Possible Mechanisms for Intermittent Blood Flow in the Murine SCCVII Carcinoma

Trotter, M.J.; Dj, Chaplin; Olive, Peggy L.

doi:10.1080/09553009114551731

Cited by 34 publications

(16 citation statements)

References 20 publications

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“…This suggests that on each day of aministration a small additional fraction of acutely hypoxic cells was killed, increasng the anti-tumour effect. The phenomenon of acute hypoxia has been described previously by Trotter et al (1990). A significantly increased anti-tumour effect was obtained with a single dose of drug combined with five fractions of radiation, although this was not as effective as that found when both modalities were administered as fractionated regimens.…”

Section: Materiak An Mth Tumour Systemmentioning

confidence: 81%

AQ4N: an alkylaminoanthraquinone N-oxide showing bioreductive potential and positive interaction with radiation in vivo

McKeown

Hejmadi²,

McIntyre³

et al. 1995

Br J Cancer

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S-y AQ4N (l,4-bLs-q25ddimthyai oo y}amin5dydroxy-anthrane-9,10-dione) is a novel alkylaminoanthraquinone N-oxide which, on reducin, forms a stable DNA affinic cytotoxi compound AQ4. The The failure to cure tumours with radiotherapy and chemotherapy has been attributed in part to the presence of treatment-resistant subpopulations of hypoxic tumour cells (Bush et at., 1978). Bioreductive agents provide a novel approach to this problem: reduction of the prodrug within a hypoxic cell to produce a cytotoxic metabolite should selectively target this sub population within tumours. Since normal tissus contain few, if any, poorly oxygenated cells, systemic reductive activation and its attendant toxicity should be minimal. Several classe of bioreductive agents have been described, icluding the nitroimidazoles, benzotriazene di-N-oXides and mitosenes (Workman, 1992). Using a different class of compounds, i.e. the anthraquinones, we have developed a novel alkylamnoanthraquinone N-oxide, AQ4N (1,4-bis-{[2-(di-methylamino-N-oxide)ethylarmino}5,8-dihydroxyanthracene-9,10-ione), which is susceptible to reduction under hypoxic conditions (Patterson, 1993). AQ4N is a weak DNA-binding agent and weak topoisomerase H inhibitor, critically, the electrically neutral N-oxide function prevents stable binding to the DNA helix (Patterson, 1993). In contrast, the reduction product of AQ4N, i.e. AQ4 (1,4-bis-{[2-(dimethylamino) ethylnamino}5,8-dihydroxyanthracene-9,10-dione) (Figure 1), is a cationic compound with high affinity for DNA. Interaction of AQ4 with DNA is facilitated by the planar, eletrondeficient antraquinone chromophore intercalating between adjcent DNA bases. Tlis complex is further stabiised by electrostatic interactions and hydrogen bonding with the deoxyribose phosphate backbone, as has been observed for similar anthraquinones (Denny and Wakelin, 1990 al., 1992). This will allow metabolism of the drug in cells which will contribute, when the hypoxic stimulus is removed, to the main growth frction within the tumour. Secondly, the drug can be combined with an agent which is selectively toxic to well-oxygenated cells to evahuate the effect of targeting the two subpopulations of cells (Brown and Lemmon, 1991;Grau and Overgaard, 1991). We have used both these approaches to study the effect of AQ4N on tumour growth in vivo. Firstly, we tested the anti-tumour effect of AQ4N when combined with hypobaric hypoxia. Following this we combined AQ4N with radiation as both single and fractionated doses. Materiak an mth Tumour systemThe T50/80 tumour is a poorly differentiated mammary carcinoma which arose in a B6D2FI mouse. Tumour and breeding colonies for mice were obtained from Dr JV Moore, Paterson Laboratory, Christie Hospital, Manchster, UK.Male B6D2FI mice aged 8-12 weeks were used for all studies, which were carried out in accordance with the UK. Animals (Scientific Procedures) Act 1986. The tumour has been maintained by intadermal passage for up to ten passages and then re-establshed from frozm stock. Tumour brei (0.05 ml) w...

