tirapazamine has been researched along with Neoplasms* in 79 studies
19 review(s) available for tirapazamine and Neoplasms
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Bioreductive prodrugs as cancer therapeutics: targeting tumor hypoxia.
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 | 2014 |
Tirapazamine: a novel agent targeting hypoxic tumor cells.
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.. 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.. 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.. 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 | 2009 |
Bioreductive drugs: from concept to clinic.
One of the key issues for radiobiologists is the importance of hypoxia to the radiotherapy response. This review addresses the reasons for this and primarily focuses on one aspect, the development of bioreductive drugs that are specifically designed to target hypoxic tumour cells. Four classes of compound have been developed since this concept was first proposed: quinones, nitroaromatics, aliphatic and heteroaromatic N-oxides. All share two characteristics: (1) they require hypoxia for activation and (2) this activation is dependent on the presence of specific reductases. The most effective compounds have shown the ability to enhance the anti-tumour efficacy of agents that kill better-oxygenated cells, i.e. radiation and standard cytotoxic chemotherapy agents such as cisplatin and cyclophosphamide. Tirapazamine (TPZ) is the most widely studied of the lead compounds. After successful pre-clinical in vivo combination studies it entered clinical trial; over 20 trials have now been reported. Although TPZ has enhanced some standard regimens, the results are variable and in some combinations toxicity was enhanced. Banoxantrone (AQ4N) is another agent that is showing promise in early phase I/II clinical trials; the drug is well tolerated, is known to locate in the tumour and can be given in high doses without major toxicities. Mitomycin C (MMC), which shows some bioreductive activation in vitro, has been tested in combination trials. However, it is difficult to assign the enhancement of its effects to targeting of the hypoxic cells because of the significant level of its hypoxia-independent toxicity. More specific analogues of MMC, e.g. porfiromycin and apaziquone (EO9), have had variable success in the clinic. Other new drugs that have good pre-clinical profiles are PR 104 and NLCQ-1; data on their clinical safety/efficacy are not yet available. This paper reviews the pre-clinical data and discusses the clinical studies that have been reported. Topics: Animals; Anthraquinones; Antineoplastic Agents; Cell Hypoxia; Genetic Therapy; Humans; Mitomycin; Neoplasms; Polycyclic Aromatic Hydrocarbons; Quinones; Radiation-Sensitizing Agents; Tirapazamine; Triazines | 2007 |
Tirapazamine: from bench to clinical trials.
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 | 2006 |
Radiation sensitization with redox modulators: a promising approach.
Radiation therapy plays a critical role in the local and regional control of malignant tumors. Its efficacy, however, is limited by a number of factors, including toxicity, tumor hypoxia, and tumor genetics. Recent attempts to enhance the efficacy of radiation therapy have focused on biologic agents that modulate reduction/oxidation reactions within tumor cells.. We review five promising redox modulators that are in development. Tirapazamine and AQ4N are known as "hypoxic cell sensitizers" and are toxic in areas of low oxygen tension. RSR13 facilitates delivery of oxygen to tumor cells, thereby rendering them more sensitive to radiation. Motexafin gadolinium, with a porphyrin-like structure, selectively accumulates in tumor cells and thereby enhances radiation-induced DNA damage. HIF-1 inhibitors target a transcription factor that regulates hypoxia-related events and cell survival.. Our review of each agent included a thorough search of published preclinical and clinical data, including that presented in abstracts and posters at international meetings. Our objectives were not to identify a superior mechanism or drug, but rather to summarize the available safety and efficacy data.. Clearly, there is an unmet need for safer agents that augment the efficacy of radiation therapy. This review highlights five promising redox modulators that are in development. None has yet been approved by the Food and Drug Administration. These drugs were selected for discussion because they exemplify the current investigative landscape of radiosensitizers and are indicative of future directions in this area. These radiation sensitizers have the potential to succeed where others have failed, by locally increasing the radiosensitivity of tumor cells without enhancing that of surrounding normal tissues. Topics: Aniline Compounds; Anthraquinones; Cell Hypoxia; Clinical Trials as Topic; DNA Damage; Drug Approval; Drug Therapy, Combination; Humans; Hypoxia-Inducible Factor 1; Maximum Tolerated Dose; Metalloporphyrins; Neoplasms; Oxidation-Reduction; Propionates; Radiation-Sensitizing Agents; Tirapazamine; Triazines | 2006 |
Hypoxia: targeting the tumour.
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 | 2006 |
Clinical studies of hypoxia modification in radiotherapy.
Hypoxic modification has been the subject of investigations in clinical radiation oncology since the early 60s. To date, this has not yet resulted in a treatment that has been widely accepted. Logistics and technical difficulties limit the routine use of hyperbaric oxygen in radiotherapy. The nitroimidazoles have not gained general acceptance, initially because of their toxicity and later because of doubts about the effectiveness of the newer generation of less toxic drugs. Nevertheless, there is good evidence from these studies that improving clinical outcome by hypoxic modulation is an achievable goal. Newer approaches including combinations of radiotherapy with tirapazamine, erythropoietin, and carbogen and nicotinamide (ARCON) are currently in phase III trial. For these new strategies to be successful, it is important that the proper patient categories are selected. Various methods to assess tumor oxygenation are now becoming available in the clinic. These potential predictive assays must be incorporated and validated in current and future large-scale clinical trials. Modifiers that target other aspects of tumor biology may also have indirect effects on tumor oxygenation. These aspects require further study in preclinical and early clinical settings. Topics: Antineoplastic Agents; Cell Hypoxia; Clinical Trials, Phase III as Topic; Dose Fractionation, Radiation; Erythropoietin; Humans; Hyperbaric Oxygenation; Neoplasms; Patient Selection; Tirapazamine; Triazines | 2004 |
The Japanese experiences with hypoxia-targeting pharmacoradiotherapy: from hypoxic cell sensitisers to radiation-activated prodrugs.
Tumour hypoxia is a negative factor in cancer radiotherapy. In order to overcome the problem, various pharmacotherapies have been investigated as an adjunct to radiotherapy. The use of hypoxic cell sensitisers is a classical strategy, and many new compounds have been developed and investigated. Development of more efficient compounds than those currently available seems difficult and clinical studies to prove the efficacy of the existing compounds are encouraged, especially in combination with radiosurgery, intraoperative radiotherapy, and interstitial irradiation, in which a single high dose of radiation is used. Following the advent of hypoxic cell sensitisers, hypoxic cytotoxins have become available. Among them, tirapazamine has already gained success when combined with cisplatin in non-small cell lung cancer. The beneficial effect of tirapazamine when combined with radiation needs to be determined. As a third-generation compound in this field, antitumour prodrugs that are activated by irradiation under hypoxic conditions via one-electron reduction have been proposed. Prodrugs of 5-fluorouracil and 5-fluoro-2'-deoxyuridine have shown in vivo as well as in vitro activity. Although clinical evaluation of the compounds is not warranted due to a relatively low in vivo effect, this strategy appears promising if the prodrug design can be applied to more potent agents that shall be developed in future. Topics: Asian People; Cell Hypoxia; Clinical Trials as Topic; Humans; Imidazoles; Neoplasms; Nitroimidazoles; Prodrugs; Radiation; Radiation-Sensitizing Agents; Tirapazamine; Triazines | 2004 |
Tumour hypoxia, chemotherapeutic resistance and hypoxia-related therapies.
Tissue hypoxia occurs where there is an imbalance between oxygen supply and consumption. Hypoxia occurs in solid tumours as a result of an inadequate supply of oxygen, due to exponential cellular proliferation and an inefficient vascular supply. It is an adverse prognostic indicator in cancer as it is associated with tumour progression and resistance to therapy. The expression of several genes controlling tumour cell survival are regulated by hypoxia, e.g., growth factors governing the formation of new blood vessels, and hypoxia-responsive transcription factors modulating the expression of genes, which promote tumour cell survival. This review outlines some of the pathways by which tumour hypoxia leads to chemotherapeutic resistance, directly due to lack of oxygen availability, and indirectly due to alterations in the proteome/genome, angiogenesis and pH changes. Some innovative therapies are also detailed which may potentially minimise or eliminate these problems associated with targeting solid tumours. Topics: Acidosis, Respiratory; Animals; Antineoplastic Agents; Apoptosis; Cell Hypoxia; DNA-Binding Proteins; Drug Resistance, Neoplasm; Endothelial Growth Factors; Genetic Therapy; Humans; Hydrogen-Ion Concentration; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Intercellular Signaling Peptides and Proteins; Lymphokines; Macrophages; Mutation; Neoplasms; Neovascularization, Pathologic; Nuclear Proteins; Oxygen Consumption; Risk Factors; Tirapazamine; Transcription Factors; Triazines; Tumor Suppressor Protein p53; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors | 2003 |
Endogenous markers of tumor hypoxia predictors of clinical radiation resistance?
Eppendorf electrode measurements of tumor oxygenation have defined an adverse effect of tumor hypoxia on prognosis after radiotherapy and other treatment modalities, in particular in head and neck and cervix carcinomas as well as soft tissue sarcomas. Recently, the immunohistochemical detection of proteins involved in the "hypoxic response" of tumor cells has been discussed as a method to estimate hypoxia in clinical tumor specimens.. This review focuses on clinical and experimental data, regarding prognostic impact and comparability with other methods of hypoxia detection, for three proteins suggested as endogenous markers of tumor hypoxia: hypoxia-inducible factor-1alpha(HIF-1alpha), carbonic anhydrase 9 (CA 9), and glucose transporter 1 (GLUT1).. None of the three potential hypoxia markers is exclusively hypoxia-specific, and in each case protein can be detected under normoxic conditions in vitro. HIF-1alpha responds rapidly to hypoxia but also to reoxygenation, making this marker quite unstable in the context of clinical sample collection. The perinecrotic labeling pattern typical of chronic hypoxia and a reasonable agreement with injectable hypoxia markers such as pimonidazole have most consistently been described for CA 9. All three markers showed correlation with Eppendorf electrode measurements of tumor oxygenation in carcinoma of the cervix. In nine of 13 reports, among them all three that refer to curative radiotherapy for head and neck cancer, HIF-1alpha overexpression was associated with poor outcome. CA 9 was an adverse prognostic factor in cervix, head and neck and lung cancer, but not in two other head and neck cancer reports. GLUT1 predicted for poor survival in colorectal, cervix and lung cancer.. Endogenous markers have the potential to indicate therapeutically relevant levels of hypoxia within tumors. Clinical trials assessing a marker's ability to predict a benefit from specific hypoxia-directed treatment (e. g., tirapazamine, "ARCON" concept) are necessary to define the potential of individual markers. Topics: Antineoplastic Agents; Biomarkers, Tumor; Carbonic Anhydrases; Cell Hypoxia; Cell Line, Tumor; Female; Forecasting; Glucose Transporter Type 1; Head and Neck Neoplasms; HeLa Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Lung Neoplasms; Male; Monosaccharide Transport Proteins; Neoplasms; Oxygen; Prognosis; Radiation Tolerance; Radiation-Sensitizing Agents; Tirapazamine; Transcription Factors; Treatment Outcome; Triazines; Uterine Cervical Neoplasms | 2003 |
Electron transfer and oxidative stress as key factors in the design of drugs selectively active in hypoxia.
Hypoxia is a feature of some regions of many tumours, ischaemic events, and arthritis. Drugs activated in hypoxia have wide potential application, particularly in overcoming the resistance of hypoxic tumour cells to radiotherapy. Key features of such drugs include redox properties appropriate for activation by reductase enzymes (typically flavoproteins), and oxygen-sensitive reduction chemistry such that normal levels of oxygen inhibit or reverse reduction. In many cases this selectivity is achieved by a fast, free-radical reaction in which the drug radical (often an obligate intermediate in drug reduction) reduces oxygen to form superoxide radicals and thus 'futile cycles' the drug in normoxic tissues. However, this enhances cellular oxidative stress, which may be linked to normal tissue toxicity. Appropriate redox properties are found with nitroarene, quinone, or aromatic N-oxide moieties. A particularly promising and versatile exploitation of bioreductive activation is for reduction of such 'triggers' to activate release of an 'effector', an agent that can obviously be active against diverse conditions associated with hypoxia. The same approach can also be used in diagnosis of hypoxia. Much information concerning the reactions of intermediates in drug action and the quantitative prediction of redox properties of analogues has been accrued. Drug design can be mechanism-led, with the wealth of literature quantifying redox properties of drug candidates a rich source of potential new leads. There is a clear appreciation of the kinetic factors that limit drug efficacy or selectivity. Thus the potential for rapid expansion of these concepts to diverse diseases is considerable. Topics: Drug Delivery Systems; Drug Design; Electron Transport; Enzyme Activation; Flavoproteins; Free Radical Scavengers; Humans; Hypoxia; Neoplasms; Oxidation-Reduction; Oxidative Stress; Quinones; Tirapazamine; Triazines | 2001 |
Exploiting the hypoxic cancer cell: mechanisms and therapeutic strategies.
