Annals of Oncology Advance Access originally published online on April 17, 2007
Annals of Oncology 2007 18(6):1098-1103; doi:10.1093/annonc/mdm120
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© 2007 European Society for Medical Oncology
phase I and pharmacokinetics |
The use of pharmacokinetic and pharmacodynamic end points to determine the dose of AQ4N, a novel hypoxic cell cytotoxin, given with fractionated radiotherapy in a phase I study
1 Department of Oncology, Leicester Royal Infirmary, Leicester
2 Department of Oncology, Churchill Hospital, Oxford
3 University of Bradford, Bradford
4 Cancer Research UK, Drug Development Office, London
5 Cancer Research UK, Formulation Unit, Strathclyde University, Glasgow, UK
* Correspondence to: Prof. W. P. Steward, Department of Oncology, 2nd Floor, Osborne Building, Leicester Royal Infirmary, Leicester LE1 5WW, UK. Tel: +44 0116-258-7597; Fax: +44 0116-258-7599; E-mail: wps1{at}le.ac.uk
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Abstract |
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Background: AQ4N (1,4-bis[[2-(dimethylamino)ethyl] amino]-5,8-dihydroxyanthracene-9, 10-dione bis-N-oxide dihydrochloride) is a prodrug which is selectively activated within hypoxic tissues to AQ4, a topoisomerase II inhibitor and DNA intercalator.
Patients and methods: In the phase I study, 22 patients with oesophageal carcinoma received an i.v. infusion of AQ4N (22.5–447 mg/m2) followed, 2 weeks later, by further infusion and radiotherapy. Pharmacokinetics and lymphocyte AQ4N and AQ4 levels were measured after the first dose. At 447 mg/m2, biopsies of tumour and normal tissue were taken after AQ4N administration.
Results: Drug-related adverse events were blue discolouration of skin and urine, grade 2–3 lymphopenia, grade 1–3 fatigue, grade 1–2 anaemia, leucopenia and nausea. There were no drug-related serious adverse events (SAEs). Three patients had reductions in tumour volume >50%, nine had stable disease. Pharmacokinetics indicated predictable clearance. Plasma area under the curve (AUC) at 447 mg/m2 exceeded AQ4N concentrations in mice at therapeutic doses and tumour biopsies contained concentrations of AQ4 greater than those in normal tissue. Tumour concentrations of AQ4 exceeded in vitro IC50 values for most cell lines investigated.
Conclusions: No dose-limiting toxic effects were observed and a maximum tolerated dose was not established. Tumour AQ4 concentrations and plasma AUC at 447 mg/m2 exceeded active levels in preclinical models. This dose was chosen for future studies with radiotherapy.
Key words: AQ4N, bioreductive, pharmacodynamics, pharmacokinetics, phase I study
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Most patients with oesophageal cancer have locally inoperable or metastatic disease at presentation. Survival is poor, with 40% alive at 1 year and <10% at 5 years [1]. The aim of treatment is to reduce symptoms and improve quality of life using chemotherapy, stents, radiotherapy, argon laser ablation or a combination of techniques. First-line chemotherapy produces response rates of 40%, with attendant improvement in symptoms, quality of life and survival [2]. The patient's performance status (PS) frequently precludes such treatment and local measures to relieve symptoms are required. Dysphagia is common and, although radiotherapy produces effective palliation in 60%–80% of patients, with a mean duration of 5–10 months [3], there is scope to improve both the frequency and duration of symptom control.
Hypoxia is a characteristic of most solid tumours due to their incomplete and chaotic blood supply [4]. Hypoxic cells may contribute up to 20% of tumour mass and have reduced capacity for cell division making them relatively resistant to chemotherapy and radiotherapy. These cells require radiation doses two- to three-fold greater than normal cells to achieve equivalent cell kill such that residual viable cells may result in further tumour growth following re-oxygenation after therapy [5]. Several attempts have been made to target hypoxic cells to overcome resistance to chemotherapy and radiotherapy.