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Section: Materiak An Mth Tumour Systemmentioning

confidence: 81%

AQ4N: an alkylaminoanthraquinone N-oxide showing bioreductive potential and positive interaction with radiation in vivo

McKeown

Hejmadi²,

McIntyre³

et al. 1995

Br J Cancer

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“…With our original dual stain mismatch data indicating relatively large perfusion changes in (some) tumor blood vessels (22), it was tempting to assume that transient hypoxia was largely a result of complete stoppages of flow through tumor blood vessels. Although larger scale changes in perfusion are the most impressive to observe, they have perhaps taken attention away from more modest (and more frequently observed) changes in perfusion that may also impact tumor hypoxia (23,24). Indeed, other studies monitoring erythrocyte flux through tumor blood vessels in murine tumors have shown that modest changes in flux are more common than complete stoppages in tumor blood flow (42).…”

mentioning

confidence: 99%

“…Differences between the relative staining intensities of two i.v. injected fluorescent dyes indicate tumor areas that were subject to perfusion changes during the time between stain injections (22)(23)(24). Presumably, regions of a tumor that are subject to fluctuations in blood flow (and thus oxygen delivery) may also exhibit changes in hypoxia depending on the degree and duration of the perfusion fluctuations.…”

Section: Introductionmentioning

confidence: 99%

“…A time-integrated tumor hypoxic fraction was estimated using hourly injections of pimonidazole, which could then be compared with the more "typical" hypoxic fraction determined with a single subsequent injection of CCI-103F. Importantly, the use of flow cytometry allowed quantification of transient hypoxia on a cell-by-cell basis, which provided an improvement in resolution when compared with the insertion of probes (17)(18)(19)(20)(21) or the analyses of tumor sections for changes in microregional perfusion (22)(23)(24) or hypoxia (4,28). Moreover, flow cytometry analysis provides hundreds of thousands of data points for a single tumor, while also allowing the exclusion of necrosis and host cells from the measurements.…”

Section: Introductionmentioning

confidence: 99%

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Quantifying Transient Hypoxia in Human Tumor Xenografts by Flow Cytometry

2004

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Transient hypoxia is a poorly understood and potentially important factor that may limit tumor response to various forms of therapy. We assessed transient hypoxia on a global scale in two different human tumor xenografts by sequentially administering two hypoxia markers followed by quantification of hypoxic cells using flow cytometry. High levels of the first hypoxia marker (pimonidazole) were maintained in the circulation over an 8-hour period by multiple hourly injections, providing a "time-

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“…Since the discovery of diffusion limited tumor hypoxia in the 1960s, most strategies for overcoming or targeting hypoxic areas in tumors have been developed using a paradigm of chronically hypoxic areas in tumors or areas of hypoxia that are oxygen-deficient because they are beyond the typical diffusion limit of O 2 . Although many investigators have measured the presence of so-called intermittent or acute hypoxia in preclinical (4)(5)(6)(7)(8)(9)(10)(11) and clinical tumors (12), instabilities in tumor oxygenation were presumed to be temporally rare, spatially isolated events attributed to transient episodes of vascular stasis (6,7,(13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

The Pervasive Presence of Fluctuating Oxygenation in Tumors

Cárdenas-Navia¹,

et al. 2008

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Tumor hypoxia is a persistent obstacle for traditional therapies in solid tumors. Strategies for mitigating the effects of hypoxic tumor cells have been developed under the assumption that chronically hypoxic tumor cells were the central cause of treatment resistance. In this study, we show that instabilities in tumor oxygenation are a prevalent characteristic of three tumor lines and previous characterization of tumor hypoxia as being primarily diffusion-limited does not accurately portray the tumor microenvironment. Phosphorescence lifetime imaging was used to measure fluctuations in vascular pO 2 in rat fibrosarcomas, 9L gliomas, and R3230 mammary adenocarcinomas grown in dorsal skin-fold window chambers (n = 6 for each tumor type) and imaged every 2.5 minutes for a duration of 60 to 90 minutes. O 2 delivery to tumors is constantly changing in all tumors, resulting in continuous reoxygenation events throughout the tumor. Vascular pO 2 maps show significant spatial heterogeneity at each time point, as well as between time points. The fluctuations in oxygenation occur with a common periodicity within and between tumors, suggesting a common mechanism, but have tumor type-dependent spatial patterns. The widespread presence of fluctuations in tumor oxygenation has broad ranging implications for tumor progression, stress response, and signal transduction, which are altered by oxygenation/reoxygenation events. [Cancer Res 2008;68(14):5812-9]

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Possible Mechanisms for Intermittent Blood Flow in the Murine SCCVII Carcinoma

Cited by 34 publications

References 20 publications

AQ4N: an alkylaminoanthraquinone N-oxide showing bioreductive potential and positive interaction with radiation in vivo

AQ4N: an alkylaminoanthraquinone N-oxide showing bioreductive potential and positive interaction with radiation in vivo

Quantifying Transient Hypoxia in Human Tumor Xenografts by Flow Cytometry

The Pervasive Presence of Fluctuating Oxygenation in Tumors

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