABC transporter polar-binding protein YtfQ were significantly downregulated. The oxidoreductase activity-related proteins pyridine nucleotide-disulfide oxidoreductase, glutaredoxin 2 (Grx2), NAD(+)-dependent aldehyde reductase, and acetaldehyde dehydrogenase, which participate in the elimination of harmful oxygen free radicals in the oxidation-reduction process pathway, were also significantly downregulated. Moreover, TPZ improved the survival rate of infected mice; significantly reduced the bacteria load in the liver, spleen, and colon; and alleviated E. coli-associated pathological damages. The gut microbiota also changed in TPZ-treated mice, and these genera were considerably differentiated: Candidatus Arthromitus, Eubacterium coprostanoligenes group, Prevotellaceae UCG-001, Actinospica, and Bifidobacterium.
CONCLUSIONS
TPZ may represent an effective and promising lead molecule for the development of antimicrobial agents for the treatment of E. coli infections.
Topics: Animals; Mice; Tirapazamine; Escherichia coli; Antineoplastic Agents; Triazines; Proteomics; Oxidoreductases; Anti-Bacterial Agents
PubMed: 37433388
DOI: 10.1016/j.ijantimicag.2023.106923 -
Radiation Oncology Investigations 1999Malignant gliomas remain refractory to intensive radiotherapy and cellular hypoxia enhances clinical radioresistance. Under hypoxic conditions, the benzotriazine...
Malignant gliomas remain refractory to intensive radiotherapy and cellular hypoxia enhances clinical radioresistance. Under hypoxic conditions, the benzotriazine di-N-oxide (3-amino-1,2,4-benzotriazine 1,4-dioxide) (tirapazamine) is reduced to yield a free-radical intermediate that results in DNA damage and cellular death. For extracranial xenografts, tirapazamine treatments have shown promise. We therefore incorporated tirapazamine into the synthetic, biodegradable polymer, measured the release, and tested the efficacy both alone and in combination with external beam radiotherapy in the treatment of experimental intracranial human malignant glioma xenografts. The [(poly(bis(p-carboxyphenoxy)-propane) (PCPP):sebacic acid (SA) (PCPP:SA ratio 20:80)] polymer was synthesized. The PCPP:SA polymer and solid tirapazamine were combined to yield proportions of 20% or 30% (wt/wt). Polymer discs (3 x 2 mm) (10 mg) were incubated (PBS, 37 degrees C), and the proportion of the drug released vs. time was recorded. Male nu/nu nude mice were anesthetized and received intracranial injections of 2 x 10(5) U251 human malignant glioma cells. For single intraperitoneal (i.p.) drug and/or external radiation treatments, groups of mice had i.p. 0.3 mmol/kg tirapazamine, 5 Gy cranial irradiation, or combined treatments on day 8 after inoculation. For fractionated drug and radiation treatments, mice had i.p. 0.15 mmol/kg tirapazamine, 5 Gy radiation, or combined treatments on days 8 and 9 after inoculation. For intracranial (i.c.) polymer treatments, mice had craniectomies and intracranial placement of polymer discs at the site of cellular inoculation. The maximally tolerated percentage loading of tirapazamine in the polymer.disc was determined. On day 7 after inoculation, groups of mice had i.c. empty or 3% tirapazamine alone or combined with radiation (5 Gy x 2 doses) or combined with i.p. drug (0.15 mmol/kg x 2 doses on days 8 and 9). Survival was recorded. Polymers showed controlled, protracted in vitro release for over 100 days. The 5 Gy x 1 treatment resulted in improved survival; 28.5 +/- 3.7 days (P = 0.01 vs. controls), while the single i.p. 0.3 mmol/kg tirapazamine treatment, 17.5 +/- 1.9 days (P = NS) and combined treatments; 21.5 +/- 5.0 days (P = NS) were not different. The fractionated treatments: 5 Gy x 2, i.p. 0.15 mmol/kg tirapazamine x 2 and the combined treatments resulted in improved survival: 44.5 +/- 3.9 (P < 0.001), 24.5 +/- 2.3 (P = 0.05) and 50.0 +/- 6.0 (P < 0.001), respectively. Survival after intracranial empty polymer was 16.5 +/- 3.0 days and increased to 31.0 +/- 3.0 (P = 0.003) days when combined with the 5 Gy x 2 treatment. The survival after the polymer bearing 3% tirapazamine alone vs. combined with radiation was not different. The combined 3% tirapazamine polymer, i.p. tirapazamine, and radiation treatments resulted in both early deaths and the highest long-term survivorship. The basis for potential toxicity is discussed. We conclude that implantable biodegradable polymers provide controlled intracranial release for treatment of experimental glioma. For treatment of malignant gliomas, the combination of continuous polymer-mediated delivery and fractionated systemic delivery of tirapazamine with external beam radiotherapy warrants further exploration.
