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British Journal of Cancer Jun 1998Tirapazamine is a novel bioreductive agent with selective cytotoxicity against hypoxic tumour cells. Synergy with cisplatin and other chemotherapeutic agents has been... (Review)
Review
Tirapazamine is a novel bioreductive agent with selective cytotoxicity against hypoxic tumour cells. Synergy with cisplatin and other chemotherapeutic agents has been shown in preclinical trials. Pharmacokinetic studies of tirapazamine have revealed that exposure increases with dose over the range of 18-450 mg m(-2) for a single dose and of 9-390 mg m(-2) for multiple doses. Plasma clearance is high. Tirapazamine has been clinically tested in combination with cisplatin at escalating doses in a phase I trial and at therapeutic doses in three separate phase II trials in patients with advanced non-small-cell lung cancer (NSCLC) in 11 study centres. Limiting toxicity for tirapazamine at an intravenous dose of 390 mg m(-2) was acute, reversible hearing loss. Other frequently observed side-effects included muscle cramping and gastrointestinal symptoms. Tirapazamine did not cause myelosuppression, and no toxic deaths were reported in these trials. The anti-tumour efficacy against previously untreated, advanced NSCLC was evaluated by cumulative intent-to-treat analysis of 132 patients. The objective response rate (confirmed by two independent measurements) was 25% [confidence interval (CI) 17.8-33.33], with a median survival of 38.9 weeks (CI 29.4-49.9). The efficacy of tirapazamine plus cisplatin shown in these trials was better than that of historical controls with cisplatin monotherapy. Two large-scale international trials have been conducted, involving more than 70 centres, to confirm these results. The CATAPULT I trial compares tirapazamine plus cisplatin with cisplatin and has finished accrual with 446 patients. The CATAPULT II trial, which is comparing tirapazamine plus cisplatin with etoposide plus cisplatin, had enrolled 550 patients by June 1997. Follow-up is ongoing. Tirapazamine is the promising first drug from a new class of cytotoxic agents with a novel mechanism of action. It can be effectively combined with cisplatin, and possibly with other agents, because of its safety profile and lack of overlapping dose-limiting toxicity, such as myelosuppression. The combination of tirapazamine and cisplatin appears to be safe and effective in the treatment of NSCLC.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Synergism; Humans; Lung Neoplasms; Multicenter Studies as Topic; Tirapazamine; Triazines
PubMed: 9647615
DOI: 10.1038/bjc.1998.431 -
Current Clinical Pharmacology Jan 2006Tumour hypoxia continues to remain one of the greatest challenges in the treatment of solid tumours. An important avenue to follow with both radiotherapy and... (Review)
Review
Tumour hypoxia continues to remain one of the greatest challenges in the treatment of solid tumours. An important avenue to follow with both radiotherapy and chemotherapy is the development of hypoxic cytotoxins such as tirapazamine. The present review covers the history of tirapazamine from preclinical models to clinical trials. The biochemistry as well as the pharmacokinetics of this bioreductive agent are presented. Laboratory data demonstrating the enhanced effect of radiation and cisplatin when combined with tirapazamine are also discussed. There is considerable evidence supporting the potentiation of anti-tumour effect of cisplatin by tirapazamine. Several clinical trials for various tumour sites have been testing the synergistic effect of cisplatin-tirapazamine with and without radiotherapy. These are also reviewed in the present paper. The current literature data on tirapazamine leaves unanswered questions about its action and toxicity. While the current number of phase III trials limits comprehensive conclusions about the administration of this drug, there is a unanimous indication that further clinical studies are warranted.