Human solid tumours are considerably less well oxygenated than normal tissues. This leads to resistance to radiotherapy and anticancer chemotherapy, as well as predisposing to increased tumour metastases. However, tumour hypoxia can be exploited in cancer treatment. One such strategy is to use drugs that are toxic only under hypoxic conditions, and the first drug of this class to enter clinical testing, tirapazamine, is showing considerable promise. The second way to exploit hypoxia is to take advantage of the selective induction of the transcription factor hypoxia-inducible factor 1 (HIF-1) under hypoxic conditions; gene therapy strategies based on this are in development. Topics: Anthraquinones; Antineoplastic Agents; Cell Hypoxia; DNA-Binding Proteins; Drug Resistance, Neoplasm; Genetic Therapy; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Neoplasms; Nuclear Proteins; Radiation-Sensitizing Agents; Tirapazamine; Transcription Factors; Triazines; Tumor Cells, Cultured | 2000 |
Tirapazamine: a bioreductive anticancer drug that exploits tumour hypoxia.
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 | 2000 |
Novel radiation sensitizers targeting tissue hypoxia.
That hypoxic tissues are more resistant to the effects of radiation than well-oxygenated tissues has been known for many decades, and repeated in vitro demonstrations have confirmed that to achieve the same degree of cytotoxicity, hypoxic cells require about three times the radiation dose that well-oxygenated cells need. Hypoxic cell sensitizers enhance the tissue response to standard radiation, generally by mimicking the effects of oxygen, which induces the formation and stabilization of toxic DNA radicals. Although many hypoxic cell sensitizers like the nitroimidazoles have been evaluated in combination with radiation, these agents have had no or only minimal therapeutic impact due to either their limited potency or their toxicity at biologically relevant concentrations. This article reviews several new modalities that either increase oxygen delivery or sensitize hypoxic tissues. These modalities, all currently in early clinical evaluations, include: (1) tirapazamine, a bioreductive agent; (2) gadolinium texaphyrin, a hypoxic cell sensitizer with biolocalization properties using magnetic resonance imaging; (3) RSR13, an allosteric modifier of hemoglobin; and (4) bovine hemoglobin modified by the attachment of polyethylene glycol polymers. Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Clinical Trials as Topic; Combined Modality Therapy; DNA Damage; Hemoglobins; Humans; Metalloporphyrins; Neoplasms; Radiation-Sensitizing Agents; Tirapazamine; Triazines | 1999 |
The hypoxic cell: a target for selective cancer therapy--eighteenth Bruce F. Cain Memorial Award lecture.
It has been appreciated for more than 50 years that very low levels of oxygenation, or hypoxia, both protect cells from killing by X-irradiation and are present in solid tumors but not in normal tissues. Until recently, however, there has been no definitive proof that hypoxia in human tumors contributes to radiotherapy treatment failure. We now know that hypoxia in solid tumors is not only a major problem for radiation therapy but also leads to resistance to most anticancer drugs and, importantly, appears to accelerate malignant progression and increase metastasis. To date, efforts to overcome the problem of hypoxia have had only limited success. However, the recent development of new drugs that are nontoxic until they are activated in the hypoxic cell opens a new era. The first of these new drugs to be tested clinically, tirapazamine, a drug that is highly toxic to hypoxic but not aerobic cells, has already demonstrated efficacy in selective potentiation of cisplatin in randomized Phase III trials with non-small cell lung cancer. The unique presence of hypoxic cells in human tumors provides an important target for selective cancer therapy. Topics: Animals; Antineoplastic Agents; Awards and Prizes; Cell Hypoxia; Cisplatin; Clinical Trials, Phase III as Topic; Humans; Medical Oncology; Neoplasms; Randomized Controlled Trials as Topic; Tirapazamine; Triazines | 1999 |
Exploiting tumour hypoxia and overcoming mutant p53 with tirapazamine.
Human solid tumours are composed of a significant proportion of hypoxic cells, i.e. cells with oxygen levels lower than those of normal tissues. Tumour hypoxic cells have been shown to have a negative impact on the response of solid tumours to radiation therapy and chemotherapy. However, these low cellular oxygen levels can be exploited by a drug that is specifically activated to a cytotoxic metabolite at these low levels. Tirapazamine is a novel bioreductive agent with selective cytotoxicity to hypoxic tumour cells, irrespective of their p53 status or apoptotic response, and acts synergistically with cisplatin. This potentiation is dependent on an interaction that can only take place in a hypoxic environment, resulting in a significant sensitization of the cells to cisplatin cell killing, with no increase in the systemic toxicity of cisplatin. Thus, the low cellular oxygen levels common in solid tumours can be turned from disadvantage to advantage using the hypoxia-selective cytotoxic drug tirapazamine. Topics: Antineoplastic Agents; Cell Hypoxia; Cisplatin; Genes, p53; Humans; Mutation; Neoplasms; Tirapazamine; Triazines | 1998 |
The experimental development of bioreductive drugs and their role in cancer therapy.
Bioreductive drugs undergo metabolic reduction to generate cytotoxic metabolites. This process is facilitated by bioreductive enzymes and the lower oxygen conditions present in solid tumours compared to normal tissues. Because of this specificity, bioreductive drugs have enormous potential to contribute to modern cancer therapy. Examples undergoing clinical trials include N-oxides such as tirapazamine, aziridinylnitroimidazoles RSU 1069/RBU 6145 and quinones such as indoloquinone EO9. Other novel structures are also under study. Here we review the experimental development of bioreductive drugs and their role in cancer therapy. Topics: Animals; Antineoplastic Agents; Aziridines; Combined Modality Therapy; DNA Damage; Humans; Indolequinones; Indoles; Misonidazole; Neoplasms; Radiation-Sensitizing Agents; Tirapazamine; Triazines | 1993 |
Bioreductive drugs in cancer therapy.
Topics: Animals; Antineoplastic Agents; Antioxidants; Cell Hypoxia; Humans; Misonidazole; Neoplasms; Nitroimidazoles; Prodrugs; Radiation-Sensitizing Agents; Tirapazamine; Triazines | 1992 |
DT-diaphorase and cancer chemotherapy.
Topics: Animals; Antineoplastic Agents; Aziridines; Benzoquinones; Dihydrolipoamide Dehydrogenase; Drug Design; Enzyme Induction; Gene Expression Regulation, Enzymologic; Humans; Indolequinones; Indoles; Mitomycin; Neoplasms; Precancerous Conditions; Tirapazamine; Triazines | 1992 |
6 trial(s) available for tirapazamine and Neoplasms
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Phase I trial of tirapazamine and cyclophosphamide in children with refractory solid tumors: a pediatric oncology group study.
To determine the dose limiting toxicity (DLT), maximum-tolerated dose (MTD), and pharmacokinetic profile of tirapazamine (Sanofi Synthelabo Research, Malvern, PA) combined with cyclophosphamide in children with recurrent solid tumors.. Patients received a 2-hour infusion of tirapazamine, followed by 1,500 mg/m(2) cyclophosphamide, and mesna once every 3 weeks. Dose escalation of tirapazamine began at 250 mg/m(2) and was increased by 30% in subsequent cohorts. If DLT was hematologic, less-heavily pretreated patients were to be enrolled until their DLTs were encountered, and MTDs defined. Pharmacokinetic profiles were also characterized.. Twenty-three patients were enrolled onto the study. Pharmacokinetic data were calculated for 22 patients. Prolonged neutropenia was the DLT at 420 mg/m(2) in heavily pretreated patients. Grade 3, reversible ototoxicity was the DLT in less-heavily pretreated patients at 420 mg/m(2). Two (one with neuroblastoma and one with rhabdomyosarcoma) had partial responses. One child with neuroblastoma had prolonged stable disease (10 cycles) at a dose of 250 mg/m(2). This patient had disease detectable in the bone marrow only and all evidence of bone marrow involvement resolved for 17 cycles of therapy. Four other patients had stable disease. An apparent dose-proportional increase in tirapazamine maximal concentration and area under the curve(last) was observed. Tirapazamine clearance, volume of distribution at steady-state, and terminal half-life did not appear to be dose-dependent.. The recommended dose of tirapazamine given with 1,500 mg/m(2) of cyclophosphamide once every 3 weeks is 325 mg/m(2). Neutropenia and ototoxicity were dose-limiting. Based on early evidence of antitumor activity, additional studies appear warranted. Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cyclophosphamide; Female; Humans; Male; Neoplasm Recurrence, Local; Neoplasms; Neutropenia; Tirapazamine; Triazines | 2004 |
Tirapazamine plus carboplatin and paclitaxel in advanced malignant solid tumors: a california cancer consortium phase I and molecular correlative study.
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.. 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.. 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.. 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 | 2003 |
Phase I trial of the hypoxic cell cytotoxin tirapazamine with concurrent radiation therapy in the treatment of refractory solid tumors.
Patients with refractory solid tumors were treated with the combination of fractionated radiation therapy and multiple-dose intravenous tirapazamine to determine the toxicities and maximum tolerated dose of tirapazamine when given concurrently with radiation therapy.. Patients received radiation therapy in accordance with standard treatment practice in relation to fraction size and number of fractions for their particular cancer. In all cases, the course of radiation therapy exceeded the time of tirapazamine administration. Initially, tirapazamine was administered 5 days per week for 2 weeks for a total of 10 doses. After the first 8 patients, the schedule was changed to 3 times per week (Monday, Wednesday, Friday) for 4 weeks for a total of 12 doses. Between 3 and 6 patients were treated at each dose level.. A total of 43 patients were treated in the study between 1991 and 1995. All patients were 18 years old or older, had a Karnofsky performance status of > or = 60% and had adequate hematologic, hepatic, and renal function. Dose escalation began at 9 mg/m(2)/dose and was increased using a modified Fibonacci schema. The maximum tolerated dose was not reached and dose escalation was stopped at 260 mg/m(2) because of other data that became available suggesting 330 mg/m(2) was associated with dose-limiting toxicity (1, 2).. Tirapazamine in doses of up to 260 mg/m(2) times 12 doses can be given safely with fractionated radiation therapy. This dose appears to result in adequate plasma exposure (2) for radiation sensitization, and this schedule is being tested in a Phase II trial by the Radiation Therapy Oncology Group to determine if tirapazamine is a radiation enhancer in the clinic. Topics: Adult; Aged; Antineoplastic Agents; Cell Hypoxia; Dose Fractionation, Radiation; Drug Administration Schedule; Drug Eruptions; Female; Humans; Hypotension; Infusions, Intravenous; Male; Middle Aged; Muscle Cramp; Neoplasms; Radiation-Sensitizing Agents; Tirapazamine; Triazines | 1999 |
Phase I trial of tirapazamine in combination with cisplatin in a single dose every 3 weeks in patients with solid tumors.
Tirapazamine (SR4233, WIN 59075) is a benzotriazine-di-N-oxide bioreductive agent that is selectively activated to a reactive DNA-damaging species in hypoxic tumors. Preclinical studies show that synergistic antitumor activity results from a schedule-dependent interaction between tirapazamine and several cytotoxic drug classes, including cisplatin. In a phase I combination study, tirapazamine (130 to 260 mg/m2) was administered as a 1-hour intravenous (IV) infusion beginning 3 hours before cisplatin (75 to 100 mg/m2). Thirteen patients received 41 courses of therapy. These patients had an excellent performance status and were not heavily pretreated. The predominant diagnosis was lung cancer.. The major acute side effects were nausea and vomiting, which were controlled with an intensive antiemetic regimen. Other acute effects included diarrhea and muscle cramping, while with repeated dosing, anorexia and fatigue predominated. Full doses of each agent were well tolerated in combination, although in this previously treated population, fatigue increased markedly after three cycles of therapy. Partial responses were observed in two patients (one with non-small-cell lung cancer and one with breast cancer), and a minor response occurred in a patient with mesothelioma. Tirapazamine pharmacokinetics were linear with respect to increasing dose with a mean maximum plasma concentration (Cmax) of 5.97 +/- 2.25 microg/mL and an area under the concentration-time curve (AUC) of 811.4 +/- 311.9 microg/mL.min at 260 mg/m2. These results are consistent with other ongoing single-agent and combination studies and indicate that therapeutically relevant levels of tirapazamine are achievable in patients based on animal models. The mean cisplatin AUC was 285.6 +/- 46.4 microg/mL.min with mean Cmax values of 3.38 +/- 0.43 microg/mL at 75 mg/m2. The clearance of cisplatin was unaffected by coadministration with tirapazamine.. This trial shows that in previously treated patients, full doses of cisplatin are well tolerated with increasing doses of tirapazamine up to 260 mg/m2. The observation of clinical responses in this trial supports the phase II investigation of this regimen. Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Neoplasms; Tirapazamine; Treatment Outcome; Triazines | 1997 |
Phase I and pharmacokinetic study of tirapazamine (SR 4233) administered every three weeks.