AQ4N (1,4-bis[[2-(dimethylamino)ethyl] amino]-5,8-dihydroxyanthracene-9, 10-dione bis-N-oxide dihydrochloride) was designed to preferentially kill hypoxic and immediately adjacent cells [6]. It is unique in being a prodrug with minimal toxicity to hypoxic cells but is selectively activated within hypoxic tissues by enzyme-mediated reduction (cytochromes P450 3A4, 1A1 and 2B6, and possibly other haemoproteins) and converted to a stable and nuclear-persistent agent, AQ4. AQ4 is a chemically stable cytotoxic agent which acts as a topoisomerase II inhibitor and DNA intercalator [7]. AQ4N has minimal anticancer activity as a single agent in animal models but demonstrates significant benefit in combination with radiotherapy and other cytotoxic agents. When given immediately before radiotherapy, AQ4N enables a 50% reduction in radiation dose for the same antitumour effect. There is a prolonged radio-potentiating effect in vivo, with maximal interaction when the drug was administered from 4 days before to 6 h after radiation [8]. The radio-potentiating effect appeared to be greatest with administration of AQ4N between 24 and 4 h before radiotherapy (the time window chosen for investigation in this study). Experiments using the murine eccrine sweat gland model showed no increase in normal tissue damage when AQ4N was added to radiotherapy [9].
Evidence that AQ4N acts as a hypoxia-activated cytotoxin comes from giving it with tumour vascular clamping or hydralazine pre-treatment. 100% tumour hypoxia enhances the antitumour effect of single-agent AQ4N supporting the contention that AQ4N can be bioreductively activated in vivo [10]. AQ4N is active against the mouse mammary tumour MDAH-MCa-4 when combined with the tumour blood flow inhibitor 5,6-dimethylxanthenone-4-acetic acid [11]. The antitumour effect of AQ4N is potentiated by hypobaric hypoxia in T50/80 tumours in vivo with a dose enhancement ratio of 5 : 1 [12].
Formal toxicology studies were carried out in rodents on a daily x5 schedule. No lethality was seen but the maximum tolerated dose (MTD) was determined at 75 or 150 mg/kg body weight per day for male mice and male and female rats, respectively. MTD was determined by loss of body weight and cytotoxicity for lymphoid, erythroid and testis cells.
Preclinical evaluation of AQ4N indicated its potential for clinical development when administered with radiotherapy or the cytotoxic agents cyclophosphamide and cisplatin [13]. The current study was developed with the combination of AQ4N and radiotherapy. Oesophageal carcinoma was chosen as radiotherapy is frequently indicated and it could also provide access to tumour biopsies for pharmacodynamic evaluation. The study examined toxicity, pharmacokinetics and pharmacodynamics to determine the AQ4N dose proposed for future development.
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patients and methods |
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patients
Eligibility criteria were as follows: age
18 years, World Health Organization PS of zero to two, histologically confirmed inoperable or recurrent squamous cell carcinoma or adenocarcinoma of the oesophagus or gastro-oesophageal junction causing dysphagia or pain for which radiotherapy was appropriate, haemoglobin >10 g/dl, white blood cells >3.5 x 109/l, platelets >100 x 109/l, creatinine <120 µmol/l, bilirubin within normal limits, alkaline phosphatase <2.5 x upper limit of normal (ULN) or <5 x ULN with liver metastases. Prior radiotherapy to the thorax or prior chemotherapy, major thoracic and/or abdominal surgery within 4 weeks, uncontrolled serious non-malignant systemic disease and prior malignancies within 5 years were exclusion criteria.
study design
This was a two-centre, phase I dose escalation study of AQ4N given alone and in combination with radiotherapy. The study was approved by the Research Ethics Committees of both hospitals involved. The primary goal was determination of the MTD and dose-limiting toxic effects (DLT) of AQ4N +/– radiotherapy. As it was appreciated that significant toxicity may not occur, secondary end points included pharmacokinetic analysis of AQ4N and its metabolites and pharmacodynamics as assessed by measurement of tumour, tissue and lymphocyte levels of AQ4N and its metabolites. It was anticipated that these may be required to guide choice of dose for future studies. Tumour response was also measured. A DLT was defined according to National Cancer Institute Common Toxicity Criteria (version 2.0) as grade 4 neutropenia, fever >7 days, thrombocytopenia grade 4, anaemia grade 3, grade 3 or 4 non-haematological toxicity (excluding alopecia and nausea, vomiting or diarrhoea in patients not given optimal antiemetics or antidiarrhoeals) or death. The MTD was defined as a dose producing DLTs in 
1 of six assessable patients when 2 patients experienced DLT at the next higher dose.
A single patient was treated at each dose level with dose doubling between initial cohorts. When drug-related toxicity (grade 2) was observed (excluding nausea or vomiting) three patients were treated at each dose level with dose escalation by 40% or less as clinically indicated. Further dose escalation to a new cohort was allowed when all patients in each cohort had completed week 3 (AQ4N/radiotherapy +2 days). Dose escalation occurred following a teleconference at which the results of toxicity and pharmacokinetics (and, when assessed, pharmacodynamics) for the previous dose level were available.
