Pharmacokinetics and binding of the bioreductive probe for hypoxia, NITP: effect of route of administration

Hodgkiss, R.J.; Stratford, Michael R.L.; Dennis, Madeleine F.; Hill, SA

doi:10.1038/bjc.1995.530

Cited by 14 publications

(9 citation statements)

References 12 publications

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“…Thus, in the present experiments, we were guided by protocols that have been used in tumor-bearing mice in which hypoxia was assessed by flow cytometry. 20 The plasma levels of NITP rose to a maximum between 11.3 and 98.1 mol/L within 1 1 ⁄2 hours and then decreased, with a half-life of Ϸ1 to 3 hours (Figure 1). The maximum concentrations tended to be lower and the half-life longer than those described in the mouse (Ϸ100 mol/L and 1 ⁄2 hour, respectively).…”

Section: Nitp In Plasmamentioning

confidence: 99%

“…The maximum concentrations tended to be lower and the half-life longer than those described in the mouse (Ϸ100 mol/L and 1 ⁄2 hour, respectively). 9,20 The NITP exposure, calculated as area under the curve (AUC), was 230Ϯ157 (range, 29 to 415) mol ⅐ h Ϫ1 ⅐ L Ϫ1 in the rabbits. In the tumor-bearing mice, the AUC was 154 mol ⅐ h Ϫ1 ⅐ L Ϫ1 .…”

Section: Nitp In Plasmamentioning

confidence: 99%

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Evidence of Hypoxic Areas Within the Arterial Wall In Vivo

Björnheden¹,

Levin²,

Evaldsson³

et al. 1999

ATVB

247

156

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Abstract-The anoxemia theory of atherosclerosis states that an imbalance between the demand and supply of oxygen in the arterial wall is a key factor for the development of atherosclerotic lesions. Direct in vitro and in situ measurements have shown that PO 2 is decreased in the more deeply situated parts of the media, but the degree of hypoxia in vivo or the distribution of hypoxia along the arterial tree is not known. For this reason, we have developed a method for the detection of hypoxia in the arterial wall in vivo by using a hypoxia marker, 7-(4Ј-(2-nitroimidazol-1-yl)-butyl)-theophylline, that may be visualized by immunofluorescence. In the present study, we have used this method in rabbits with experimentally induced atherosclerosis. Our results indicate that zones of hypoxia occur at depth in the atherosclerotic plaque. The mechanism was probably an impaired oxygen diffusion capacity due to the thickness of the lesion, together with high oxygen consumption by the foam cells. Thus, we have for the first time demonstrated that hypoxia actually does exist in the arterial wall in vivo, lending support to the anoxemia theory of atherosclerosis.

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Section: Nitp In Plasmamentioning

confidence: 99%

Section: Nitp In Plasmamentioning

confidence: 99%

Evidence of Hypoxic Areas Within the Arterial Wall In Vivo

Björnheden¹,

Levin²,

Evaldsson³

et al. 1999

ATVB

247

156

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“…Three separate Transwells per time point were sectioned and the thickness of each multicell layer was determined on five sections from each Transwell (20 measurements per section). Walton and Workman, 1993;Hodgkiss et al, 1995). In all cases, the final DMSO concentration was < 0.2%.…”

Section: Methodsmentioning

confidence: 92%

“…In the case of tirapazamine, for example, preferential DNA damage to cells in hypoxic regions of squamous cell carcinoma (SCCVII) tumours was observed using a combination of cell sorting and comet assays (Olive, 1995). NITP is detectable in tissues using antibodies raised against theophylline, and good evidence exists to show that NITP binds preferentially to cells that reside close to the necrotic regions of mammary CaNT tumours (Hodgkiss et al, 1995). Both compounds readily penetrate DLD-1 multicell layers, although penetration of tirapazamine is more rapid than NITP under standard cell culture conditions ( Figure 5).…”