Tirapazamine (SR 4233; 3-amino-1,2,4-benzotriazine-1,4-di-N-oxide) is a bioreductive agent exhibiting up to 200 x greater toxicity for hypoxic cells as compared to oxygenated cells. In murine studies, a selective increase in tumor kill was observed when tirapazamine was coadministered with other agents, notably cisplatin. A Phase I study of single-agent tirapazamine administered i.v. every 3 weeks was conducted to determine the toxicity of a schedule for use with systemic chemotherapy. A total of 28 patients were given 50 courses of tirapazamine at doses ranging from 36-450 mg/m2. No tumor responses were observed. Reversible deafness and tinnitus were dose-limiting, with ototoxicity observed in 1 of 6 patients treated at 330 mg/m2, 1 of 4 patients treated at 390 mg/m2, and 3 of 3 patients treated at 450 mg/m2. Muscle cramps, nausea, and vomiting were also observed. Pharmacokinetic studies revealed a greater than dose-proportional increase in the area under the plasma concentration x time curve (AUCs) of the two major metabolites. Patients who developed ototoxicity generally showed higher plasma AUC values for the parent drug and metabolites. The mean plasma tirapazamine AUC at 330 mg/m2 was 1026.5 microgram/ml x min (range 863. 8-1252.3), but no pharmacokinetic data are available for the solitary patient who developed otoxicity at this dose level. These AUC values were in the (estimated) range required for therapeutic effect in murine studies. Ototoxicity was not observed when the AUC of tirapazamine was equal to or less than 1252 microgram/ml x min. The dose of 330 mg/m2 was therefore chosen as an appropriate level for combination chemotherapy studies. Topics: Adult; Aged; Antineoplastic Agents; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Muscle Cramp; Nausea; Neoplasms; Thrombocytopenia; Tirapazamine; Triazines; Vomiting | 1997 |
Muscle cramping in phase I clinical trials of tirapazamine (SR 4233) with and without radiation.
Tirapazamine (SR 4233) is a benzotriazine di-N-oxide which acts as a hypoxic cytotoxic agent and as a radiation enhancer when given shortly before or after radiation. Three Phase I clinical trials were designed to determine the maximum tolerated dose, toxicities, pharmacokinetics, and effects on irradiated tumors and normal tissues.. Tirapazamine 9 mg/m2 to 21 mg/m2 was given i.v. 1/2 to 1 h prior to irradiation on a multiple dose schedule of 10 consecutive doses. This was later revised to a three times-per-week schedule for 12 doses. In a second clinical trial, tirapazamine was given in a single dose of 18 mg/m2 to 293 mg/m2 i.v. after irradiation. In a third trial, tirapazamine was administered without irradiation in single doses of 36 mg/m2 to 250 mg/m2, with an option for retreatment.. Subjects reported muscle cramping of varying degrees of severity on all three dose schedules. One patient experienced Grade 3 cramping and treatment was discontinued. The most frequent site of cramping were the lower extremities. Creatine phosphokinase (CPK) values were elevated in three patients with associated muscle soreness in one patient. MB (cardiac) isoenzymes were elevated in one patient with no evidence of cardiac muscle damage, and returned to baseline at drug completion. No consistent abnormalities in clinical laboratory values were found. Stretching of the muscle was most effective in relieving the cramping.. Muscle cramping has been the most frequently reported toxicity in Phase I studies of tirapazamine, though it does not appear to be dose limiting. Dose escalation on the three clinical trials continues. In vitro studies to investigate the cramping are ongoing. Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Humans; Male; Middle Aged; Muscle Cramp; Neoplasms; Radiation-Sensitizing Agents; Tirapazamine; Triazines | 1994 |
54 other study(ies) available for tirapazamine and Neoplasms
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A supramolecular assembly strategy for hydrophilic drug delivery towards synergistic cancer treatment.
To improve the drug loading, tumor targeting, and delivery simplicity of hydrophilic drugs, we propose a supramolecular assembly strategy that potentially benefits a wide range of hydrophilic drug delivery. Firstly, we choose a hydrophilic drug (tirapazamine) as a model drug to directly co-assemble with chlorin e6 (Ce6) at different molar ratios, and systematically evaluate the resultant Ce6-tirapazamine nanoparticles (CT NPs) in aspects of size distribution, polydispersity, morphology, optical properties and molecular dynamics simulation. Based on the assembling facts between Ce6 and tirapazamine, we summarize a plausible rule of the supramolecular assembly for hydrophilic drugs. To validate our findings, more drugs with increasing hydrophilicity, such as temozolomide, gemcitabine hydrochloride and 5-azacytidine, successfully co-assemble with Ce6 into nanostructures by following similar assembling behaviors, demonstrating that our assembling rule may guide a wide range of hydrophilic drug delivery. Next, the combination of Ce6 and tirapazamine was chosen as the representative to investigate the anti-tumor activities of the supramolecular assemblies. CT NPs showed synergistic anti-tumor efficacy, increased tumor accumulation and significant tumor progression and metastasis inhibition in tumor-bearing mice. We anticipate that the supramolecular assembly mechanism will provide broad guidance for developing easy-to-make but functional nanomedicines. STATEMENT OF SIGNIFICANCE: Although thousands of nanomedicines have been developed, only a few have been approved for clinical use. The manufacturing complexity significantly hinders the "bench-to-bed" translation of nanomedicines. Hence, we need to rethink how to conduct research on translational nanomedicines by avoiding more and more complex chemistry and complicated nanostructures. Here, we summarize a plausible rule according to multiple supramolecular assembly pairs and propose a supramolecular assembly strategy that can improve the drug loading, tumor targeting, and manufacturing simplicity of nanomedicine for hydrophilic drugs. The supramolecular assembly strategy would guide a broader range of drug delivery to provide a new paradigm for developing easy-to-make but multifunctional nanoformulations for synergistic cancer treatment. Topics: Animals; Cell Line, Tumor; Drug Delivery Systems; Mice; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Tirapazamine | 2023 |
Augmenting Immunogenic Cell Death and Alleviating Myeloid-Derived Suppressor Cells by Sono-Activatable Semiconducting Polymer Nanopartners for Immunotherapy.
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 Topics: Animals; Cell Line, Tumor; Hypoxia; Immunogenic Cell Death; Immunotherapy; Mice; Myeloid-Derived Suppressor Cells; Neoplasms; Oxygen; Polymers; Tirapazamine; Tumor Microenvironment | 2023 |
Controllable hypoxia-activated chemotherapy as a dual enhancer for synergistic cancer photodynamic immunotherapy.
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 Topics: Cell Line, Tumor; Humans; Hypoxia; Immunotherapy; Nanoparticles; Neoplasm Recurrence, Local; Neoplasms; Photochemotherapy; Photosensitizing Agents; Tirapazamine; Tumor Microenvironment | 2023 |
Autocatalytic oncotherapy nanosystem with glucose depletion for the cascade amplification of hypoxia-activated chemotherapy and H
Employing hypoxia-activated prodrugs is an appealing oncotherapy strategy, but limited by insufficient tumor hypoxia. Moreover, a standalone prodrug fails to treat tumors satisfactorily due to tumor complexity. Herein, a nanosystem (TPZ@FeMSN-GOX) was established for triple synergetic cancer starvation therapy, hypoxia-activated chemotherapy and chemodynamic therapy (CDT). TPZ@FeMSN-GOX was prepared by synthesizing iron-doped mesoporous silica nanoparticles (FeMSNs) followed by surface conjugation with glucose oxidase (GOX), and then loading with hypoxia-activated prodrug tirapazamine (TPZ). When TPZ@FeMSN-GOX entered the tumor cells, GOX could not only exhaust glucose to starve cancer cells and concomitantly produce H Topics: Cell Line, Tumor; Glucose; Glucose Oxidase; Humans; Hydrogen Peroxide; Hypoxia; Nanoparticles; Neoplasms; Prodrugs; Tirapazamine | 2022 |
Tumor microenvironment-responsive S-NSs-TPZ-ICG intelligent nanoplatforms for synergistically enhanced tumor multimodal therapy.
Nanosheet carriers loaded with drugs and phototherapeutics are used for effective cancer therapy, but the process remains challenging. Here, we prepared sulfur nanosheets (S-NSs) and then loaded tirapazamine (TPZ) and indocyanine green (ICG) with a loading efficiency of 6.3% and 94%, respectively. The obtained S-NSs-TPZ-ICG exhibits near-infrared (NIR) fluorescence, high Topics: Cell Line, Tumor; Humans; Hydrogen Peroxide; Indocyanine Green; Nanoparticles; Neoplasms; Phototherapy; Sulfur; Tirapazamine; Tumor Microenvironment | 2022 |
Enhanced photo-hypoxia-activated combination therapy traced by AIE photosensitizer and targeted by hyaluronic acid: Disulphide bond interference of detoxification barrier.
The treatment efficacy of anticancer drugs in complex physiological environments is still restricted by multi-drug resistance. To overcome this issue, a nanodrug system of HA-SS@CuS@ZIF-8@TPZ&TBMACN (HSCZTT) that breaks through the detoxification barrier for tirapazamine (TPZ) delivery was developed in this manuscript. In addition to the photothermal effect aroused by CuS in HSCZTT, which can damage tumour cells, TBMACN with photostable fluorescence in the aggregate state can also generate sufficient reactive oxygen species (ROS) to destroy tumour cells. The continuous consumption of oxygen in PDT aggravates the hypoxic environment of tumours, which further activates the TPZ released in the acidic microenvironment of the tumour to achieve apoptosis of the tumour cells. The HSCZTT can not only target the CD44 receptor overexpressed on the surface of the cancer cell, but can also effectively consume a large amount of glutathione (GSH) through the disulphide bond-modified hyaluronic acid, which serves as a targeted disulphide bond, interfering with the detoxification barrier. Our finding presents a rational strategy to overcome multidrug resistance for the improved efficacy of anticancer drugs by the targeting of Hyaluronic acid (HA), release of the drug by the acid response of ZIF-8, breakthrough of the detoxification barrier, precise positioning of the drug release and combined treatment with phototherapy and hypoxia-activated chemotherapy. Topics: Antineoplastic Agents; Cell Line, Tumor; Disulfides; Humans; Hyaluronic Acid; Hypoxia; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Tirapazamine; Tumor Microenvironment | 2022 |
Precise gliomas therapy: Hypoxia-activated prodrugs sensitized by nano-photosensitizers.
Hypoxia is one of the prominent features of solid tumors. Hypoxia activated prodrugs (HAPs), selectively killing hypoxic cells, possess the potential to transform hypoxia from a nuisance to an advantage in precision therapy. Exhibiting a more significant hypoxic microenvironment, gliomas, as the most frequent and incurable neurological tumors, provide HAPs a more attractive therapeutic prospect. However, the insufficient hypoxia and the obstruction of the blood-brain barrier (BBB) severely limit the activation and bio-availability of HAPs. Herein, a novel nanoparticle iRGD@ZnPc + TPZ was designed and synthesized to achieve gliomas inhibition by encapsulating tirapazamine (TPZ) as a HAP and zinc phthalocyanine (ZnPc) as a photosensitizer to enhance hypoxia. iRGD@ZnPc + TPZ can realize breakthrough BBB, deep penetration, and significant retention in gliomas, which is attributed to the iRGD-mediated receptor targeting and active transport. After being internalized by tumor cells and radiated, ZnPc efficiently consumes intratumoral O Topics: Antineoplastic Agents; Cell Line, Tumor; Glioma; Humans; Hypoxia; Indoles; Isoindoles; Neoplasms; Organometallic Compounds; Photosensitizing Agents; Prodrugs; Reactive Oxygen Species; Tirapazamine; Tumor Microenvironment; Zinc Compounds | 2022 |
Engineered biomimetic nanoreactor for synergistic photodynamic-chemotherapy against hypoxic tumor.
Photodynamic therapy (PDT) can produce a large amount of reactive oxygen species (ROS) in the radiation field to kill tumor cells. However, the sustainable anti-tumor efficacy of PDT is limited due to the hypoxic microenvironment of tumor. In this study, classic PDT agent indocyanine green (ICG) and hypoxia-activated chemotherapeutic drug tirapazamine (TPZ) were loaded on mesoporous polydopamine (PDA) to construct PDA@ICG-TPZ nanoparticles (PIT). Then, PIT was camouflaged with cyclic arginine-glycine-aspartate (cRGD) modified tumor cell membranes to obtain the engineered membrane-coated nanoreactor (cRGD-mPIT). The nanoreactor cRGD-mPIT could achieve the dual-targeting ability via tumor cell membrane mediated homologous targeting and cRGD mediated active targeting. With the enhanced tumor-targeting and penetrating delivery system, PIT could efficiently accumulate in hypoxic tumor cells and the loaded drugs were quickly released in response to near-infrared (NIR) laser. The nanoreactor might produce cytotoxic ROS under NIR and further enhance hypoxia within tumor to activate TPZ, which efficiently inhibited hypoxic tumor by synergistic photodynamic-chemotherapy. Mechanically, hypoxia-inhibitory factor-1α (HIF-1α) was down-regulated by the synergistic therapy. Accordingly, the cRGD-mPIT nanoreactor with sustainable and cascade anti-tumor effects and satisfied biosafety might be a promising strategy in hypoxic tumor therapy. Topics: Biomimetics; Cell Line, Tumor; Humans; Hypoxia; Indocyanine Green; Nanoparticles; Nanotechnology; Neoplasms; Photochemotherapy; Photosensitizing Agents; Reactive Oxygen Species; Tirapazamine; Tumor Microenvironment | 2022 |
A dual-response drug delivery system with X-ray and ROS to boost the anti-tumor efficiency of TPZ
The selective anti-tumor activity and less toxic nature of hypoxia-activated prodrugs including tirapazamine (TPZ) are harbored by hypoxia levels in tumors, the inadequacy of which leads to failure in clinical trials. Thus, the development of effective clinical applications of TPZ requires advanced strategies to intensify hypoxia levels in tumors effectively and safely. In this study, we designed and fabricated a paclitaxel (PTX)-loaded dual-response delivery system with a low dose ( Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Delivery Systems; Hypoxia; Mice; Neoplasms; Paclitaxel; Reactive Oxygen Species; Tirapazamine; Tumor Hypoxia; X-Rays | 2022 |
A triple-stimulus responsive melanin-based nanoplatform with an aggregation-induced emission-active photosensitiser for imaging-guided targeted synergistic phototherapy/hypoxia-activated chemotherapy.
