tirapazamine and Uterine-Cervical-Neoplasms

The advantages of cisplatin based radiochemotherapy have been proven for over one and a half decades, particularly in the treatment of advanced solid tumours. In head and neck, and cervical tumours results of prospective studies are available. Those showed that both in the early and advanced stages, local control and overall survival rates are better than radiotherapy alone. The effect of cisplatin can be probably intensified with novel, more effective molecules, such as m-TOR inhibitors and tirapazamine. The authors review cisplatin and non-cisplatin based radiochemotherapy protocols, which improve previous treatment results. It should be considered, however, radiotherapy for cervical cancer can cause hematological, urogenital and intestinal toxicity, similarly to other combined treatments. The authors briefly outline international recommendations and their own experience for the prevention of these side-effects.. Közel másfél évtizede bizonyított a ciszplatinalapú radiokemoterápia előnye, mindenekelőtt az előrehaladott szolid tumorok kezelésében. Fej-nyaki és méhnyakdaganatokban már rendelkezésre állnak az áttekintő, sőt prospektív vizsgálatok eredményei. Bizonyítást nyert, hogy mind korai, mind előrehaladott stádiumban a lokális terápiás válasz és a teljes túlélés vonatkozásában jobb az egyedüli sugárterápiához képest. A ciszplatin hatása újabb hatékony molekulákkal (például m-TOR-gátlókkal, tirapazaminnal) valószínűleg tovább fokozható. Ismertetésre kerülnek ezeken túl a jelenleg folyó, a terápiás eredményeket hasonlóan tovább javító, nem ciszplatinalapú radiokemoterápiás kezelések is. Nem szabad megfeledkezni ugyanakkor arról, hogy mindenekelőtt a méhnyakrákok radiokemoterápiája – mint minden kombinált kezelés – együtt járhat hematológiai és/vagy hólyag- és bélkárosodással. Ennek megelőzésére és elkerülésére már saját tapasztalatok és nemzetközi ajánlások is rendelkezésre állnak. Orv. Hetil., 2013, 154, 803–809.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Chemoradiotherapy; Chemotherapy, Adjuvant; Cisplatin; Female; Humans; Neoplasm Staging; Radiation-Sensitizing Agents; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Radiotherapy, Adjuvant; Radiotherapy, Computer-Assisted; Radiotherapy, Intensity-Modulated; Tirapazamine; TOR Serine-Threonine Kinases; Triazines; Uterine Cervical Neoplasms

Cervical cancer is the second-most common malignancy in women worldwide. Cisplatin was introduced as a radiosensitizer in 1999 to improve chances of survival. Tumor cell hypoxia, however, remains a major limiting factor in the treatment of solid tumors with chemotherapy and radiation. There has since been significant interest in the use of bioreductive agents to overcome the hypoxia and improve survival. The addition of tirapazamine (TPZ) to conventional chemoradiation protocols in the management of cervical cancer held promise in the initial Phase I and II clinical trials in delaying recurrence and improving survival. However, GOG recently announced early closure of the Phase III trial of tirapazamine in cervical cancer due to a lack of increased survival.. This article covers the definition of hypoxic tumor cells, the markers of tumor hypoxia, methods for measuring hypoxia as well as the pharmacologic action of tirapazamine in hypoxic media. Furthermore, it critically evaluates TPZ's role in cervical cancer treatment and the drawbacks to the GOG study. The authors review all clinical trials published to date with special emphasis on cervical cancer. A systematic review of the literature was also undertaken with PubMed and Ovid.. Despite the promising results from early clinical trials, it has been shown that the addition of tirapazamine appears to confer no benefits on progression-free or overall survival in patients with cervical cancer. Success in the future will require smaller randomized trials with biologic targets that have acceptable toxicity and efficacy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Hypoxia; Cisplatin; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Humans; Radiation-Sensitizing Agents; Secondary Prevention; Tirapazamine; Triazines; Uterine Cervical Neoplasms