Section: Discussionmentioning

confidence: 99%

“…As the rate of drug penetration through cell layers will be both concentration and time dependent, pharmacokinetic parameters are likely to play a major role in determining the extent of drug penetration from the vasculature in vivo. In mice, both tirapazamine and NITP have plasma t,2P of 26.5 min and between 20 and 30 min (depending on vehicle and route of administration) respectively (Workman and Walton, 1993;Hodgkiss et al, 1995). As both drugs have been shown to either damage DNA or bind to cells within the hypoxic tumour microenvironment, the combination of these pharmacokinetic parameters together with the inherent ability to penetrate rapidly through multicell layers suggests that these characteristics form a good guideline for predicting whether other drugs will reach the tumour microenvironment.…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of a novel in vitro assay for assessing drug penetration into avascular regions of tumours

Phillips

Loadman²,

Cronin³

1998

Br J Cancer

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SummaryThe poor blood supply to solid tumours introduces many factors that affect the outcome of chemotherapy, one of which is the problem of drug delivery to poorly vascularized regions of tumours. Whereas poor drug penetration has been recognized as a contributing factor to the poor response of many solid tumours, the question of drug penetration through multicell layers has not been thoroughly addressed, largely because of restrictions imposed upon these studies by the requirement for either radiolabelled or naturally fluorescent compounds. The aim of this study is to describe modifications made to a recently published assay that broadens the scope for assessing drug penetration during the early stages of drug development and to characterize the ability of various drugs to penetrate multicell layers. DLD-1 human colon carcinoma cells were cultured on Transwell-COL plastic inserts placed into 24-well culture plates so that a top and bottom chamber were established, the two chambers being separated by a microporous membrane. Drugs were added to the top chamber at doses equivalent to peak plasma concentrations in vivo and the rate of appearance of drugs in the bottom chamber determined by high-performance liquid chromatography (HPLC). Both 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine) and 7-[4'-(2-nitroimidazol-1-yl)-butyl]-theophylline (NITP) rapidly penetrated DLD-1 multicell layers (50.9 ± 12.1 gm thick) with t1,2 values of 1.36 and 2.38 h respectively, whereas the rate of penetration of 5-aziridino-3-hydroxymethyl-1-methyl-2-[1H-indole-4,7-dione] prop-,-en-a-ol (EO9) and doxorubicin through multicell layers was significantly slower (t1,2 = 4.62 and 13.1 h respectively). Inclusion of dicoumarol increases the rate of E09 penetration, whereas reducing the oxygen tension to 5% causes a reduction in tirapazamine penetration through multicell layers, suggesting that the extent of drug metabolism is one factor that determines the rate at which drugs penetrate multicell layers. The fact that E09 does not readily penetrate a multicell layer, in conjunction with its rapid elimination in vivo (tl,2 < 10 min), suggests that E09 is unlikely to penetrate more than a few ,um from a blood vessel within its pharmacokinetic lifespan. These results suggest that the failure of E09 in the clinic is due to a combination of poor drug penetration and rapid elimination in vivo.

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Review of methods used to study oxygen transport at the microcirculatory level

et al. 2000

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The existence of hypoxic regions in tumors has long been recognized as a key factor leading to radiation resistance. More recently, it has been found that low oxygen levels also affect drug resistance, angiogenesis, cytokine production, cell cycle control, apoptosis, and metastatic propensity of tumors. Until now, most approaches to eliminating hypoxia have been empirical. However, improved understanding of the underlying mechanisms may permit the development of more soundly based, effective approaches. As discussed in this review, critical evaluation of the factors governing oxygen transport in tumors requires a thorough understanding of the methods used to study this process. Many experimental methodologies can be used to address these issues. In this review, the emphasis is placed on techniques that measure parameters on the scale of the diffusion distance of oxygen. Studies at the microregional level provide the most detailed physiological information on such processes. Over the past few years, significant progress in technology has allowed us to measure tumor oxygenation, yet spatial and temporal heterogeneities continue to provide significant challenges to obtaining clear knowledge of oxygen transport. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 237–255 (2000). © 2000 Wiley‐Liss, Inc.

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Pharmacokinetics and binding of the bioreductive probe for hypoxia, NITP: effect of route of administration

Cited by 14 publications

References 12 publications

Evidence of Hypoxic Areas Within the Arterial Wall In Vivo

Evidence of Hypoxic Areas Within the Arterial Wall In Vivo

Evaluation of a novel in vitro assay for assessing drug penetration into avascular regions of tumours

Review of methods used to study oxygen transport at the microcirculatory level

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