Multimodal synergistic therapy has gained increasing attention in cancer treatment to overcome the limitations of monotherapy and achieve high anticancer efficacy. In this study, a synergistic phototherapy and hypoxia-activated chemotherapy nanoplatform based on natural melanin nanoparticles (MPs) loaded with the bioreduction prodrug tirapazamine (TPZ) and decorated with hyaluronic acid (HA) was developed. A self-reporting aggregation-induced emission (AIE)-active photosensitizer (PS) (BATTMN) was linked to the prepared nanoparticles by boronate ester bonds. The MPs and BATTMN-HA played roles as quenchers for PS and cancer targeting/photodynamic moieties, respectively. As a pH sensitive bond, the borate ester bonds between HA and BATTMN are hydrolysed in the acidic cancer environment, thereby separating BATTMN from the nanoparticles and leading to the induction of fluorescence for imaging-guided synergistic phototherapy/hypoxia-activated chemotherapy under dual irradiation. TPZ can be released upon activation by pH, near-infrared (NIR) and hyaluronidase (Hyal). Particularly, the hypoxia-dependent cytotoxicity of TPZ was amplified by oxygen consumption in the tumor intracellular environment induced by the AIE-active PS in photodynamic therapy (PDT). The nanoparticles developed in our research showed favorable photothermal conversion efficiency ( Topics: Animals; Antineoplastic Agents; Boronic Acids; Combined Modality Therapy; Drug Carriers; Drug Therapy; Female; Humans; MCF-7 Cells; Melanins; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms; Photosensitizing Agents; Photothermal Therapy; Prodrugs; Tirapazamine; Tumor Hypoxia; Xenograft Model Antitumor Assays | 2021 |
A multiwell plate-based system for toxicity screening under multiple static or cycling oxygen environments.
Tumor tissue contains a continuous distribution of static and dynamically changing oxygen environments with levels ranging from physiologically normal oxygen down to anoxia. However, in vitro studies are often performed under oxygen levels that are far higher than those found in vivo. A number of devices are available to alter the oxygen environment in cell culture, including designs from our laboratory. However, in our devices and most other designs, changing the media in order to feed or dose cells remains a disruptive factor in maintaining a consistent hypoxic environment. This report presents a novel 96-well plate design that recirculates the local oxygen environment to shield cells during media changes and facilitates toxicity studies of cells cultured under varying oxygen levels. The principle behind the design is presented and the response of human pancreatic cancer PANC-1 cells treated with tirapazamine and doxorubicin under eight different static or cycling oxygen levels was measured. As expected, tirapazamine is progressively more toxic as oxygen levels decrease but retains some toxicity as oxygen is cycled between hypoxic and normoxic levels. Doxorubicin sensitivity is largely unaffected by changing oxygen levels. This technology is ideal for assessing the effects of oxygen as a variable in toxicity screens. Topics: Cell Culture Techniques; Cell Hypoxia; Cell Line, Tumor; Doxorubicin; High-Throughput Screening Assays; Humans; Neoplasms; Oxygen; Pancreatic Neoplasms; Tirapazamine; Toxicity Tests; Triazines; Tumor Microenvironment | 2021 |
Optimized Combination of Photodynamic Therapy and Chemotherapy Using Gelatin Nanoparticles Containing Tirapazamine and Pheophorbide a.
In combination therapy, synergetic effects of drugs and their efficient delivery are essential. Herein, we screened 12 anticancer drugs for combination with photodynamic therapy (PDT) using pheophorbide a (Pba). On the basis of combination index (CI) values in cell viability tests, we selected tirapazamine (TPZ) and developed self-assembled gelatin nanoparticles (NPs) containing both Pba and TPZ. The resulting TPZ-Pba-NPs showed a synergetic effect to kill tumor cells because TPZ was activated under the hypoxic conditions that originated from the PDT with Pba and laser irradiation. After they were injected into tumor-bearing mice via the tail vein, TPZ-Pba-NPs showed 3.17-fold higher blood concentration and 4.12-fold higher accumulation in tumor tissue 3 and 24 h postinjection, respectively. Upon laser irradiation to tumor tissue, TPZ-Pba-NPs successfully suppressed tumor growth by efficient drug delivery and synergetic effects Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Chlorophyll; Drug Carriers; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy; Gelatin; Light; Mice, Inbred C3H; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Reactive Oxygen Species; Tirapazamine | 2021 |
Exploiting the acquired vulnerability of cisplatin-resistant tumors with a hypoxia-amplifying DNA repair-inhibiting (HYDRI) nanomedicine.
Various cancers treated with cisplatin almost invariably develop drug resistance that is frequently caused by substantial DNA repair. We searched for acquired vulnerabilities of cisplatin-resistant cancers to identify undiscovered therapy. We herein found that cisplatin resistance of cancer cells comes at a fitness cost of increased intracellular hypoxia. Then, we conceived an inspired strategy to combat the tumor drug resistance by exploiting the increased intracellular hypoxia that occurs as the cells develop drug resistance. Here, we constructed a hypoxia-amplifying DNA repair-inhibiting liposomal nanomedicine (denoted as HYDRI NM), which is formulated from a platinum(IV) prodrug as a building block and payloads of glucose oxidase (GOx) and hypoxia-activatable tirapazamine (TPZ). In studies on clinically relevant models, including patient-derived organoids and patient-derived xenograft tumors, the HYDRI NM is able to effectively suppress the growth of cisplatin-resistant tumors. Thus, this study provides clinical proof of concept for the therapy identified here. Topics: Antineoplastic Agents; Cell Line, Tumor; Cisplatin; DNA Repair; Humans; Hypoxia; Nanomedicine; Neoplasms; Tirapazamine | 2021 |
Enzyme/GSH dual-responsive biodegradable nanohybrid for spatiotemporally specific photodynamic and hypoxia-augmented therapy against tumors.
Photodynamic therapy (PDT) efficacy has been severely limited by the hypoxia in tumor microenvironment. A multitherapy modality was developed, integrating the advantages of each therapy and a nanocarrier: PDT and PDT-induced hypoxia-activated chemotherapy. Following PDT-induced hypoxia augmented in the periphery of the tumors, chemotherapy was locally activated. To this end, new indocyanine green (IR820) and a hypoxia-activated prodrug tirapazamine (TPZ) were loaded in glutathione (GSH) decomposable mesoporous organic silica nanoparticles (GMONs), tethered by hyaluronic acid (HA). This nanohybrid showed a tendency to accumulate and be retained in tumors, due to passive and active targeting. The IR820 produced singlet oxygen ( Topics: Cell Line, Tumor; Glutathione; Humans; Hypoxia; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Tirapazamine; Tumor Microenvironment | 2021 |
Encapsulating an acid-activatable phthalocyanine-doxorubicin conjugate and the hypoxia-sensitive tirapazamine in polymeric micelles for multimodal cancer therapy.
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 | 2021 |
A light and hypoxia-activated nanodrug for cascade photodynamic-chemo cancer therapy.
Combination therapy provides significantly better outcomes than a single drug treatment and becomes an efficient strategy for cancer therapy at present. Owing to the advantages of improved drug bioavailability, decreased side effects, and drug codelivery properties, polymeric carrier-based nanodrugs show great application potential in combination therapy. In this study, a pH-responsive block polymer consisting of polyethylene glycol (mPEG) and poly(asparagyl diisopropylethylenediamine-co-phenylalanine) (P(Asp(DIP)-co-Phe)) is synthesized for drug delivery. The polymer self-assembles into nanovesicles and simultaneously encapsulates the hydrophilic hypoxia-activated prodrug tirapazamine (TPZ) and the hydrophobic photosensitizer dihydrogen porphin (chlorin e6, Ce6). The formed nanodrug can be triggered by near infrared irradiation to induce photodynamic therapy (PDT), resulting in a hypoxic tumor environment to activate the prodrug TPZ to achieve efficient chemotherapy. The cascade synergistic therapeutic effect is evaluated both in vitro and in vivo in a breast cancer mice model. This study reveals a potential strategy for efficient cancer therapy by using Ce6 and TPZ co-encapsulated nanovesicles. Topics: Animals; Cell Line, Tumor; Hypoxia; Mice; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Tirapazamine | 2021 |
Selective Thrombosis of Tumor for Enhanced Hypoxia-Activated Prodrug Therapy.
One of the main challenges for tumor vascular infarction in combating cancer lies in failing to produce sustained complete thrombosis. Inspired by the capability of vascular infarction in blocking the delivery of oxygen to aggravate tumor hypoxia, the performance of selective tumor thrombus inducing hypoxia activation therapy to improve the therapeutic index of coagulation-based tumor therapy is presented. By encapsulating coagulation-inducing protease thrombin and a hypoxia-activated prodrug (HAP) tirapazamine into metal-organic framework nanoparticles with a tumor-homing ligand, the obtained nanoplatform selectively activates platelet aggregation at the tumor to induce thrombosis and vascular obstruction therapy by the exposed thrombin. Meanwhile, the thrombus can cut off the blood oxygen supply and potentiate the hypoxia levels to enhance the HAP therapy. This strategy not only addresses the dissatisfaction of vascular therapy, but also conquers the dilemma of inadequate hypoxia in HAP treatment. Since clinical operations such as surgery can be used to induce coagulation, coagulation-based synergistic therapy is promising for translation into a clinical combination regimen. Topics: Animals; Cell Survival; Hep G2 Cells; Humans; Metal-Organic Frameworks; Mice; Mice, Nude; Nanoparticles; Neoplasms; Platelet Aggregation; Prodrugs; Thrombin; Thrombosis; Tirapazamine; Transplantation, Heterologous; Tumor Hypoxia | 2021 |
A photothermal-hypoxia sequentially activatable phase-change nanoagent for mitochondria-targeting tumor synergistic therapy.
To enhance the specificity and efficiency of anti-tumor therapies, we have designed a multifunctional nanoparticle platform for photochemotherapy using fluorescence (FL) and photoacoustic (PA) imaging guidance. Nanoparticles (NPs) composed of a eutectic mixture of natural fatty acids that undergo a solid-liquid phase transition at 39 °C were used to encapsulate materials for the rapid and uniform release of the hypoxia-activated prodrug tirapazamine (TPZ) and the photosensitizer IR780, which targets the mitochondria of tumor cells and can be used to induce hypoxic cell death via photodynamic therapy and photothermal therapy. In vitro, the NPs containing TPZ and IR7890 exhibited appreciable cell uptake and triggered drug release when irradiated with a NIR laser. In vivo, photochemotherapy of the NPs achieved the best anti-tumor efficacy under PA and FL imaging guidance and monitoring. By combining IR780 mitochondria-targeting phototherapy with TPZ, we observed improved anti-tumor effectiveness and this has the potential to reduce the side effects of traditional chemotherapy. Herein, we demonstrate a new intracellular photochemotherapy nanosystem that co-encapsulates photosensitizers and hypoxia-activated drugs to enhance the overall anti-tumor effect precisely and efficiently. Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Drug Liberation; Female; Indoles; Lasers; Mice, Inbred BALB C; Nanoparticles; Neoplasms; Optical Imaging; Photoacoustic Techniques; Photochemotherapy; Photosensitizing Agents; Prodrugs; Reactive Oxygen Species; Tirapazamine | 2020 |
A redox-activatable biopolymer-based micelle for sequentially enhanced mitochondria-targeted photodynamic therapy and hypoxia-dependent chemotherapy.
A tumor redox-activatable micellar nanoplatform based on the naturally occurring biomacromolecule hyaluronic acid (HA) was developed for complementary photodynamic/chemotherapy against CD44-positive tumors. Here HA was first conjugated with l-carnitine (Lc)-modified zinc phthalocyanine (ZnPc) via disulfide linkage and then co-assembled with tirapazamine (TPZ) to afford the physiologically stable micellar nanostructure. The mitochondria-targeted photodynamic activity of ZnPc-Lc could efficiently activate the mitochondrial apoptosis cascade and deplete the oxygen in the tumor intracellular environment to amplify the hypoxia-dependent cytotoxic effect of TPZ. Topics: Animals; Antineoplastic Agents; Apoptosis; Biopolymers; Carnitine; Cell Line, Tumor; Humans; Hyaluronic Acid; Indoles; Infrared Rays; Isoindoles; Mice; Micelles; Mitochondria; Nanostructures; Neoplasms; Organometallic Compounds; Oxidation-Reduction; Photochemotherapy; Photosensitizing Agents; Tirapazamine; Transplantation, Heterologous; Zinc Compounds | 2020 |
Combinational phototherapy and hypoxia-activated chemotherapy favoring antitumor immune responses.
Topics: Animals; Antineoplastic Agents; Cell Death; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Humans; Immunotherapy; Indoles; Liposomes; Mice, Inbred BALB C; Nanoparticles; Neoplasms; Photochemotherapy; Phototherapy; Polyethylene Glycols; Reactive Oxygen Species; Temperature; Tirapazamine; Tumor Burden; Tumor Microenvironment | 2019 |
Ce6-C6-TPZ co-loaded albumin nanoparticles for synergistic combined PDT-chemotherapy of cancer.