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

This prospective, randomized phase III intergroup trial of the Gynecologic Oncology Group and National Cancer Institute of Canada Clinical Trials Group was designed to test the effectiveness and safety of adding the hypoxic cell sensitizer tirapazamine (TPZ) to standard cisplatin (CIS) chemoradiotherapy in locally advanced cervix cancer.. Patients with locally advanced cervix cancer were randomly assigned to CIS chemoradiotherapy versus CIS/TPZ chemoradiotherapy. Primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS) and tolerability.. PFS was evaluable in 387 of 402 patients randomly assigned over 36 months, with enrollment ending in September 2009. Because of the lack of TPZ supply, the study did not reach its original target accrual goal. At median follow-up of 28.3 months, PFS and OS were similar in both arms. Three-year PFS for the TPZ/CIS/RT and CIS/RT arms were 63.0% and 64.4%, respectively (log-rank P = .7869). Three-year OS for the TPZ/CIS/RT and CIS/RT arms were 70.5% and 70.6%, respectively (log-rank P = .8333). A scheduled interim safety analysis led to a reduction in the starting dose for the TPZ/CIS arm, with resulting tolerance in both treatment arms.. TPZ/CIS chemoradiotherapy was not superior to CIS chemoradiotherapy in either PFS or OS, although definitive commentary was limited by an inadequate number of events (progression or death). TPZ/CIS chemoradiotherapy was tolerable at a modified starting dose.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Canada; Carcinoma, Adenosquamous; Carcinoma, Squamous Cell; Chemoradiotherapy; Chi-Square Distribution; Cisplatin; Disease Progression; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Neoplasm Staging; Proportional Hazards Models; Prospective Studies; Time Factors; Tirapazamine; Treatment Outcome; Triazines; United States; Uterine Cervical Neoplasms

Hypoxia is an adverse prognostic factor in locoregionally advanced cervical cancer treated with radiation. The aim of this phase I study was to develop a well-tolerated regimen that added tirapazamine to the standard regimen of radiation and weekly low-dose cisplatin.. Eligible patients had previously untreated carcinoma of the cervix, stages IB2 to IVA. The starting schedule was radiotherapy (45-50.4 Gy external beam radiation followed by brachytherapy), with concomitant weekly intravenous cisplatin, 40 mg/m on weeks 1 to 6 and weekly intravenous tirapazamine, 290 mg/m in weeks 1 to 5.. Eleven patients were enrolled. The median age was 52 years (range, 31-65 years). Ten patients had squamous cell carcinoma and 1 patient had adenocarcinoma; 5 patients had stage 1B2 disease, 1 had stage IIA, 3 had stage IIB-3, 1 had stage IIIB, and 1 had stage IVA. The first 2 patients on dose level 1 experienced a dose-limiting toxicity (DLT): 1 experienced grade 3 alanine amino transferase elevation and grade 4 pulmonary embolism, and 1 experienced grade 3 ototoxicity. Doses were decreased to dose level -1 with a 30-mg/m dose of cisplatin and a 260-mg/m dose of tirapazamine. Three patients were treated without any DLTs. Six patients were then treated on dose level -1a: a 35-mg/m dose of cisplatin and a 260-mg/m doses of tirapazamine with 2 DLTs--grade 3 neutropenia with dose omission and grade 4 pulmonary embolism with major hemodynamic compromise. Three of 10 evaluable patients have experienced locoregional failure.. The combination of weekly tirapazamine and cisplatin with radiation for locally advanced cervical cancer was associated with more toxicity than anticipated with the recommended dose level being tirapazamine 260 mg/m and cisplatin 30 mg/m. Further study of this weekly schedule is not warranted.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Female; Humans; Middle Aged; Neoplasms, Squamous Cell; Tirapazamine; Triazines; Uterine Cervical Neoplasms