Topics: Absorbable Implants; Animals; Antineoplastic Agents; Brain Neoplasms; Decanoic Acids; Drug Carriers; Drug Implants; Glioma; Humans; Male; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; Polyesters; Tirapazamine; Treatment Outcome; Triazines; Tumor Cells, Cultured
PubMed: 10492162
DOI: 10.1002/(SICI)1520-6823(1999)7:4<218::AID-ROI3>3.0.CO;2-C -
Investigational New Drugs Jun 2021Background Tirapazamine's (TPZ) tolerability after an intra-arterial (IA) injection remains unclear. We investigated TPZ's safety and tolerability in rats by first...
Background Tirapazamine's (TPZ) tolerability after an intra-arterial (IA) injection remains unclear. We investigated TPZ's safety and tolerability in rats by first injecting into the left hepatic artery and then performing a hepatic artery ligation, which recapitulates the transarterial embolization used clinically. Research design and methods: Forty-six rats in five groups were respectively injected with 0, 0.25, 0.50, 1.0, or more than 1.5 mL IA of TPZ (0.7 mg/mL) into the left hepatic artery and then subjected to hepatic artery ligation under laparotomy. Blood samples were collected four times daily up to day 15 after which the rats were euthanized and necropsied. The toxicity profile of IA injection of TPZ followed by hepatic artery ligation was then assessed. Results No significant changes to the rats' body weight and serum total bilirubin were observed. Serum alanine aminotransferase (ALT) levels increased slightly but remained below 100 U/L one day after treatment for most rats. Three rats in Groups 3 and 4 exhibited an over two-fold transient elevation of ALT. All ALT recovered to the baseline at day 14. Liver tissues were collected on day 15 using H&E staining. One rat in Group 3 showed ischemic coagulative necrosis in its liver tissue. Other sporadic pathological changes not related to TPZ doses were observed in Groups 2, 3, 4, and 5. Conclusion TPZ by IA injection followed by embolization is tolerated up to 7 mg/kg. This finding supports the strategy of administering an IA injection of TPZ followed by trans-arterial embolization to the liver.
Topics: Alanine Transaminase; Animals; Antineoplastic Agents; Bilirubin; Female; Hepatic Artery; Injections, Intra-Arterial; Ligation; Liver; Male; Rats; Tirapazamine; Tumor Hypoxia
PubMed: 33428079
DOI: 10.1007/s10637-020-01057-3 -
International Journal of Pharmaceutics Jul 2012Combination of tirapazamine (TPZ) with cisplatin has been studied extensively in clinical trial for tumor therapy. However, in phase III clinical trial, the combination...
Combination of tirapazamine (TPZ) with cisplatin has been studied extensively in clinical trial for tumor therapy. However, in phase III clinical trial, the combination therapy did not show overall survival improvement in patients. To decrease the side effects and increase the efficacy of the combination therapy, TPZ was conjugated with transferrin (Tf-G-TPZ) for targeted delivery and co-administered with cisplatin. In vitro toxicity study showed that the combination of Tf-G-TPZ with cisplatin induced substantially higher cytotoxicity of tumor cells than the combination of TPZ and cisplatin. After Tf-G-TPZ was intravenously injected into tumor-bearing mice, its total accumulation in tumor was 2.3 fold higher than that of the unmodified TPZ, suggesting transferrin-mediated target delivery of TPZ into the tumor tissue. With the increased accumulation of Tf-G-TPZ in tumor, the synergistic anti-tumor effects of Tf-G-TPZ and cisplatin were also enhanced as showed by the 53% tumor inhibition rate. Meanwhile, the side effects such as body weight lost were not significantly increased. Therefore, Tf-G-TPZ holds great promise to a better substitute for TPZ in the combination therapy with cisplatin.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Cisplatin; Humans; Hydrogen-Ion Concentration; Male; Mice; Neoplasm Transplantation; Neoplasms; Tirapazamine; Transferrin; Triazines; Tumor Burden
PubMed: 22531857
DOI: 10.1016/j.ijpharm.2012.04.032 -
British Journal of Cancer Apr 1995Previously we showed that tirapazamine (SR 4233, Win 59075) is cytotoxic towards hepatocytes under conditions of hypoxia but not in 10% or 95% oxygen and that...