Photodynamic therapy (PDT), as an essential tumor treatment method, has received great attention; however, there are still some challenges such as hydrophobicity of most of the photosensitizers, safety of in vivo transport, and characteristics of oxygen consumption. Herein, we used albumin as the nanocarrier for the loading of Chlorin e6 (Ce6) photosensitizer. In the meantime, tirapazaming (TPZ) was co-loaded onto the nanocomposite, which could be activated by hypoxia caused by PDT for enhanced therapy. Considering the over irradiation problem, a strategy for measuring PDT degree by ratio fluorescence was utilized. The PDT monitoring design relies on ratio emissions of C6 (Coumarin 6) and Ce6 molecules since the red emission of Ce6 is dependent on the PDT capability. Based on the characterization of the albumin nanocomposites, we further explored the combined therapy effect at both the in vitro and in vivo levels and attained the corresponding results. Topics: Animals; Cattle; Cell Line, Tumor; Cell Survival; Chlorophyllides; Coumarins; Humans; Light; Liver; Mice; Microscopy, Confocal; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Serum Albumin, Bovine; Thiazoles; Tirapazamine; Transplantation, Homologous | 2019 |
Near-infrared light triggered liposomes combining photodynamic and chemotherapy for synergistic breast tumor therapy.
Photodynamic therapy (PDT) as a promising noninvasive and effective treatment modality has been clinically approved for cancer therapy. However, the poor selectivity of tumor and hypoxia-induced resistance constrain PDT efficacy immensely. To further enhance PDT's potency, we developed a drug delivery system based on liposome combining PDT and chemotherapeutics. The lipophilic IR780 was loaded into the lipid bilayer while hydrophilic chemotherapeutic agent tirapazamine (TPZ) was encapsulated in the hydrophilic core. IR780 could generate reactive oxygen species and hypoxic microenvironment in local site because of the continuous consumption of oxygen, resulting in the TPZ encapsulated in the aqueous liposome chamber brings out TPZ radicals to cause DNA double-strand breaks and chromosome aberrations. In vivo studies demonstrated that the liposomes which encapsulate IR780 and TPZ showed great antitumor efficacy via combining photodynamic therapy with chemotherapy. Therefore, the investigation combines PDT and hypoxia-activated chemotherapy from the TPZ. It is a simple but effective liposome platform to achieve multiple synergistic antitumor efficacy and shows potential for clinical use. Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Combined Modality Therapy; Drug Compounding; Drug Liberation; Female; Hypoxia; Indoles; Infrared Rays; Injections, Subcutaneous; Kinetics; Liposomes; Mammary Glands, Animal; Mice; Neoplasms; Photochemotherapy; Radiation-Sensitizing Agents; Reactive Oxygen Species; Tirapazamine; Tumor Burden | 2019 |
Combined Cancer Chemo-Photodynamic and Photothermal Therapy Based on ICG/PDA/TPZ-Loaded Nanoparticles.
Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Survival; Drug Delivery Systems; Humans; Hyperthermia, Induced; Indocyanine Green; Indoles; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Nanoparticles; Neoplasms; Photochemotherapy; Polymers; Prodrugs; Radiation-Sensitizing Agents; Reactive Oxygen Species; Tirapazamine; Tissue Distribution; Treatment Outcome; Tumor Burden; Xenograft Model Antitumor Assays | 2019 |
Organosilica-Based Hollow Mesoporous Bilirubin Nanoparticles for Antioxidation-Activated Self-Protection and Tumor-Specific Deoxygenation-Driven Synergistic Therapy.
Topics: Animals; Antioxidants; Bilirubin; Cell Line, Tumor; Drug Synergism; Humans; Hydrogen Peroxide; Nanoparticles; Neoplasms; Organosilicon Compounds; Prodrugs; Silicon Dioxide; Tirapazamine; Tumor Hypoxia | 2019 |
Hypoxia-specific therapeutic agents delivery nanotheranostics: A sequential strategy for ultrasound mediated on-demand tritherapies and imaging of cancer.
The hypoxic microenvironment induced by sonodynamic therapy (SDT) via sonochemical oxygen consumption usually triggered tumor resistance to SDT, impeding therapeutic efficacy. In this sense, it was highly desired to tackle the hypoxia-related negative issues. Here we provide the therapeutic agents delivery system, TPZ/HMTNPs-SNO, which was constructed by loading tirapazamine (TPZ) into hollow mesoporous titanium dioxide nanoparticles (HMTNPs) with modification of S-nitrosothiol (R-SNO). Upon encountering ultrasound waves, the HMTNPs as sonosensitizers would generate reactive oxygen species (ROS) for SDT. In a sequential manner, the followed SDT-induced hypoxia further activated the "hypoxic cytotoxin", TPZ, for hypoxia-specific killing effect. Meanwhile, the generated ROS could sensitize -SNO groups for on-demand nitric oxide (NO) release in an "anticancer therapeutic window", resulting in the NO sensitized SDT effect. This study confirmed that the TPZ/HMTNPs-SNO with multi-mechanisms exploited the merits of synergistic combination of the three therapeutic modes, consequently potentiating the anticancer efficacy of SDT. Moreover, the echogenic property of NO made the nanoplatform as an ultrasound contrast agent to enhance ultrasound imaging. In this sense, we developed a sequential strategy for ultrasound mediated all-in-one nanotheranostic platform of TPZ/HMTNPs-SNO, which highlighted new possibilities of advancing cancer theranostics in biomedical fields. Topics: Animals; Antineoplastic Agents; Humans; Hypoxia; MCF-7 Cells; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms; S-Nitrosothiols; Theranostic Nanomedicine; Tirapazamine; Titanium; Tumor Burden; Ultrasonography | 2018 |
Light-triggered theranostic liposomes for tumor diagnosis and combined photodynamic and hypoxia-activated prodrug therapy.
Hypoxia tumor microenvironment is a major challenge for photodynamical therapy (PDT), and hypoxia-activated chemotherapy combined PDT could be promising for enhanced anticancer therapy. In this study, we report an innovative 2-nitroimidazole derivative conjugated polyethylene glycol (PEG) amphoteric polymer theranostic liposome encapsulated a photosensitizer Chlorin e6 (Ce6), hypoxia-activated prodrug Tirapazamine (TPZ) and gene probe for synergistic photodynamic-chemotherapy. Ce6-mediated PDT upon irradiation with a laser induces hypoxia, which leads to the disassembly of the liposome and activates the antitumor activity of TPZ for improved cancer cell-killing. The released co-delivered gene probe could effectively detect the oncogenic intracellular biomarker for diagnosis. Both in vitro and in vivo studies demonstrated the greatly improved anti-cancer activity compared to conventional PDT. This work contributes to the design of hypoxia-responsive multifunctional liposome for tumor diagnosis and hypoxia-activated chemotherapy combined PDT for synergetic therapy, which holds great promise for future cancer therapy. Topics: Animals; Antineoplastic Agents; Chlorophyllides; Delayed-Action Preparations; Humans; Light; Liposomes; MCF-7 Cells; Mice; Neoplasms; Nitroimidazoles; Optical Imaging; Photosensitizing Agents; Polyethylene Glycols; Porphyrins; Theranostic Nanomedicine; Tirapazamine; Tumor Hypoxia | 2018 |
Cancer cell membrane-coated biomimetic platform for tumor targeted photodynamic therapy and hypoxia-amplified bioreductive therapy.
Modulating tumor microenvironment to amplify the therapeutic efficiency would be a novel strategy for effective cancer treatment. In this work, based on the TPZ-loaded porphyrinic metal organic framework PCN-224 (PCN stands for porous coordination network), a cancer cell membrane-coated nanoplatform (TPZ@PCN@Mem) was fabricated for tumor targeted PDT and the successively resulting hypoxia-amplified bioreductive therapy. After administration, TPZ@PCN@Mem exhibited the selective accumulation and long-term retention at tumor tissue due to the immune escape and homologous targeting endowed by the cancer membrane coating. Upon light irradiation, PCN-224-mediated toxic reactive oxygen species (ROS) were generated for PDT, and the resulting local hypoxia microenvironment would further accelerate the activation of TPZ for enhanced chemotherapy in 4T1 orthotopic tumor. The cascade synergistic therapeutic effects of TPZ@PCN@Mem could significantly suppress the primary tumor growth, and also inhibit its distal metastasis with minimal side effects. The study indicated an overwhelming superiority of utilizing this bioinspired strategy for tumor targeted PDT and hypoxia-activated bioreductive therapy, which provided a new insight for precise and effective tumor treatment. Topics: Animals; Biomimetic Materials; Cell Death; Cell Hypoxia; Cell Line, Tumor; Cell Membrane; Coated Materials, Biocompatible; Endocytosis; Fluorescence; Injections, Intravenous; Liver Neoplasms; Lung Neoplasms; Mice; Neoplasms; Photochemotherapy; Porosity; RAW 264.7 Cells; Reactive Oxygen Species; Tirapazamine; Triazines | 2017 |
Prodrug-embedded angiogenic vessel-targeting nanoparticle: A positive feedback amplifier in hypoxia-induced chemo-photo therapy.
Photodynamic therapy (PDT) induced hypoxia can significantly upregulate the expression of vascular endothelial growth factor (VEGF) at the tumor-stromal interface, resulting in a promoted angiogenesis. Thus, an angiogenesis vessel-targeting nanoparticle (AVT-NP) consisting of photosensitizer, angiogenic vessel-targeting peptide, and bioreductive prodrug is developed for a chemo-photo synergistic cancer therapy, with which anti-cancer effect is achieved first by PDT and immediately followed with hypoxia-activated cytotoxic free radicals. With targeting capability, the AVT-NPs can effectively accumulate at the tumor site due to the promoted angiogenesis in response to PDT-induced hypoxia. The more nanoparticles delivered to the tumor tissue, the higher efficacy of PDT can be achieved, resulting in a more severe hypoxia and increased angiogenesis. Therefore, the prodrug embedded AVT-NP functions as a positive feedback amplifier in the combinational chemo-photo treatment and indeed achieves an enhanced anti-tumor effect in both in vitro and in vivo studies. Topics: 3T3 Cells; Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Delivery Systems; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia; Male; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Mice, Nude; Nanoparticles; Neoplasms; Neovascularization, Pathologic; Photochemotherapy; Photosensitizing Agents; Prodrugs; Reactive Oxygen Species; Tirapazamine; Triazines; Vascular Endothelial Growth Factor A | 2017 |
Photodynamic Therapy with Liposomal Zinc Phthalocyanine and Tirapazamine Increases Tumor Cell Death via DNA Damage.
The efficacy of photodynamic therapy (PDT) in some solid tumors is limited by the poor biodistributive properties of conventional photosensitizers and a natural predisposition of tumor cells to survive hypoxia and oxidative stress. This study investigated the therapeutic potential of a third-generation photosensitizer, liposomal zinc phthalocyanine (ZnPC), in combination with the hypoxic cytotoxin tirapazamine (TPZ). TPZ induces DNA double strand breaks (DSBs) under hypoxic conditions and subsequent apoptosis via p53 signaling. Experiments were performed in tumor cells with functional p53 (Sk-Cha1) and dysfunctional p53 (A431). The combination therapy of TPZ and PDT induced DNA DSBs and cell cycle stalling and enhanced the cytotoxicity of PDT by exacerbating apopotic and non-apoptotic tumor cell death. These phenomena occurred regardless of oxygen tension and the mechanism of cell death differed per cell line. Liposomes containing both ZnPC and TPZ exhibited no dark toxicity but were more lethal to both cell types after PDT compared to ZnPC-liposomes lacking TPZ—an effect that was more pronounced under hypoxic conditions. In conclusion, TPZ is a suitable pharmaceutical compound to increase PDT efficacy by exploiting the post-PDT tumor hypoxia. The inclusion of TPZ and ZnPC into a single liposomal delivery system was feasible. The PDT strategy described in this study may be valuable for the treatment of PDT-recalcitrant tumors. Topics: Antineoplastic Agents; Cell Death; Cell Line, Tumor; Cell Survival; DNA Damage; Humans; Indoles; Isoindoles; Liposomes; Neoplasms; Organometallic Compounds; Oxidative Stress; Photochemotherapy; Photosensitizing Agents; Reactive Oxygen Species; Tirapazamine; Triazines; Zinc Compounds | 2017 |
Mini-pillar array for hydrogel-supported 3D culture and high-content histologic analysis of human tumor spheroids.