This is a Phase I/II dose escalation study to determine the tolerable dose of tirapazamine (TPZ), and the toxicity of a regimen using TPZ with cisplatin, and radiotherapy in women with locally advanced cervical cancer.. Eligible women for this study were those with a diagnosis of locally advanced cervix cancer, who were less than 75 years of age, having provided informed consent, and who had undergone the necessary prestudy investigations. External-beam radiotherapy (RT) was given to a minimum dose of 4500 cGy in 25 fractions (Day 1-35), and brachytherapy then delivered to bring the total dose at point A to 8500 cGy. The first dose level of the study used TPZ 190 mg/m(2) and cisplatin 75 mg/m(2) on Days 1, 15, and 29 of RT. TPZ 160 mg/m(2) alone was used on Days 8, 10, 12 and 22, 24, 26 of RT. A conventional dose-escalation step method was then used to determine the maximum tolerated dose (MTD) of TPZ.. Four patients were treated at Level 1, 6 at Level 2, and 5 at Level 3. Only 1 patient experienced a dose-limiting toxicity (DLT) at Level 2, but 2 of the 5 patients at Level 3 incurred DLTs. Level 2 was declared the MDT (TPZ 290 mg/m(2) on Days 1, 15, 29 and 220 mg/m(2) on Days 8, 10, 12 and 22, 24, 26). At 6 months, 13 of 15 patients had complete pelvic control of disease.. Level 2 of this regime was identified as the MDT. The use of TPZ with concurrent cisplatin and pelvic radiotherapy has acceptable toxicity and should be considered for further Phase 2 testing in view of the promising responses noted.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Middle Aged; Neoplasm Staging; Radiotherapy Dosage; Tirapazamine; Triazines; Uterine Cervical Neoplasms

Tirapazamine (SR 4233) is a benzotriazine compound exhibiting substantial differential toxicity for hypoxic cells. A large enhancement in tumor cell killing has been demonstrated in preclinical studies when tirapazamine was combined with cisplatin. This phase I study was undertaken to establish a safe dose combination of tirapazamine and cisplatin when administered to patients with recurrent cervical carcinoma.. Tirapazamine was administered as an intravenous infusion over 2 hr, followed 1 hr later by cisplatin intravenously over 1 hr, every 21 days. All patients received prophylactic antiemetics consisting of ondansetron, dexamethasone, and lorazepam. The planned dose escalation levels of tirapazamine were 195, 260, 330, and 390 mg/m2. The cisplatin dose was fixed at 75 mg/m2.. A total of 12 patients were treated with 43 courses of therapy. Patients were heavily pretreated. Eleven of the 12 had prior radiotherapy and 5 of the 12 had prior cisplatin-based chemotherapy. A maximally tolerated dose of 330 mg/m2 was defined for this patient population. The dose-limiting toxicity was nausea and vomiting. All 12 patients were also evaluated for response. Two major responses were seen (17%). In addition, there were three minor responses (25%) and 4 patients achieved disease stabilization (33%). All major and minor responses were seen at the highest dose level tested of 330 mg/m2.. Tirapazamine and cisplatin is an interesting drug combination in the treatment of cervical cancer. Phase II testing is planned.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Tirapazamine; Triazines; Uterine Cervical Neoplasms

Tirapazamine (TPZ), a bioreductive drug with selective toxicity for hypoxic cells in tumors, is currently in Phase III clinical trials. It has been suggested to have a dual mechanism of action, both generating DNA radicals and oxidizing these radicals to form DNA breaks; whether the second (radical oxidation) step is rate-limiting in cells is not known. In this study we exploit the DNA radical oxidizing ability of the 1-N-oxide metabolite of TPZ, SR 4317, to address this question. SR 4317 at high, but nontoxic, concentrations potentiated the hypoxic (but not aerobic) cytotoxicity of TPZ in all four of the human tumor cell lines tested (HT29, SiHa, FaDu, and A549), thus providing a 2-3-fold increase in the hypoxic cytotoxicity ratio. In potentiating TPZ, SR 4317 was 20-fold more potent than the hypoxic cell radiosensitizers misonidazole and metronidazole but was less potent than misonidazole as a radiosensitizer, suggesting that the initial DNA radicals from TPZ and radiation are different. SR 4317 had favorable pharmacokinetic properties in CD-1 nude mice; coadministration with TPZ provided a large increase in the SR 4317 plasma concentrations relative to that for endogenous SR 4317 from TPZ. It also showed excellent extravascular transport properties in oxic and anoxic HT29 multicellular layers (diffusion coefficient 3 x 10(-6) cm(2)s(-1), with no metabolic consumption). Coadministration of SR 4317 (1 mmol/kg) with TPZ at a subtherapeutic dose (0.133 mmol/kg) significantly enhanced hypoxic cell killing in HT29 tumor xenografts without causing oxic cell killing, and the combination at its maximum tolerated dose was less toxic to hypoxic cells in the retina than was TPZ alone at its maximum tolerated dose. This study demonstrates that benzotriazine mono-N-oxides have potential use for improving the therapeutic utility of TPZ as a hypoxic cytotoxin in cancer treatment.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Colonic Neoplasms; Drug Synergism; Female; Humans; Lung Neoplasms; Mice; Pharyngeal Neoplasms; Tirapazamine; Triazines; Uterine Cervical Neoplasms