AQ4N was provided by the Drug Formulation Unit of Cancer Research UK, Department of Pharmaceutical Sciences, University of Strathclyde. Two different formulations were used, the first being as a lyophilised cake in vials containing 80 mg/2 ml of AQ4N in sodium hydroxide and 0.025 M phosphate buffer pH 7.0, which was reconstituted with water for injection. The second formulation used after June 2003 was as a liquid in ampoules containing 200 mg/5 ml of AQ4N in sodium hydroxide and 0.025 M phosphate buffer pH 7.0. Change to the new formulation occurred as it did not need reconstitution and had improved stability levels of the impurity, AQ4-mono-N-oxide, that eliminated the need to cap dosing at 350 mg/m2. Both formulations were then diluted in 250 ml 0.9% sodium chloride and administered by 30 min i.v. infusion. Single-agent AQ4N was administered on day 1 with a 2 week break (to allow assessment of any toxicity from single-agent administration) before patients received AQ4N at the same dose followed 6 h later by the first of five daily fractions (each 4 Gy to the midplane) of radiotherapy. This was the standard palliative technique used in the UK. Radiotherapy was based on treating the tumour volume [as determined by diagnostic Computed Tomography (CT) and barium contrast studies] plus a 2–3 cm margin to a maximum of 15 x 8 cms in two opposing fields, using at least 6 mV photons. The starting dose of AQ4N was 22.5 mg/m2, based on animal data (1/10th of the MTD in mice, 75 mg/kg/day, when given on a daily x5 schedule).
evaluation criteria and procedures
Baseline evaluation within 28 days of study entry included history, physical examination, full blood count and blood chemistry, EDTA clearance, electrocardiogram, chest X-ray and tumour assessment. Laboratory tests were repeated before infusion of AQ4N and 1 week later. In week 3, physical examination, vital signs, haematology, biochemistry and EDTA clearance were repeated before infusion of AQ4N. Physical examination and adverse event (AE) recording occurred weekly following the second infusion. Patients went off study at week 7 with a repeat of all assessments carried out at baseline. Five millilitres of heparinised blood was taken for pharmacokinetics with the first infusion of AQ4N pre-dose, 5 min before the end of the infusion and then at 10 min, 30 min, 1, 2, 4, 8 and 24 h following the infusion. Urine was collected from 0 to 8 and 8–24 h following the first infusion. Plasma was separated, frozen and analysed at the Institute of Cancer Therapeutics, University of Bradford, UK. AQ4N and AQ4 together with intermediate metabolites were determined by high-performance liquid chromatography (HPLC) [14]—detailed below.
AQ4N and AQ4 levels were analysed in lymphocytes and leucocytes in 16 patients by confocal microscopy and liquid chromatography/mass spectroscopy (LC/MS). During the study, the protocol was amended to allow endoscopic oesophageal tumour and normal tissue biopsies to be taken 24 h after week 1 administration to evaluate AQ4N at doses likely to result in measurable drug activation and tumour DNA damage. Such biopsies became mandatory at expansion of the highest dose level studied (447 mg/m2).
Tumour responses were evaluated using Response Evaluation Criteria in Solid Tumours (RECIST) criteria [15] by contrast-enhanced CT scans at baseline and at week 7.
measurement of AQ4N and its metabolites
tumour/normal tissue sample preparation
Tumour tissue was weighed and homogenised in ice-cold MeCN with 0.2% H2O2. Following centrifugation at 10 000 g for 5 min at 4°C, 200 µl of the supernatant was taken, evaporated to dryness and reconstituted in 100 µl of mobile phase.
calibration standards for tumour
H460 human tumour xenografts were used to prepare the calibration curve and were homogenised and spiked with AQ4N or AQ4 concentrations between 0 and 2 µg/ml (µg/g). AQ4N and AQ4 calibration curves were prepared separately to ensure that AQ4 was not created as an artefact of AQ4N reduction during sample work-up
sample analysis
Chromatographic analysis of AQ4N was adapted from the method of Swaine et al. [14]. Mobile phase A [5% acetonitrile 95% ammonium formate (0.05 M, pH 3.6)] and mobile phase B [50% acetonitrile 50% ammonium formate (0.05 M, pH 3.6)] were used in two gradient systems. Plasma analysis used a gradient of 20% B to 81% B over 45 min and was then returned to initial conditions for 10 min before the next injection. Tumour analysis used a gradient of 30% B to 55.6% B >10 min and then returned to initial conditions for 10 min to equilibrate before the next injection. The HPLC was attached in series to a Waters Quattro Ultima (Micromass, Manchester, UK) triple quadrupole mass spectrometer [16]. To increase sensitivity for tumour analysis, two multiple reaction monitoring were setup. These were m/z 445.50 > 384.20 (AQ4N) and 413.50 > 72.10 (AQ4), each with a dwell time of 1.0 s.
statistical methods
Statistical methodology was primarily descriptive and focused on AEs, particularly those that were serious, dose limiting, associated with discontinuation or had a severity of Common Toxicity Criteria grade 3 or 4. AEs as well as laboratory abnormalities were tabulated by dose cohort. Safety data included all patients who received AQ4N. The qualitative pharmacokinetic data were summarised by frequency and percentages, while the quantitative data were summarised by descriptive statistics.