Three-dimensional (3D) cancer cell culture models mimic the complex 3D organization and microenvironment of human solid tumor tissue and are thus considered as highly predictive models representing avascular tumor regions. Confocal laser scanning microscopy is useful for monitoring drug penetration and therapeutic responses in 3D tumor models; however, photonic attenuation at increasing imaging depths and limited penetration of common fluorescence tracers are significant technical challenges to imaging. Immunohistological staining would be a good alternative, but the preparation of tissue sections from rather fragile spheroids through fixing and embedding procedures is challenging. Here we introduce a novel 3 × 3 mini-pillar array chip that can be utilized for 3D cell culturing and sectioning for high-content histologic analysis. The mini-pillar array chip facilitated the generation of 3D spheroids of human cancer cells within hydrogels such as alginate, collagen, and Matrigel. As expected, visualization of the 3D distribution of calcein AM and doxorubicin by optical sectioning was limited by photonic attenuation and dye penetration. The integrity of the 3D microtissue section was confirmed by immunostaining on paraffin sections and cryo-sections. The applicability of the mini-pillar array for drug activity evaluation was tested by measuring viability changes in spheroids exposed to anti-cancer agents, 5-fluorouracil and tirapazamine. Thus, our novel mini-pillar array platform can potentially promote high-content histologic analysis of 3D cultures and can be further optimized for field-specific needs. Topics: Alginates; Antineoplastic Agents; Cell Culture Techniques; Cell Line, Tumor; Collagen; Drug Combinations; Drug Screening Assays, Antitumor; Fluorouracil; Glucuronic Acid; Hexuronic Acids; Humans; Hydrogel, Polyethylene Glycol Dimethacrylate; Lab-On-A-Chip Devices; Laminin; Microscopy, Confocal; Neoplasms; Paraffin Embedding; Proteoglycans; Spheroids, Cellular; Tirapazamine; Triazines | 2016 |
Radiation-/hypoxia-induced solid tumor metastasis and regrowth inhibited by hypoxia-specific upconversion nanoradiosensitizer.
Tumor resistance to ionizing irradiation and cancer cell's metastasis stimulated by radiation often lead to anti-cancer failure, and can be negatively caused by a key role--cellular hypoxia. In this regard, the exploitation of hypoxia-specific cytotoxic agents which assist to potentiate the anti-tumor effect of radiotherapy (RT) as well as efficiently counteract radiation-/hypoxia-induced cancer cell metastasis, becomes especially important, but has been widely overlooked. Herein, a core/shell-structured multifunctional nanoradiosensitizer with upconversion nanoparticle (UCNP) as an inside core, mesoporous silica as the shell and a cavity in between, has been constructed, in which UCNP core serves as radiation dose amplifiers and bio-reductive pro-drug--tirapazamine (TPZ) loaded in cavity is an hypoxia-selective cytotoxin and the silica shell provides the protection and diffusion path for TPZ. Such nanoradiosensitizer has been employed to inhibit the hypoxia-reoxygenation and the subsequent replication of cancer cells that often occurs after a single unaccompanied RT at low doses, and to silence the expression of transcription factors that support the progression of malignancy in cancer. This study confirms the radiotherapeutic benefits of utilizing nanoradiosensitizer as adjuvant to low-dose RT, and the results demonstrate the highly efficient hypoxia-specific killing in oxygen-dependent anti-tumor therapies. Topics: Animals; Cell Death; Cell Proliferation; Cell Survival; Extracellular Matrix; Female; Fluorescent Antibody Technique; HeLa Cells; Humans; Hypoxia; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasm Metastasis; Neoplasms; Oxygen; Radiation-Sensitizing Agents; Tirapazamine; Triazines | 2015 |
A computational model of drug delivery through microcirculation to compare different tumor treatments.
Starting from the fundamental laws of filtration and transport in biological tissues, we develop a computational model to capture the interplay between blood perfusion, fluid exchange with the interstitial volume, mass transport in the capillary bed, through the capillary walls and into the surrounding tissue. These phenomena are accounted at the microscale level, where capillaries and interstitial volume are viewed as two separate regions. The capillaries are described as a network of vessels carrying blood flow. We apply the model to study drug delivery to tumors. The model can be adapted to compare various treatment options. In particular, we consider delivery using drug bolus injection and nanoparticle injection into the blood stream. The computational approach is suitable for a systematic quantification of the treatment performance, enabling the analysis of interstitial drug concentration levels, metabolization rates and cell surviving fractions. Our study suggests that for the treatment based on bolus injection, the drug dose is not optimally delivered to the tumor interstitial volume. Using nanoparticles as intermediate drug carriers overrides the shortcomings of the previous delivery approach. This work shows that the proposed theoretical and computational framework represents a promising tool to compare the efficacy of different cancer treatments. Topics: Algorithms; Antineoplastic Agents; Capillaries; Drug Carriers; Humans; Microcirculation; Models, Biological; Nanoparticles; Neoplasms; Oxygen; Shear Strength; Tirapazamine; Triazines | 2014 |
Targeting the tumour vasculature: exploitation of low oxygenation and sensitivity to NOS inhibition by treatment with a hypoxic cytotoxin.
Many cancer research efforts focus on exploiting genetic-level features that may be targeted for therapy. Tissue-level features of the tumour microenvironment also represent useful therapeutic targets. Here we investigate the presence of low oxygen tension and sensitivity to NOS inhibition of tumour vasculature as potential tumour-specific features that may be targeted by hypoxic cytotoxins, a class of therapeutics currently under investigation. We have previously demonstrated that tirapazamine (TPZ) mediates central vascular dysfunction in tumours. TPZ is a hypoxic cytotoxin that is also a competitive inhibitor of NOS. Here we further investigated the vascular-targeting activity of TPZ by combining it with NOS inhibitor L-NNA, or with low oxygen content gas breathing. Tumours were analyzed via multiplex immunohistochemical staining that revealed irreversible loss of perfusion and enhanced tumour cell death when TPZ was combined with either low oxygen or a NOS inhibitor. Tumour growth rate was reduced by TPZ + NOS inhibition, and tumours previously resistant to TPZ-mediated vascular dysfunction were sensitized by low oxygen breathing. Additional mapping analysis suggests that tumours with reduced vascular-associated stroma may have greater sensitivity to these effects. These results indicate that poorly oxygenated tumour vessels, also being abnormally organized and with inadequate smooth muscle, may be successfully targeted for significant anti-cancer effects by inhibition of NOS and hypoxia-activated prodrug toxicity. This strategy illustrates a novel use of hypoxia-activated cytotoxic prodrugs as vascular targeting agents, and also represents a novel mechanism for targeting tumour vessels. Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cytotoxins; Female; HCT116 Cells; HT29 Cells; Humans; Hypoxia; Immunohistochemistry; Mice; Mice, Inbred C3H; Mice, Inbred NOD; Mice, SCID; Neoplasms; Neovascularization, Pathologic; Nitric Oxide Synthase; Nitroarginine; Tirapazamine; Treatment Outcome; Triazines; Tumor Burden; Xenograft Model Antitumor Assays | 2013 |
Enhanced antitumor efficacy of cisplatin by tirapazamine-transferrin conjugate.
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 | 2012 |
Avascular tumour growth dynamics and the constraints of protein binding for drug transportation.
The potential for the use of in-silico models of disease in progression monitoring is becoming increasingly recognised, as well as its contribution to the development of complete curative processes. In this paper we report the development of a hybrid cellular automaton model to mimic the growth of avascular tumours, including the infusion of a bioreductive drug to study the effects of protein binding on drug transportation. The growth model is operated within an extracellular tumour microenvironment. An artificial Neural Network based scheme was implemented that modelled the behaviours of each cell (proliferation, quiescence, apoptosis and/or movement) based on the complex heterogeneous microenvironment; consisting of oxygen, glucose, hydrogen ions, inhibitory factors and growth factors. To validate the growth model results, we conducted experiments with multicellular tumour spheroids. These results showed good agreement with the predicted growth dynamics. The outcome of the avascular tumour growth model suggested that tumour microenvironments have a strong impact on cell behaviour. To address the problem of cellular proteins acting as resistive factors preventing efficient drug penetration, a bioreactive drug (tirapazamine) was added to the system. This allowed us to study the drug penetration through multicellular layers of tissue after its binding to cellular proteins. The results of the in vitro model suggested that the proteins reduce the toxicity of the drug, reducing its efficacy for the most severely hypoxic fractions furthest from a functional blood vessel. Finally this research provides a unique comparison of in vitro tumour growth with an intelligent in silico model to measure bioreductive drug availability inside tumour tissue through a set of experiments. Topics: Antineoplastic Agents; Biological Transport; Cell Hypoxia; Cell Proliferation; Cell Survival; Diffusion; HT29 Cells; Humans; Models, Biological; Neoplasms; Neural Networks, Computer; Protein Binding; Reproducibility of Results; Spheroids, Cellular; Tirapazamine; Triazines | 2012 |
Synthesis, hypoxia-selective cytotoxicity of new 3-amino-1,2,4-benzotriazine-1,4-dioxide derivatives.
We reported the synthesis, hypoxic cytotoxic activities and selectivities of 18 new 3-(alkoxymethylamino)-1,2,4-benzotriazine 1,4-dioxides. The synthesized compounds were screened in vitro against 5 cell lines: K562, SMMC-7721, A549, PC-3 and KB in hypoxia and in normoxia. Some of them showed higher or similar cytotoxic activity when compared to tirapazamine. Physico-chemical study showed the positive correlation between hypoxic activity and lipophilicity within a certain range. Preliminary mechanism study on the potent derivatives 4b, 4l and 4m indicated that the cytotoxic activities of these compounds might be mediated by inducing apoptosis. Topics: Antineoplastic Agents; Cell Hypoxia; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Neoplasms; Structure-Activity Relationship; Tirapazamine; Triazines | 2011 |
Hypoxia-dependent retinal toxicity of NLCQ-1 (NSC 709257) in BALB/c mice. Comparison with tirapazamine.
Bioreductive drugs can cause retinal toxicity, mediated by extensive apoptosis in the outer retina of rodents and monkeys. In the present study, we have investigated whether or not the novel and promising hypoxia-selective cytotoxin 4-[3-(2-nitro-1-imidazolyl)-propylamino]-7-chloroquinoline hydrochloride (NLCQ-1, NSC 709257) can cause hypoxia-dependent retinal toxicity in BALB/c mice alone or in combination with cyclophosphamide (CPM), one of the anti-cancer agents that acts synergistically with NLCQ-1 against mouse tumours and human xenografts. The bioreductive agent tirapazamine (TPZ) was included for comparison purposes. Retinal damage was quantified by morphometric analysis of histological sections following IP treatment of female BALB/c mice. No retinal toxicity was observed with 10 or 22 mg/kg of NLCQ-1 or 23 mg/kg TPZ alone, whereas statistically significant retinal toxicity was observed with the higher TPZ dose of 52 mg/kg (p < 0.001). Thus, a normalized photoreceptor layer thickness (NPT) value of 0.50 ± 0.04, 0.48 ± 0.03 and 0.33 ± 0.06 was determined for untreated, NLCQ-1 and TPZ-treated mice at the highest dose, respectively. Marginal retinal toxicity was observed with the lower dose of TPZ in combination with CPM. Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytotoxins; Dose-Response Relationship, Drug; Drug Synergism; Female; Humans; Hypoxia; Imidazoles; Mice; Mice, Inbred BALB C; Neoplasms; Quinolines; Retina; Tirapazamine; Triazines | 2011 |
Quinoxalino[2,3-c]cinnolines and their 5-N-oxide: alkoxylation of methyl-substituted quinoxalino[2,3-c]cinnolines to acetals and orthoesters.
We report the alkoxylation of methyl-substituted quinoxalino[2,3-c]cinnolines to give acetals and orthoesters in high yields. Routes to the precursors of this alkoxylation reaction as well as other quinoxalino[2,3-c]cinnoline and their 5-oxide derivatives are reported. Most of these quinoxalino[2,3-c]cinnolines were prepared by cyclization of the corresponding 2-amino-3-(2-nitrophenyl)quinoxaline, which, in turn, result from an unusual Beirut reaction from benzofurazan oxides plus 2-nitrobenzylcyanides. Mechanistic explanations for these intriguing reactions are presented. Topics: Acetals; Alcohols; Antineoplastic Agents; Benzoxazoles; Chemistry, Pharmaceutical; Cyanides; Cyclization; Esters; Heterocyclic Compounds, 2-Ring; Humans; Magnetic Resonance Spectroscopy; Neoplasms; Oxides; Quinoxalines; Tirapazamine; Triazines | 2011 |
Pharmacokinetic/pharmacodynamic modeling identifies SN30000 and SN29751 as tirapazamine analogues with improved tissue penetration and hypoxic cell killing in tumors.
Tirapazamine (TPZ) has attractive features for targeting hypoxic cells in tumors but has limited clinical activity, in part because of poor extravascular penetration. Here, we identify improved TPZ analogues by using a spatially resolved pharmacokinetic/pharmacodynamic (SR-PKPD) model that considers tissue penetration explicitly during lead optimization.. The SR-PKPD model was used to guide the progression of 281 TPZ analogues through a hierarchical screen. For compounds exceeding hypoxic selectivity thresholds in single-cell cultures, SR-PKPD model parameters (kinetics of bioreductive metabolism, clonogenic cell killing potency, diffusion coefficients in multicellular layers, and plasma pharmacokinetics at well tolerated doses in mice) were measured to prioritize testing in xenograft models in combination with radiation.. SR-PKPD-guided lead optimization identified SN29751 and SN30000 as the most promising hypoxic cytotoxins from two different structural subseries. Both were reduced to the corresponding 1-oxide selectively under hypoxia by HT29 cells, with an oxygen dependence quantitatively similar to that of TPZ. SN30000, in particular, showed higher hypoxic potency and selectivity than TPZ in tumor cell cultures and faster diffusion through HT29 and SiHa multicellular layers. Both compounds also provided superior plasma PK in mice and rats at equivalent toxicity. In agreement with SR-PKPD predictions, both were more active than TPZ with single dose or fractionated radiation against multiple human tumor xenografts.. SN30000 and SN29751 are improved TPZ analogues with potential for targeting tumor hypoxia in humans. Novel SR-PKPD modeling approaches can be used for lead optimization during anticancer drug development. Topics: Algorithms; Animals; Antineoplastic Agents; Cell Hypoxia; HT29 Cells; Humans; Male; Mice; Mice, Nude; Models, Biological; Neoplasms; Oxygen; Radiation-Sensitizing Agents; Rats; Rats, Sprague-Dawley; Tirapazamine; Triazines; Xenograft Model Antitumor Assays | 2010 |
Effects of cytokine-induced macrophages on the response of tumor cells to banoxantrone (AQ4N).