Topics: Antineoplastic Agents; Cisplatin; Clinical Trials as Topic; Humans; Neoplasms; Radiation-Sensitizing Agents; Tirapazamine; Triazines
PubMed: 18666379
DOI: 10.2174/157488406775268192 -
Expert Opinion on Investigational Drugs Dec 2000Tirapazamine is the second clinical anticancer drug (after porfiromycin) that functions primarily as a hypoxia-selective cytotoxin. Hypoxic cells in tumours are... (Review)
Review
Tirapazamine is the second clinical anticancer drug (after porfiromycin) that functions primarily as a hypoxia-selective cytotoxin. Hypoxic cells in tumours are relatively resistant to radiotherapy and to some forms of chemotherapy and are also biologically aggressive, thus representing an important target population in oncology. Tirapazamine undergoes metabolism by reductases to form a transient oxidising radical that can be efficiently scavenged by molecular oxygen in normal tissues to re-form the parent compound. In the absence of oxygen, the oxidising radical abstracts a proton from DNA to form DNA radicals, largely at C4' on the ribose ring. Tirapazamine can also oxidise such DNA radicals to cytotoxic DNA strand breaks. It therefore shows substantial selective cytotoxicity for anoxic cells in culture (typically approximately 100-fold more potent than under oxic conditions) and for the hypoxic subfraction of cells in tumours. Preclinical studies showed enhanced activity of combinations of tirapazamine with radiation (to kill oxygenated cells) and with conventional cytotoxics, especially cisplatin (probably through inhibition of repair of cisplatin DNA cross-links in hypoxic cells). Phase II and III clinical studies of tirapazamine and cisplatin in malignant melanoma and non-small cell lung cancer suggest that the combination is more active than cisplatin alone and preliminary results with advanced squamous cell carcinomas of the head and neck indicate that tirapazamine may enhance the activity of cisplatin with fractionated radiotherapy.
Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Humans; Neoplasms; Tirapazamine; Triazines
PubMed: 11093359
DOI: 10.1517/13543784.9.12.2889 -
Expert Opinion on Investigational Drugs Jan 2009Tumor hypoxia remains one of the greatest challenges in the treatment of solid tumors, as cancer cells in these regions are resistant to killing by radiation therapy and... (Review)
Review
BACKGROUND
Tumor hypoxia remains one of the greatest challenges in the treatment of solid tumors, as cancer cells in these regions are resistant to killing by radiation therapy and most anticancer drugs. Tirapazamine (TPZ) is a newer class of cytotoxic drugs with selective toxicity towards hypoxic mammalian cells.
OBJECTIVE
This article reviews the mechanism of action, toxicity and antitumor activity of the drug and provides insights into factors that may have contributed to the disappointing results in some of the Phase III trials. It also identifies the need to explore dependable markers of tumor hypoxia and limit future trials of this agent to patients who have significant populations of hypoxic tumor cells.
METHODS
We reviewed all clinical trials published to date and present a summary of the results. There are also several ongoing studies, the results of which are pending and may yet impact the clinical use of the drug.
RESULTS/CONCLUSION
Despite the very promising results obtained in various preclinical studies and early-Phase clinical trials, several Phase III trials have failed to demonstrate any survival benefit of adding TPZ to chemotherapy or radiation therapy in non-small cell lung cancer or head and neck cancer. Several clinical trials have yet to be completed and reported.
Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Clinical Trials as Topic; Humans; Neoplasms; Tirapazamine; Treatment Outcome; Triazines
PubMed: 19053884
DOI: 10.1517/13543780802567250 -
Expert Opinion on Drug Metabolism &... Dec 2012Cervical cancer is the second-most common malignancy in women worldwide. Cisplatin was introduced as a radiosensitizer in 1999 to improve chances of survival. Tumor cell... (Review)
Review
INTRODUCTION
Cervical cancer is the second-most common malignancy in women worldwide. Cisplatin was introduced as a radiosensitizer in 1999 to improve chances of survival. Tumor cell hypoxia, however, remains a major limiting factor in the treatment of solid tumors with chemotherapy and radiation. There has since been significant interest in the use of bioreductive agents to overcome the hypoxia and improve survival. The addition of tirapazamine (TPZ) to conventional chemoradiation protocols in the management of cervical cancer held promise in the initial Phase I and II clinical trials in delaying recurrence and improving survival. However, GOG recently announced early closure of the Phase III trial of tirapazamine in cervical cancer due to a lack of increased survival.
AREAS COVERED
This article covers the definition of hypoxic tumor cells, the markers of tumor hypoxia, methods for measuring hypoxia as well as the pharmacologic action of tirapazamine in hypoxic media. Furthermore, it critically evaluates TPZ's role in cervical cancer treatment and the drawbacks to the GOG study. The authors review all clinical trials published to date with special emphasis on cervical cancer. A systematic review of the literature was also undertaken with PubMed and Ovid.