We reported recently that exposure of hamster V79 fibroblasts to 6 drugs that varied in their ability to produce DNA double-strand breaks stimulated formation of phosphorylated histone H2AX (serine 139 phosphorylated histone H2AX; gammaH2AX). Using flow cytometry to analyze gammaH2AX antibody-stained cells 1 h after a 30-min drug treatment, the fraction of cells that showed the control levels of gammaH2AX correlated well with the fraction of cells that survived to form colonies. This observation is now extended to V79 and SiHa human cervical carcinoma cells grown as multicell spheroids and SiHa xenografts and SCCVII tumors in mice. Animals were injected with etoposide, a topoisomerase-II inhibitor that targets proliferating cells or 3-amino-1,2,4-benzotriazine-1,3-dioxide (tirapazamine), a bioreductive cytotoxin that targets hypoxic cells. For spheroids, gammaH2AX intensity predicted clonogenic cell survival for cells recovered 90 min after drug injection, regardless of position of the cells within the spheroid. Similar results were obtained for etoposide in tumors; however, the gammaH2AX signal for tirapazamine was smaller than expected for the observed amount of cell killing. Frozen sections of tumors confirmed the greater intensity of gammaH2AX staining in cells close to blood vessels of tumors soon after treatment with etoposide and the opposite pattern for tumors exposed to tirapazamine. Analysis of cells or frozen sections from mouse spleen and kidney suggests that information can also be obtained on initial damage in normal tissues. These results support the possibility of using gammaH2AX antibody staining as a method to aid in prediction of tumor and normal tissue response to treatment.

Topics: Animals; Antineoplastic Agents; Cell Survival; DNA Damage; Etoposide; Female; Flow Cytometry; Histones; Humans; Hypoxia; Kidney; Mice; Mice, Inbred NOD; Mice, SCID; Phosphorylation; Spheroids, Cellular; Spleen; Tirapazamine; Transplantation, Heterologous; Triazines; Tumor Stem Cell Assay; Uterine Cervical Neoplasms

The penetration of anticancer agents into tumor tissue has recently attracted considerable attention. This study examines the effect of carbogen breathing on the antitumor activity of tirapazamine combined with radiation. Our hypothesis is based on the observation that the diffusion of tirapazamine through tissue is dependent on oxygen tension. We postulated that carbogen breathing might enhance the ability of tirapazamine to diffuse to hypoxic cells located distal to functional blood vessels in tumors. We first determined that carbogen breathing caused no significant change in the pharmacokinetics of tirapazamine, suggesting that any effect of carbogen breathing on the activity of tirapazamine is not attributable to modulation of pharmacokinetics. Cell survival in SCCVII and SiHa tumors after 10 Gy X rays alone was similar. However, when tirapazamine was administered 30 min after radiation treatment under air-breathing conditions, cell killing was greater in SCCVII tumors compared to SiHa tumors. Carbogen breathing during the exposure to tirapazamine did not change the cell survival in SCCVII tumors, but it enhanced cell killing in the SiHa tumors. Interestingly, carbogen breathing during radiation treatment produced greater cell killing in the SiHa tumors than in the SCCVII tumors. The vascular architecture and type of hypoxia in the two tumors probably underlie the differences in the responses of the two tumors. These findings suggest that the effectiveness of tirapazamine and other hypoxic cytotoxins may be dependent on tumor type.