Previously we showed that tirapazamine (SR 4233, Win 59075) is cytotoxic towards hepatocytes under conditions of hypoxia but not in 10% or 95% oxygen and that bioreduction by DT-diaphorase or cytochrome P450 is not a major pathway. In the present study, we report that tirapazamine is highly cytotoxic to isolated rat hepatocytes maintained under 1% oxygen and the molecular cytotoxic mechanism has been elucidated. Cytotoxicity was prevented by the cytochrome P450 2E1 inhibitors phenyl imidazole, isoniazid, isopropanol or ethanol, suggesting that cytochrome P450 2E1 catalysed tirapazamine reductive bioactivation. By contrast, dicoumarol, a DT-diaphorase inhibitor, markedly increased tirapazamine-induced cytotoxicity. Cytotoxicity was also inhibited in normal but not DT-diaphorase-inactivated hepatocytes by increasing cellular NADH levels with lactate or ethanol or the mitochondrial respiratory inhibitors. Evidence that oxygen activation contributed to cytotoxicity was that glutathione oxidation occurred well before cytotoxicity ensued and that tirapazamine was more cytotoxic towards catalase- or glutathione reductase-inactivated hepatocytes. Furthermore, polyphenolic antioxidants such as quercetin, caffeic acid or purpurogallin, the radical trap Tempol or the iron chelator desferrioxamine prevented tirapazamine-mediated cytotoxicity. However, the antioxidants diphenylphenylenediamine, butylated hydroxyanisole or butylated hydroxytoluene did not prevent cytotoxicity and malonaldehyde formation was not increased, suggesting that lipid peroxidation was not important. The above results suggest that DT-diaphorase detoxifies tirapazamine whereas reduced cytochrome P450 reduces tirapazamine to a nitrogen oxide anion radical which forms cytotoxic reactive oxygen species as a result of redox cycling.
Topics: Animals; Antineoplastic Agents; Antioxidants; Cell Hypoxia; Cell Survival; Cells, Cultured; Cytochrome P-450 CYP2E1; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Electron Transport; Kinetics; Liver; Male; Mitochondria, Liver; NAD(P)H Dehydrogenase (Quinone); Oxidoreductases, N-Demethylating; Radiation-Protective Agents; Rats; Rats, Sprague-Dawley; Tirapazamine; Triazines
PubMed: 7710944
DOI: 10.1038/bjc.1995.151 -
Chinese Journal of Cancer Feb 2014Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain... (Review)
Review
Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct classes of bioreactive prodrugs have been developed to target hypoxic cells in solid tumors. These hypoxia-activated prodrugs, including nitro compounds, N-oxides, quinones, and metal complexes, generally share a common mechanism of activation whereby they are reduced by intracellular oxidoreductases in an oxygen-sensitive manner to form cytotoxins. Several examples including PR-104, TH-302, and EO9 are currently undergoing phase II and phase III clinical evaluation. In this review, we discuss the nature of tumor hypoxia as a therapeutic target, focusing on the development of bioreductive prodrugs. We also describe the current knowledge of how each prodrug class is activated and detail the clinical progress of leading examples.
Topics: Anthraquinones; Antineoplastic Agents; Aziridines; Cell Hypoxia; Humans; Indolequinones; Molecular Structure; NAD(P)H Dehydrogenase (Quinone); Neoplasms; Nitrogen Mustard Compounds; Nitroimidazoles; Phosphoramide Mustards; Prodrugs; Tirapazamine; Triazines
PubMed: 23845143
DOI: 10.5732/cjc.012.10285 -
Annals of Oncology : Official Journal... 1999Tirapazamine (TPZ), a new anti-cancer drug activated to a toxic free radical under hypoxic conditions, produces a tumor specific potentiation of cell kill by cisplatin....