EXPERT OPINION
Despite the promising results from early clinical trials, it has been shown that the addition of tirapazamine appears to confer no benefits on progression-free or overall survival in patients with cervical cancer. Success in the future will require smaller randomized trials with biologic targets that have acceptable toxicity and efficacy.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Hypoxia; Cisplatin; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Humans; Radiation-Sensitizing Agents; Secondary Prevention; Tirapazamine; Triazines; Uterine Cervical Neoplasms
PubMed: 23033890
DOI: 10.1517/17425255.2012.730518 -
Seminars in Oncology Feb 2002Preclinical models in vitro and in vivo have shown that tumor hypoxia alters the malignant cell phenotype, selecting for p53 mutations, stimulating angiogenesis and... (Review)
Review
Preclinical models in vitro and in vivo have shown that tumor hypoxia alters the malignant cell phenotype, selecting for p53 mutations, stimulating angiogenesis and metastasis, and markedly reducing the efficacy of both radiotherapy and chemotherapy. Similarly, clinical studies measuring pretreatment tumor oxygen status confirm that the presence of hypoxia confers a negative impact on local control, disease-free survival, and overall survival. Despite these data and extensive past research efforts, the promise of developing selective hypoxic-cell sensitizers has been largely unfulfilled. In contrast, tirapazamine is the rationally designed prototype for a new class of therapeutic agents targeting tumor hypoxia: hypoxic cytotoxins. Tirapazamine is bioreductively activated in hypoxic cells and has been shown to potentiate the cytotoxicity of radiation and a number of chemotherapeutic drug classes, in particular platinum compounds and taxanes. This article reviews the preclinical and clinical development of tirapazamine, as well as current trials in non-small cell lung cancer designed to provide proof of principle for this new category of cancer therapeutics.
Topics: Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Interactions; Drug Resistance, Neoplasm; Humans; Hypoxia; Lung Neoplasms; Phenotype; Radiation-Sensitizing Agents; Tirapazamine; Triazines
PubMed: 11894020
DOI: 10.1053/sonc.2002.31531 -
Biochemical and Biophysical Research... Aug 2021Osteosarcoma is the most common primary orthopedic malignant bone tumor in adolescents. However, the traditional neoadjuvant chemotherapy regimen has reached the...
Osteosarcoma is the most common primary orthopedic malignant bone tumor in adolescents. However, the traditional neoadjuvant chemotherapy regimen has reached the bottleneck. TPZ is a hypoxic prodrug that has a powerful anti-tumor effect in the hypoxic microenvironment of tumors. And ferroptosis is a newly discovered cell death in 2012, and ferroptosis inducers have been used in anti-tumor therapy research in recent decades. Though, the role of TPZ and ferroptosis in osteosarcoma remains unclear. The aim of this study was to investigate the role of TPZ in osteosarcoma and the specific mechanism. MTT assay showed the extraordinary inhibition of TPZ on three osteosarcoma cells under hypoxia. And fluorescence of Fe staining was enhanced by TPZ. Western blotting showed decreased expression of SLC7A11 and GPX4. Lipid peroxidation was confirmed by MDA assay and C11 BODIPY 581/591 staining. SLC7A11 overexpression could restored the proliferation and migration abilities inhibited by TPZ. Thus, we for the first time demonstrated that TPZ could inhibit the proliferation and migration of osteosarcoma cells, and induce ferroptosis in part through inhibiting SLC7A11.
Topics: Amino Acid Transport System y+; Antineoplastic Agents; Bone Neoplasms; Cell Line, Tumor; Ferroptosis; Humans; Osteosarcoma; Tirapazamine
PubMed: 34147710
DOI: 10.1016/j.bbrc.2021.06.036 -
Anti-cancer Drug Design Sep 1998Tirapazamine (TPZ, SR 4233, WIN 59075, 3-amino-1,2,4-benzotriazine 1,4-dioxide, Tirazone) is the lead compound in the benzotriazine di-N-oxide class of bioreductive... (Review)
Review
Tirapazamine (TPZ, SR 4233, WIN 59075, 3-amino-1,2,4-benzotriazine 1,4-dioxide, Tirazone) is the lead compound in the benzotriazine di-N-oxide class of bioreductive anticancer agents. Extensive preclinical testing has established that the mechanism for the selective toxicity towards hypoxic cells is the result of a one-electron reduction of the parent molecule to a free radical species that interacts with DNA to produce single- and double-strand breaks and lethal chromosome aberrations. It has also shown activity when combined with fractionated irradiation and when combined with some chemotherapy agents, particularly cisplatin and carboplatin. In this review we address those questions about the drug that are most relevance to the clinical use of the compound. In particular we review the evidence for the mechanism of action of the drug, and also show that a large portion of the synergy seen in experimental tumors when TPZ is combined with cisplatin is the result of a cellular interaction between TPZ and cisplatin that depends on hypoxia. Also of relevance to clinical use is whether the toxicity of TPZ is cumulative such as occurs with nitroimidazoles, another class of hypoxia-activated agents. Such cumulative toxicity is not evident. Finally, we present an analysis based on the area under the curve for mice and humans that demonstrates that the doses being used in current Phase II radiotherapy protocols and Phase III chemotherapy protocols should be sufficient to produce clinical activity. We conclude that the preclinical data suggest that it is likely that TPZ will be active in the clinic, particularly when combined with cisplatin.
Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Cisplatin; Drug Interactions; Free Radicals; Humans; Oxidation-Reduction; Radiation-Sensitizing Agents; Tirapazamine; Triazines
PubMed: 9755717
DOI: No ID Found -
Journal of Colloid and Interface Science Mar 2023Chemodynamic therapy (CDT), an emerging oncology treatment, has received considerable attention owing to its high selectivity, less aggressiveness, and endogenous...
Chemodynamic therapy (CDT), an emerging oncology treatment, has received considerable attention owing to its high selectivity, less aggressiveness, and endogenous stimulation. However, the complex intra-tumor environment limits the therapeutic effect. In this study, Cu was directly doped into the structure of the UiO-66 matrix using an in situ one-pot oil bath method. The as-formed UiO-66/Cu possessed a large surface area, making it feasible to modify folic acid (FA) and carry more chemotherapeutic agents like tirapazamine (TPZ), thus forming UiO-66/Cu-FA-TPZ nanoplatforms. For CDT, the nanoplatform catalyzed the cyclic generation of the highly oxidizing hydroxyl radical (·OH) from HO. Particularly, low-frequency ultrasound enhanced the curative effect. Notably, in a tumor, a severe hypoxic environment and ultrasound can activate more TPZ for safe and efficient chemotherapy, achieving synergistic and hypoxia-activated tumor treatment with a low risk of side effects. Moreover, the nanoplatform exhibits computed tomography imaging functions for combined diagnosis and treatment. Our designed nanoplatform overcomes the dilemma of insufficient efficacy from conventional therapy attributed to a hypoxic environment, expecting to guide the design of future treatment regimens for hypoxic tumors.
Topics: Humans; Tirapazamine; Antineoplastic Agents; Hydrogen Peroxide; Neoplasms; Hypoxia; Cell Line, Tumor
PubMed: 36542978
DOI: 10.1016/j.jcis.2022.12.015 -
Biomaterials Science Jan 2020Despite the great advances achieved in hypoxia-associated tumor therapy, the efficacy of hypoxia-activated prodrugs alone is usually limited owing to the moderate oxygen...
Despite the great advances achieved in hypoxia-associated tumor therapy, the efficacy of hypoxia-activated prodrugs alone is usually limited owing to the moderate oxygen supply at the tumor area. Herein, we develop a polymerized platinum(iv) compound-based nanogel (polyprodrug) containing a bioreductive and hypoxia-activated prodrug (tirapazamine, TPZ) as a prodrug combo (polyprodrug@TPZ) for synergistic chemotherapy. Upon exposure to the tumor microenvironment, platinum(iv) moieties in the polyprodrug are reduced to platinum(ii) species, which significantly upregulates the expression of NADPH oxidases (NOXs) to accelerate oxygen (O2) depletion and promote reactive oxygen species (ROS) production, as confirmed by reverse transcription-PCR (RT-PCR) and fluorescence probes. In the exaggerated hypoxia environment, highly cytotoxic radicals are generated due to TPZ activation, which serve as second antitumor agents working together with platinum(ii) species in synergistic chemotherapy. With the rational design of nanosized architecture, the platinum(iv)-based polyprodrug@TPZ complex exhibits the advantages of redox-responsive drug release, superior tumor accumulation, and long-term circulation during the synergistic antitumor treatment in a mouse model. These results indicate that combination of an oxygen depletion prodrug and hypoxia-activated antitumor agents would serve as a promising strategy to realize a better synergistic chemotherapy.
Topics: A549 Cells; Antineoplastic Agents; Cell Proliferation; Drug Therapy, Combination; Humans; Organoplatinum Compounds; Oxygen; Prodrugs; Reactive Oxygen Species; Tirapazamine; Tumor Hypoxia
PubMed: 31777870
DOI: 10.1039/c9bm01640f