Topics: Administration, Inhalation; Animals; Carbon Dioxide; Carcinoma, Squamous Cell; Drug Synergism; Female; Gamma Rays; Humans; Mice; Mice, Inbred C3H; Mice, SCID; Oxygen; Radiation-Sensitizing Agents; Tirapazamine; Triazines; Uterine Cervical Neoplasms

Efficient extravascular penetration is essential for the optimal activity of most anticancer drugs and is particularly relevant to bioreductive cytotoxins which target hypoxic cells that can be located distal to functional blood vessels within tumours. Tirapazamine (3-amino-1,2,4-benzotriazine-1,4-di-N-oxide; Triazone; SR 259075; formerly SR 4233) is a lead bioreductive cytotoxin currently undergoing clinical evaluation. It exhibits preferential cytotoxicity towards cells at reduced oxygen tension, and could complement existing anticancer therapies where hypoxic cells are believed to constitute a refractory population. We assessed the ability of tirapazamine to penetrate tumour tissue using an in vitro multilayered cell culture (MCC) model.. Diffusion of tirapazamine through oxic and hypoxic multilayered cell cultures composed of SiHa. human cervical carcinoma cells, was measured using a dual reservoir diffusion apparatus from which samples were quantified via HPLC. Drug concentration kinetics from both reservoirs were analysed using a mathematical model for diffusion and metabolism within the MCC. Results were then applied to a second mathematical model which described extravascular drug penetration within a tumour cord, the sheath of cells surrounding a blood vessel.. The diffusion coefficient of tirapazamine within SiHa MCCs was determined as 7.0+/-0.5 x 10(-7) cm2/s and the maximal metabolic rate for hypoxic MCCs, Vmax, as 1.5+/-0.4 microM/s. The thickness of individual tissue cultures was determined by diffusion of tritiated water (HTO). A linear relationship was shown to exist between tissue thickness and the inverse of permeability to HTO. Experimental results were used to simulate drug distribution within a tumour cord. These simulations indicate that, when tirapazamine is administered via intravenous infusion, a stable tirapazamine distribution throughout the cord occurs within 15 min with cells most peripheral to the blood vessel exposed to only 10% of the blood drug concentration. Under these conditions, the simulations predict cell kill to be limited to the first 75 microm of tissue surrounding a blood vessel.. This study indicates that extravascular penetration of tirapazamine to peripheral cells existing at low oxygen tension may be limited by the metabolism of tirapazamine by more proximal cells existing at moderate oxygen tension. Simulations found that tirapazamine reached only 10% of the blood concentration at cells most peripheral to blood vessels. These results indicate that tirapazamine would be significantly cytotoxic only to cells located within approximately 75 microm of blood vessels. Further MCC-based modelling of extravascular drug penetration would serve as a means of identifying new antitumour agents with location-specific activity.

Topics: Algorithms; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Survival; Chromatography, High Pressure Liquid; Diffusion; Female; Humans; Membranes, Artificial; Models, Biological; Polytetrafluoroethylene; Tirapazamine; Tissue Distribution; Triazines; Tumor Cells, Cultured; Uterine Cervical Neoplasms

A system for growing three-dimensional cell culture has been developed which exhibits many features of solid tumours. This system comprises cells growing as a thick mat on a semipermeable membrane suspended in stirred media. SiHa cells grown as these multilayered cell cultures (MCCs) have produced cultures up to ca. 20 cell diameters in thickness. The MCCs, like solid tumours growing in vivo. develop diffusion-dependent necrosis and hypoxia and the cell packing acts as a barrier to the diffusion of drugs. These cultures can, therefore, be used to study aspects of cancer biology and drug transport that are difficult to study using other techniques.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Survival; Female; Flow Cytometry; Fluorescence; Humans; Tirapazamine; Triazines; Tumor Cells, Cultured; Uterine Cervical Neoplasms