Tumor-associated macrophages (TAMs) are found in many solid tumors and have often been shown to accumulate in the hypoxic regions surrounding areas of necrosis. TAMs are the major site of expression of nitric oxide synthase (NOS), a heme-containing homodimeric enzyme consisting of oxygenase and reductase domains. The latter has a high degree of sequence homology to cytochrome P450 reductase and a functional consequence of this is the ability of NOS, under hypoxic conditions, to activate the bioreductive drugs tirapazamine and RSU1069. Banoxantrone (AQ4N) is a bioreductive prodrug activated in hypoxia by an oxygen-dependent two-electron reductive process to yield the topoisomerase II inhibitor AQ4. A feature of this process is that the final product could potentially show bystander cell killing. Thus, in this study, we investigated the ability of inducible NOS (iNOS)-expressing TAMs to activate AQ4N and elicit toxicity in cocultured human tumor cells. Murine macrophages were induced to overexpress iNOS by treatment with a combination of cytokines, mixed with HT1080 and HCT116 human tumor cells, and the toxicity of AQ4N was determined under aerobic or hypoxic conditions. The aerobic toxicity of AQ4N toward tumor cells was not affected through coculturing with macrophages. However, under hypoxic conditions, the induction of iNOS activity in the macrophages was associated with an increase in AQ4N metabolism and a substantial increase in tumor cell toxicity, which was dependent on the proportion of macrophages in the culture. This study is the first demonstration of TAM-mediated prodrug activation to result in bystander killing of human tumor cells. Topics: Animals; Anthraquinones; Antineoplastic Agents; Cell Cycle; Cell Hypoxia; Cell Line; Cell Survival; Cytokines; Gene Expression Regulation, Neoplastic; Humans; Macrophages; Mice; Neoplasms; Nitric Oxide Synthase Type II; Tirapazamine; Triazines | 2009 |
Detecting vascular-targeting effects of the hypoxic cytotoxin tirapazamine in tumor xenografts using magnetic resonance imaging.
To determine whether vascular-targeting effects can be detected in vivo using magnetic resonance imaging (MRI).. MR images of HCT-116 xenograft-bearing mice were acquired at 7 Tesla before and 24 hours after intraperitoneal injections of tirapazamine. Quantitative dynamic contrast-enhanced MRI analyses were performed to evaluate changes in tumor perfusion using two biomarkers: the volume transfer constant (K(trans)) and the initial area under the concentration-time curve (IAUC). We used novel implanted fiducial markers to obtain cryosections that corresponded to MR image planes from excised tumors; quantitative immunohistochemical mapping of tumor vasculature, perfusion, and necrosis enabled correlative analysis between these and MR images.. Conventional histological analysis showed lower vascular perfusion or greater amounts of necrosis in the central regions of five of eight tirapazamine-treated tumors, with three treated tumors showing no vascular dysfunction response. MRI data reflected this result, and a striking decrease in both K(trans) and IAUC values was seen with the responsive tumors. Retrospective evaluation of pretreatment MRI parameters revealed that those tumors that did not respond to the vascular-targeting effects of tirapazamine had significantly higher pretreatment K(trans) and IAUC values.. MRI-derived parameter maps showed good agreement with histological tumor mapping. MRI was found to be an effective tool for noninvasively monitoring and predicting tirapazamine-mediated central vascular dysfunction. Topics: Animals; Antineoplastic Agents; Area Under Curve; Blood Volume; Blood Volume Determination; Cell Hypoxia; Contrast Media; Magnetic Resonance Imaging; Mice; Mice, Inbred NOD; Mice, SCID; Necrosis; Neoplasm Transplantation; Neoplasms; Prostheses and Implants; Radiation-Sensitizing Agents; Regional Blood Flow; Tirapazamine; Transplantation, Heterologous; Triazines | 2009 |
Increased tumor oxygenation and drug uptake during anti-angiogenic weekly low dose cyclophosphamide enhances the anti-tumor effect of weekly tirapazamine.
Metronomic cyclophosphamide treatment is associated with anti-angiogenic activity and is anticipated to generate exploitable hypoxia using hypoxia-activated prodrugs. Weekly administration of tirapazamine (TPZ; 5 mg/kg body weight i.p.) failed to inhibit the growth of 9L gliosarcoma tumors grown s.c. in scid mice. However, the anti-tumor effect of weekly cyclophosphamide (CPA) treatment (140 mg/kg BW i.p.) was substantially enhanced by weekly TPZ administration. An extended tumor free period and increased frequency of tumor eradication without overt toxicity were observed when TPZ was given 3, 4 or 5 days after each weekly CPA treatment. Following the 2(nd) CPA injection, Electron Paramagnetic Resonance (EPR) Oximetry indicated significant increases in tumor pO(2), starting at 48 hr, which further increased after the 3(rd) CPA injection. pO(2) levels were, however, stable in growing untreated tumors. A strong negative correlation (-0.81) between tumor pO(2) and tumor volume during 21 days of weekly CPA chemotherapy was observed, indicating increasing tumor pO(2) with decreasing tumor volume. Furthermore, CPA treatment resulted in increased tumor uptake of activated CPA. CPA induced increases in VEGF RNA, which reached a maximum on day 1, and in PLGF RNA which was sustained throughout the treatment, while anti-angiogenic host thrombospondin-1 increased dramatically through day 7 post-CPA treatment. Weekly cyclophosphamide treatment was anticipated to generate exploitable hypoxia. However, our findings suggest that weekly CPA treatment induces a functional improvement of tumor vasculature, which is characterized by increased tumor oxygenation and drug uptake in tumors, thus counter-intuitively, benefiting intratumoral activation of TPZ and perhaps other bioreductive drugs. Topics: Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cyclophosphamide; Drug Administration Schedule; Humans; Hypoxia; Mice; Mice, SCID; NADPH-Ferrihemoprotein Reductase; Neoplasms; Oxygen; Time Factors; Tirapazamine; Triazines; Xenograft Model Antitumor Assays | 2009 |
Pharmacokinetic/pharmacodynamic model-guided identification of hypoxia-selective 1,2,4-benzotriazine 1,4-dioxides with antitumor activity: the role of extravascular transport.
Pharmacokinetic/pharmacodynamic (PK/PD) modeling has shown the antitumor activity of tirapazamine (TPZ), a bioreductive hypoxia-selective cytotoxin, to be limited by poor penetration through hypoxic tumor tissue. We have prepared a series of 1,2,4-benzotriazine 1,4-dioxide (BTO) analogues of TPZ to improve activity against hypoxic cells by increasing extravascular transport. The 6 substituents modified lipophilicity and rates of hypoxic metabolism. 3-Alkylamino substituents increased aqueous solubility and also influenced lipophilicity and hypoxic metabolism. PK/PD model-guided screening was used to select six BTOs for evaluation against hypoxic cells in HT29 human tumor xenografts. All six BTOs were active in vivo, and two provided greater hypoxic cell killing than TPZ because of improved transport and/or plasma PK. This PK/PD model considers two causes of therapeutic failure (limited tumor penetration and poor plasma pharmacokinetics) often not addressed early in drug development and provides a general strategy for selecting candidates for in vivo evaluation during lead optimization. Topics: Algorithms; Animals; Biological Transport; Cell Hypoxia; Cell Line, Tumor; Humans; Mice; Mice, Nude; Models, Biological; Neoplasm Transplantation; Neoplasms; Transplantation, Heterologous; Triazines | 2007 |
DNA strand damage product analysis provides evidence that the tumor cell-specific cytotoxin tirapazamine produces hydroxyl radical and acts as a surrogate for O(2).
The compound 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, TPZ) is a clinically promising anticancer agent that selectively kills the oxygen-poor (hypoxic) cells found in solid tumors. It has long been known that, under hypoxic conditions, TPZ causes DNA strand damage that is initiated by the abstraction of hydrogen atoms from the deoxyribose phosphate backbone of duplex DNA, but exact chemical mechanisms underlying this process remain unclear. Here we describe detailed characterization of sugar-derived products arising from TPZ-mediated strand damage. We find that the action of TPZ on duplex DNA under hypoxic conditions generates 5-methylene-2-furanone (6), oligonucleotide 3'-phosphoglycolates (7), malondialdehyde equivalents (8 or 9), and furfural (10). These results provide evidence that TPZ-mediated strand damage arises via hydrogen atom abstraction from both the most hindered (C1') and least hindered (C4' and C5') positions of the deoxyribose sugars in the double helix. The products observed are identical to those produced by hydroxyl radical. Additional experiments were conducted to better understand the chemical pathways by which TPZ generates the observed DNA-damage products. Consistent with previous work showing that TPZ can substitute for molecular oxygen in DNA damage reactions, it is found that, under anaerobic conditions, reaction of TPZ with a discrete, photogenerated C1'-radical in a DNA 2'-oligodeoxynucleotide cleanly generates the 2-deoxyribonolactone lesion (5) that serves as the precursor to 5-methylene-2-furanone (6). Overall, the results provide insight regarding the chemical structure of the DNA lesions that confront cellular repair, transcription, and replication machinery following exposure to TPZ and offer new information relevant to the chemical mechanisms underlying TPZ-mediated strand cleavage. Topics: Antineoplastic Agents; Chromatography, High Pressure Liquid; Cytotoxins; DNA Damage; Furaldehyde; Hydrogen; Hydroxyl Radical; Malondialdehyde; Models, Chemical; Neoplasms; Oligonucleotides; Sugar Acids; Time Factors; Tirapazamine; Transcription, Genetic; Triazines | 2007 |
Tumor hypoxia in cancer therapy.
Human solid tumors are invariably less well-oxygenated than the normal tissues from which they arose. This so-called tumor hypoxia leads to resistance to radiotherapy and anticancer chemotherapy as well as predisposing for increased tumor metastases. In this chapter, we examine the resistance of tumors to radiotherapy produced by hypoxia and, in particular, address the question of whether this resistance is the result of the physicochemical free radical mechanism that produces resistance to radiation killing of cells in vitro. We conclude that a major part of the resistance, though perhaps not all, is the result of the physicochemical free radical mechanism of the oxygen effect in sensitizing cells to ionizing radiation. However, in modeling studies used to evaluate the effect of fractionated irradiation on tumor response, it is essential to consider the fact that the tumor cells are at a wide range of oxygen concentrations, not just at the extremes of oxygenated and hypoxic. Prolonged hypoxia of the tumor tissue also leads to necrosis, and necrotic regions are also characteristic of solid tumors. These two characteristics--hypoxia and necrosis--represent clear differences between tumors and normal tissues and are potentially exploitable in cancer treatment. We discuss strategies for exploiting these differences. One such strategy is to use drugs that are toxic only under hypoxic conditions. The second strategy is to take advantage of the selective induction under hypoxia of the hypoxia-inducible factor (HIF)-1. Gene therapy strategies based on this strategy are in development. Finally, tumor hypoxia can be exploited using live obligate anaerobes that have been genetically engineered to express enzymes that can activate nontoxic prodrugs into toxic chemotherapeutic agents. Topics: Anthraquinones; Antineoplastic Agents; Cell Hypoxia; Cytotoxins; Gene Targeting; Genetic Therapy; Humans; Hypoxia-Inducible Factor 1; Neoplasms; Nitrogen Mustard Compounds; Oxygen; Prodrugs; Tirapazamine; Triazines | 2007 |
Low-dose metronomic daily cyclophosphamide and weekly tirapazamine: a well-tolerated combination regimen with enhanced efficacy that exploits tumor hypoxia.
The recent clinical successes of antiangiogenic drug-based therapies have also served to highlight the problem of acquired resistance because, similar to other types of cancer therapy, tumors that initially respond eventually stop doing so. Consequently, strategies designed to delay resistance or treat resistant subpopulations when they arise have assumed considerable importance. This requires a better understanding of the various possible mechanisms for resistance. In this regard, reduced oxygenation is thought to be a key mediator of the antitumor effects of antiangiogenic therapies; accordingly, increased hypoxia tolerance of the tumor cells presents a potential mechanism of resistance. However, hypoxia can also be exploited therapeutically through the use of hypoxic cell cytotoxins, such as tirapazamine. With this in mind, we measured the oxygenation of PC-3 human prostate cancer xenografts subjected to chronic low-dose metronomic (LDM) antiangiogenic chemotherapy using cyclophosphamide given through the drinking water. We found that LDM cyclophosphamide impairs the oxygenation of PC-3 xenografts even during relapse, coinciding with reduced microvessel density. Combination of LDM cyclophosphamide with tirapazamine results in significantly improved tumor control in the PC-3, HT-29 colon adenocarcinoma, and MDA-MB-231 breast cancer human xenograft models without having a negative effect on the favorable toxicity profile of LDM cyclophosphamide. These results provide further evidence that reduced vascular dependence/increased hypoxia tolerance may be a basis for eventual resistance of tumors exposed to long-term LDM chemotherapy. Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Growth Processes; Cell Hypoxia; Cell Line, Tumor; Colonic Neoplasms; Cyclophosphamide; Female; Humans; Male; Mice; Mice, Inbred BALB C; Neoplasms; Neovascularization, Pathologic; Oxygen; Prostatic Neoplasms; Tirapazamine; Triazines; Xenograft Model Antitumor Assays | 2006 |
The usefulness of continuous administration of hypoxic cytotoxin combined with mild temperature hyperthermia, with reference to effects on quiescent tumour cell populations.