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results |
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patients
Twenty-two patients (characteristics shown in Table 1) were enrolled at eight dose levels (22.5–447 mg/m2—Table 2). Only three patients had received prior chemotherapy because the majority had symptoms predominantly related to local disease for which radiotherapy was felt to be optimal. All patients received the first dose of AQ4N and 21 received both courses with subsequent radiotherapy. One patient, at 246 mg/m2, developed a grade 4 infection on day 9 after the first infusion and died on day 16 despite antibiotic treatment. This was felt to be related to the primary tumour (pneumonia related to aspiration) and not to treatment (haematological parameters were normal). She did not receive the second infusion of AQ4N and was not replaced.
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safety
AQ4N (which is a deep blue colour) was well tolerated with grade 1–3 AEs (shown in Table 3) which were reversible and of short duration. The most frequent AE was a blue discolouration of the skin and urine which started during infusion and generally resolved within 24 h. This was the only drug-related AE seen after single-agent AQ4N. Grade 2–3 lymphopenia occurred in 73% of patients with onset in the third week. Other AEs included grade 1–3 fatigue (45.5% patients), grade 1–2 anaemia (41% patients), leucopenia (27% patients) and nausea (23% patients). Although grade 3 fatigue could have indicated DLT, it is common in advanced malignancy and could also be ascribed to radiotherapy such that definite causality to AQ4N could not be made. Mild (grade 1) transient rises in creatinine were seen following combination therapy in six patients but this was attributed to nausea and vomiting which occurred with the radiotherapy/AQ4N. Five patients experienced grade 1 transient thrombocytopenia in the third week and this may have been caused by the AQ4N and/or radiotherapy. There were nine SAEs in seven patients, all non-laboratory events and unrelated to study drug. The incidence and grade of blue discolouration of the skin and urine increased with dose of AQ4N but the frequency and grade of other AEs were unrelated to dose. No DLTs were seen. There was no reported exacerbation of dysphagia after the combination of radiotherapy and AQ4N indicating that there was no enhanced normal tissue damage.
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pharmacokinetics
Twenty-one patients had samples which were evaluable for pharmacokinetic assessment. Good systemic exposure of AQ4N was observed in all patients with a volume of distribution at steady state ranging from 5.4 to 18.6 l/m2 across all doses, with a trend towards a decreased volume of distribution at higher doses. Cmax values increased with dose, ranging from 3.88 to 100.1 µg/ml. Systemic exposure based on area under the curve (AUC) values increased with dose and ranged from 10.5 to 408 µg h/ml. Half-life values, calculated from non-compartmental analysis, ranged from 2.39 to 5.38 h (mean = 3.74 h) across all doses with no obvious dose-related trend. Systemic clearance values ranged from 1.09 to 5.76 (l/h)/m2 (mean = 2.67) (l/h)/m2, again with no marked dose-related trends. Modelling of the data using a two-compartment infusion model indicated a bi-phasic system with a distribution phase half-life ranging from 0.14 to 1.45 h (mean = 0.69 h) and the terminal elimination half-life ranging from 2.17 to 7.5 h (mean = 3.85 h), the latter being similar to that observed in the non-compartmental analysis procedure. Graphical plots of AUC and Cmax values versus dose administered (Figure 1) also give a good indication of inter-patient variability. No drug metabolites could be detected in plasma >5% parent AQ4N. In several patients with occasional haemolysed samples, the reduction products AQ4M and AQ4 could be detected. These were treated as artefacts most likely due to the non-specific breakdown of AQ4N by degraded haeme in the haemolysed blood. Approximately 57% (56.9 +/– 23.1) of total dose was detected in the urine. All metabolites detected in urine were consistently <1% of total drug present with >98% of drug being parent AQ4N. Typical graphs showing compartmental modelling plots are shown in Figure 2.