BACKGROUND
Tirapazamine (TPZ), a new anti-cancer drug activated to a toxic free radical under hypoxic conditions, produces a tumor specific potentiation of cell kill by cisplatin. In the present study we discuss the mechanism and clinical potential of this effect, as well as investigate the influence of p53 mutations on the activity of TPZ.
MATERIALS AND METHODS
For in vitro experiments we have used mouse SCCVII tumor cells, minimally transformed mouse embryo fibroblasts (MEFs) from wild-type and p53 knockout mice, and several human NSCLC cell lines. For in vivo experiments we have used RIF-1 tumors implanted subcutaneously into C3H mice.
RESULTS
Prior injection of TPZ into tumor-bearing mice markedly potentiated tumor cell kill by cisplatin, but produced no effect on systemic toxicity. The maximum potentiation occurred when TPZ was injected two to three hours prior to cisplatin administration. Experiments performed with cells in vitro showed a similar synergistic interaction between the two drugs when cells were exposed to TPZ under hypoxic conditions prior to exposure to cisplatin. Experiments with MEFs from either p53 wild-type or p53-knockout mice showed no influence of p53 on the sensitivity of cells to killing by TPZ under hypoxia. A similar lack of influence of p53 on the toxicity to TPZ was obtained for a panel of NSCLC cell lines.
CONCLUSIONS
TPZ is a novel anticancer drug that produces tumor selective potentiation of cisplatin and carboplatin in both pre-clinical and clinical studies. The fact that the drug produces no potentiation of the systemic side effects of these drugs, or of other anticancer drugs used in combination with platinum in NSCLC, suggests that TPZ could become a useful agent in the treatment of lung cancer.
Topics: Animals; Antineoplastic Agents; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cell Death; Cisplatin; Drug Interactions; Genes, p53; Humans; Hypoxia; Lung Neoplasms; Mice; Mice, Knockout; Tirapazamine; Transplantation, Heterologous; Triazines; Tumor Cells, Cultured
PubMed: 10582136
DOI: 10.1093/annonc/10.suppl_5.s29 -
Clinical Lung Cancer Mar 2005This phase I/II study was conducted to evaluate the safety and efficacy of tirapazamine in combination with cisplatin and vinorelbine for patients with advanced-stage... (Clinical Trial)
Clinical Trial
This phase I/II study was conducted to evaluate the safety and efficacy of tirapazamine in combination with cisplatin and vinorelbine for patients with advanced-stage IIIB/IV chemonaive non-small-cell lung cancer. Seventy patients with a Karnofsky performance status of > or = 60% were included. In the phase I part of the study, 21 patients were treated on day 1 with tirapazamine (escalating doses of 260, 330, or 390 mg/m(2)), cisplatin (75 or 100 mg/m(2)), and vinorelbine (25 or 30 mg/m(2)) for a maximum of 6 cycles every 4 weeks. Vinorelbine was repeated every week. In the phase II part of the study, 49 patients were treated on day 1 with tirapazamine 390 mg/m(2), cisplatin 100 mg/m(2), and vinorelbine 30 mg/m(2). The maximum tolerated dose was not reached. Muscle cramps, vomiting, nausea, tinnitus, neutropenia, and diarrhea were the most frequently reported adverse events in the phase I part of the study. Most of these events were grade 1 or 2. In the phase II part of the study, response rate was 47%, and median survival was 50 weeks. The most frequently reported adverse event was neutropenia. Asthenia, fever, anemia, vomiting, weight decrease, nausea, and muscle cramps were also noted. For patients treated at the maximum dose, dose reductions occurred 14% of tirapazamine cycles and in 4% of cisplatin cycles. The median number of cycles was 3. This regimen has a manageable toxicity profile. Response rate and median survival suggest that this combination might be more active than the cisplatin/vinorelbine combination. This triplet is currently being evaluated in a phase III study.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Female; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Survival Analysis; Tirapazamine; Treatment Outcome; Triazines; Vinblastine; Vinorelbine
PubMed: 15845180
DOI: 10.3816/clc.2005.n.008