To evaluate the usefulness of continuous administration of hypoxic cytotoxins in terms of targeting acute hypoxia in solid tumours and the significance of combination with mild temperature hyperthermia (MTH) (40 degrees C, 60 min), the cytotoxic effects of singly or continuously administered tirapazamine (TPZ) and TX-402 were examined in combination with or without MTH in vivo. Further, the effects were also analysed on total (=proliferating (P)+quiescent (Q)) and Q cell populations in solid tumours with the method for selectively detecting the Q cell response. C3H/He mice bearing SCC VII tumours received a continuous administration of 5-bromo-2'-deoxyuridine (BrdU) for 5 days to label all P cells. The tumour-bearing mice then received a single intra-peritoneal injection or 24 h continuous subcutaneous infusion of hypoxic cytotoxin, TPZ or TX-402, with or without MTH. On the other hand, to detect the changes in the hypoxic fraction (HF) in the tumours by MTH, another group of mice with or without MTH received a series of test doses of gamma-rays while alive or after tumour clamping. After each treatment, the tumour cells were isolated and incubated with a cytokinesis blocker (=cytochalasin-B) and the micronucleus (MN) frequency in cells without BrdU labelling (=Q cells) was determined using immunofluorescence staining for BrdU. The MN frequency in total tumour cells was determined from the tumours that were not pre-treated with BrdU. The sensitivity to TX-402 was slightly higher than that to TPZ in both total and Q tumour cells. Continuous administration elevated the sensitivity of both total and Q cells, especially total cells. MTH raised the sensitivity of Q cells more remarkably than that of total cells in both single and continuous administrations. It was thought to be probably because of the higher dose distribution of hypoxic cytotoxin in intermediately hypoxic areas derived mainly from chronic hypoxia through MTH. From the viewpoint of tumour control as a whole including both total and Q tumour cells, the continuous administration of hypoxic cytotoxin combined with MTH may be useful for sensitizing tumour cells in vivo. Topics: Animals; Antineoplastic Agents; Bromodeoxyuridine; Carcinoma, Squamous Cell; Combined Modality Therapy; Cyclic N-Oxides; Female; Fluorescent Antibody Technique; Hyperthermia, Induced; Mice; Mice, Inbred C3H; Micronucleus Tests; Neoplasm Transplantation; Neoplasms; Quinoxalines; Tirapazamine; Triazines | 2005 |
Therapeutic targets in radiotherapy.
Enormous progress has been made in the past 5 years in our understanding of the gene products governing the response of mammalian cells to ionizing radiation. Many of these are potential targets for enhancing the effectiveness of radiotherapy. However, a major barrier to such efforts is the requirement for a preferential effect on tumor vs. normal cells. Such a requirement can only come about by exploiting a known difference between tumor and normal cells.. This review highlights three differences between tumor and normal cells that are being exploited with fractionated radiotherapy.. The three strategies to enhance preferentially tumor response to radiotherapy are inhibition of ras activity using farnesyltransferase inhibitors (FTIs), inhibition of epidermal growth factor receptors (EGFRs), and the use of drugs that preferentially kill hypoxic cells. Each of these strategies exploits a known difference between at least some tumors and their surrounding normal tissues, and each has shown encouraging results when combined with fractionated radiation in preclinical studies.. For each of the three strategies to enhance preferentially the sensitivity of cancers, the preclinical and early clinical data are promising for their successful application in radiotherapy. Topics: Alkyl and Aryl Transferases; Antibodies, Monoclonal; Antineoplastic Agents; Cell Division; Cell Hypoxia; Dose Fractionation, Radiation; Enzyme Inhibitors; ErbB Receptors; Farnesyltranstransferase; Genes, ras; Head and Neck Neoplasms; Humans; Methionine; Neoplasms; Radiation Tolerance; Radiation-Sensitizing Agents; Signal Transduction; Tirapazamine; Triazines; Tumor Cells, Cultured | 2001 |
Radiosensitization effect by combination with paclitaxel in vivo, including the effect on intratumor quiescent cells.
To evaluate the radiosensitization effect on solid tumors upon combination treatment with paclitaxel (TXL), including the effect on intratumor quiescent (Q) cells.. Mice bearing SCC VII or EL4 solid tumors received 5-bromo-2'-deoxyuridine (BrdU) continuously for 5 days to label all proliferating (P) cells. The mice then received gamma-irradiation with or without tirapazamine (TPZ) at various time points after TXL administration. Another group of mice received a series of test doses of gamma-rays while alive or after tumor clamping to obtain hypoxic fractions (HFs) in the tumors at various time points after TXL administration. Immediately after irradiation, the tumor cells were isolated and incubated with a cytokinesis blocker. The micronucleus (MN) frequency in cells without BrdU labeling (Q cells) was determined using immunofluorescence staining for BrdU. Meanwhile, 6 h after irradiation, the tumor cells were isolated from the solid tumors in another group of mice, and the apoptosis frequency in Q cells was also determined with immunofluorescence staining for BrdU. The MN and apoptosis frequency in total (P + Q) tumor cells were determined from the tumors that were not pretreated with BrdU. For the measurement of the HFs, the MN or apoptosis frequency of Q cells was then used to calculate the surviving fraction of Q cells from the regression line for the relationship between the MN or apoptosis frequency and the surviving fraction of total tumor cells.. In both SCC VII and EL4 tumors, maximum values of mitotic index (MI) and apoptosis frequency were observed 9 and 24 h after TXL administration, respectively. However, on the whole, the apoptosis frequency for SCC VII was very low. gamma-Irradiation 9 h after TXL administration induced significant radiosensitization effects on the total cells of both tumors. Irradiation at 60 h had a more significant effect on total cells of EL4 tumor, but no significant effect on total cells of SCC VII tumor. Combined treatment with TXL induced no radiosensitization effect on Q cells in either tumor. The effect on Q cells was observed only after TPZ was administered. The HF of total cells in EL4 tumors decreased significantly 60 h after TXL administration.. No radiosensitization effect upon combination treatment with TXL is induced in Q tumor cells. However, the effect on P cells is produced by irradiation at the time when the maximum values of MI are induced following TXL administration. In addition, for tumors that are susceptible to apoptosis after TXL administration alone, irradiation at the time of sufficient reoxygenation in tumors after TXL administration produces a greater radioenhancement effect on P cells. Topics: Animals; Apoptosis; Bromodeoxyuridine; Carcinoma, Squamous Cell; Cell Survival; Humans; Mice; Mice, Inbred C3H; Micronucleus Tests; Neoplasms; Paclitaxel; Radiation Tolerance; Radiation-Sensitizing Agents; Radiobiology; Radiotherapy Dosage; Time Factors; Tirapazamine; Triazines | 2001 |
Optimizing the use of combined radioimmunotherapy and hypoxic cytotoxin therapy as a function of tumor hypoxia.
Combined radioimmunotherapy (RAIT) and hypoxic cytotoxin therapy (SR4233 or NLCQ-1) have been evaluated with both modalities administered on the same day with only moderate improvement compared with the effects of RAIT alone. In a series of studies using oxygen electrodes, immunohistochemistry and radiotracers, we have demonstrated that RAIT induces a prolonged state of hypoxia in most tumors, without affecting the pO(2) levels in normal tissues. Using serial microelectrode measurements through subcutaneous (s.c.) GW-39 human colonic xenografts, we established that the median pO(2) was unrelated to the initial size of the tumor, over a range of sizes from 1.0 to 4.0 cm. Fourteen days after mice were given a 240-microCi dose of (131)I-MN-14 anti-carcinoembryonic antigen immunoglobulin G, their median pO(2) declined from 26.1 +/- 9.6 mmHg to 9.8 +/- 3.9 mmHg (p < 0.001). Using the radiotracer (3)H-MISO that accumulates in hypoxic regions, uptake in GW-39, LoVo and LS174T s.c. human colonic tumors increased 3.0- to 4.2-fold from day 14 through day 28 post-RAIT, but uptake of (3)H-MISO in CALU-3 tumors remained unchanged after RAIT. Normal tissue (liver, kidney, lung) uptake of (3)H-MISO did not exhibit significant changes. The increase in tumor hypoxia was also demonstrated visually using anti-PIMO staining of tumor sections. We postulated that sequential delivery of the 2 therapeutic agents, with the hypoxic cytotoxin given 2 weeks after RAIT when tumor pO(2) levels were at their nadir, would improve the therapeutic response above either modality alone or above the 2 agents delivered on the same day. Tumor growth was compared in mice given either RAIT or cytotoxin alone, the combined treatment on the same day or with the cytotoxin delivered 14 days after RAIT. Tumor size on day 35 for RAIT-treated and SR4233-treated GW-39 were 3.56 +/- 0.40 and 7.98 +/- 2.50 cm(3). When RAIT + SR4233 were delivered on the same day, tumor size dropped to 2.78 +/- 0.80 cm(3). If RAIT was given on day 0 and SR4233 on day 14, size further declined further to 1.74 +/- 0.32 cm(3) (p < 0.05 compared with same day delivery). For LS174T, tumor size on day 28 for RAIT-treated and SR4233-treated tumors were 1.14 +/- 0.36 cm(3) and 3.65 +/- 0.78 cm(3), respectively. When RAIT + SR4233 were delivered on the same day, size was 0.51 +/- 0.174 cm(3). If RAIT was dosed on day 0 and SR4233 was given on day 14, tumor size was 0.13 +/- 0.07 cm(3) (p < 0.05). Similar results were obtained for L Topics: Animals; Antineoplastic Agents; Carcinoembryonic Antigen; Cell Hypoxia; Combined Modality Therapy; Cytotoxins; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hypoxia; Imidazoles; Immunoglobulin G; Mice; Mice, Nude; Microelectrodes; Neoplasm Transplantation; Neoplasms; Oxygen; Quinolines; Radiation-Sensitizing Agents; Radioimmunotherapy; Time Factors; Tirapazamine; Triazines; Tumor Cells, Cultured | 2001 |
11th Lorne Cancer Conference, Lorne, Victoria, Australia, 11-14th February 1999.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Cytokines; Genes, APC; Genes, Tumor Suppressor; Genetic Techniques; Humans; Neoplasms; Telomere; Tirapazamine; Triazines; Wilms Tumor | 1999 |
CuTira brachytherapy: a new combination of radioactive copper isotopes and the hypoxic cytotoxin, tirapazamine, for targeted tumor therapy.
We previously showed a significant enhancement of tirapazamine-induced cytotoxicity and DNA damage after binding with copper. This result suggests that conjugates of tirapazamine with radioactive copper, i.e., 64Cu and 67Cu, may offer potential for targeted therapy of a wide range of advanced stage tumors including a possible treatment for patients with solitary hepatocellular carcinoma by intrahepatic arterial infusion. Major supporting considerations include: (a) tirapazamine having a high selective toxicity against hypoxic cells; (b) the nature of radioactive decay of these copper isotopes and obtainable high specific activity; and (c) simple procedure for the production of copper-tirapazamine complex. Topics: Brachytherapy; Humans; Neoplasms; Organometallic Compounds; Tirapazamine; Triazines | 1998 |
Vasoactivity, a potentially important variable in the sequencing of tirapazamine (SR 4233) and radiation.
Topics: Animals; Cell Survival; Combined Modality Therapy; Drug Administration Schedule; Humans; Mice; Neoplasms; Radiotherapy; Regional Blood Flow; Tirapazamine; Triazines; Vasomotor System | 1995 |
Bioreductive drugs for cancer therapy: the search for tumor specificity.
The activity of three different classes of bioreductive drug, i.e., heterocyclic nitro compounds, N-oxides and quinones are compared. The major characteristics of RB-6145, tirapazamine and E09 are summarized and future directions for development of new bioreductive drugs are outlined. The concept of potentiating bioreductive drug activity by increasing tumor hypoxia is described and illustrated in particular by the use of photodynamic therapy (PDT) in combination with RSU-1069. Examples of how the therapeutic effectiveness of this approach can be studied by the use of 31P magnetic resonance spectroscopy is described. The effects of manipulation of nitric oxide (NO) levels in tumors by the use of modifiers of NO-synthase activity is illustrated by studies with the inhibitor nitro-L-arginine in experimental tumors. Associated changes in tumor physiology indicate promise for potential applications in therapy. Finally, changes in expression of reductase enzyme levels are considered in the context of the heterogenous nature of the tumor microenvironment. Topics: Animals; Antineoplastic Agents; Humans; Neoplasms; Nitric Oxide; Nitroimidazoles; Oxidation-Reduction; Photochemotherapy; Porfiromycin; Prodrugs; Tirapazamine; Triazines | 1994 |