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pharmacodynamics
Adequate lymphocyte samples were available for analysis from 16 patients. Studies using confocal microscopy showed minimal nuclear fluorescence in all samples. Only at the highest dose (447 mg/m2) was fluorescence of a similar intensity to that seen in a 10 ng/ml AQ4 spiked standard detected. This level is only marginally above background auto-fluorescence levels and is therefore difficult to quantify. Analytical studies using LC/MS on lymphocyte preparations showed AQ4 was not detected (<10 ng/ml) in any of the preparations. Analytical studies using LC/MS on lymphocyte preparations showed AQ4N was detected in some of the samples at the highest doses at concentrations ranging from 0.3 to 1 µg/ml. Approximately 10% of this was present as the intermediate AQ4M (the mono-N-oxide). Tumour and normal tissue biopsy samples were analysed from three patients. Calculated concentrations (ng/g) of AQ4 in tumour : normal tissue were 1744 : 295, 316 : <101 and 585 : 265, respectively for three individual patients. In each case, tumour tissue concentrations were greater than those in normal tissue with a mean ratio >3.7-fold. AQ4N was detected in samples from two of three patients with concentrations ranging from 16 to 2788 ng/g. No differential in AQ4N concentration could be detected between tumour and normal tissue.
response
Eighteen patients were assessable for response. One patient experienced a partial response (PR) (30% decrease in the sums of the longest diameters of lesions confirmed at 4 weeks) by RECIST criteria and two had >50% tumour volume reduction (scan not repeated at 4 weeks). Nine patients (41%) had stable disease (neither a 30% decrease nor a 20% increase in the sums of the longest diameters of measured lesions with no new lesions).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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This is the first phase I clinical study of AQ4N, an agent which was designed to be selectively activated by bioreduction in hypoxic cells to AQ4, a highly potent and stable topoisomerase II inhibitor.
AQ4N was generally well tolerated with reversible grade 1–3 drug-related AEs of short duration, the most common being blue discolouration of the skin and urine. There were no DLTs and, therefore, an MTD was not determined. Parallel pharmacokinetic and pharmacodynamic data were used to terminate dose escalation before DLTs were observed. Grade 2–3 treatment-related lymphopenia was reported in 73% of patients at all dose levels but, as this was seen 1 week after concomitant radiotherapy, it may, in part at least, have been due to the radiation. It is well established that radiotherapy induces a rapid and sustained reduction in circulating lymphocytes, usually lasting 3–5 weeks [17], and this is exacerbated by chemotherapy [18, 19].
As the parent compound, AQ4N, is not cytotoxic, it was anticipated that DLT may not be seen. In order to guide the choice of dose for future studies, detailed pharmacokinetics were undertaken and, at the highest dose level, tumour and normal tissue biopsies were taken. Linear pharmacokinetics of AQ4N between the lowest and highest doses were seen and indicated that this prodrug has predictable clearance. At 447 mg/m2, the highest dose tested, the plasma AUC of AQ4N (408 µg h/ml) was in excess of that which produced therapeutic effects in mice (83.5 µg h/ml at 100 mg/kg) when given with radiation therapy [16].
Tumour and normal tissue biopsies from three patients at 447 mg/m2 demonstrated tumour concentrations of AQ4 which were greater than those in normal tissue with a mean tumour : normal tissue ratio >3.7. This data supports the rationale for development of AQ4N as being a prodrug which is preferentially metabolised to the active agent AQ4 in relatively hypoxic tumour cells. Concentrations of AQ4 in the tumour samples (ranging from 316 to 1744 ng/g) exceeded the IC50 values for most cell lines investigated in vitro. It was therefore felt that a dose of 447 mg/m2 produced sufficient tumour levels in humans to be cytotoxic.
Of the 18 patients assessable for response, one achieved a PR by RECIST criteria and two had tumour volume reductions >50% (scans not repeated 4 weeks later). Nine patients had stable disease and six had progression. As radiotherapy was also administered, it is not possible to draw any conclusions about the therapeutic potential of AQ4N alone.
In summary, this phase I study of AQ4N has confirmed preclinical predictions that it would be safe and well tolerated. The results of assays of AQ4, the bioreductive metabolite, in normal tissue and tumour biopsies support the hypothesis that preferential conversion of AQ4N would occur in relatively hypoxic tumour cells. On the basis of pharmacokinetic and pharmacodynamic assays, the dose of 447 mg/m2 is recommended for future phase II evaluation when given with radiotherapy as AQ4 levels in tumour cells are consistent with preclinical data indicating that radiation enhancement should occur. AQ4N is currently under investigation as a single agent and in combination with cytotoxic chemotherapy.
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This work was funded from British Technology Group and supported by Cancer Research UK.
Received for publication January 21, 2007. Revision received February 28, 2007. Accepted for publication March 1, 2007.
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