Intermittent blood flow in the KHT sarcoma--flow cytometry studies using Hoechst 33342

Minchinton, A.I.; Durand, RE; Dj, Chaplin

doi:10.1038/bjc.1990.259

Cited by 48 publications

(23 citation statements)

References 23 publications

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“…Chaplin and co-workers defined a dominant periodicity for flow instability and radioresistance of around 20 min for a variety of different preclinical tumour models [72][73][74][75][76] . In their first experiments, the investigators administered a dye that binds to the nuclei of cells surrounding micro-vessels to animals either simultaneously with or sequentially with radiation treatment 77 .…”

Section: Kineticsmentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumour development. The hypoxic environment of tumours is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia-reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumour cell survival. As discussed here, a constant theme emerges: inhibition of HIF1 activity will have therapeutic benefit.Virchow first described the abnormal structure of tumour vessels using contrast agents in human tumours as early as the mid 1800s 1 . A few decades later, Goldman was among the first to suggest that angiogenesis was associated with tumour growth 2 . A number of other investigators in the nineteenth and early twentieth centuries evaluated tumour angiogenesis, using techniques such as microangiography, vascular casting and window chamber models. Warren has reviewed this early work in great detail 3 . Folkman illuminated the crucial role of tumour angiogenesis by hypothesizing that tumour growth was dependent upon angiogenesis and that, if angiogenesis could be inhibited, it could maintain tumour deposits in a quiescent state 4 . These early works set the stage for the concept that tumours require angiogenesis to provide a nutrient supply. Although it is well-established that angiogenesis occurs in nearly all human solid tumours, it does not occur in an efficient manner, leading to spatial and temporal inadequacies in delivery of oxygen and other nutrients. These inefficiencies in nutrient delivery lead to a brutal cycle of unsatisfied demand by the tumour, which drives continued aberrant angiogenesis.The transcription factor hypoxia-inducible factor 1 (HIF1) plays an important part in tumour progression by upregulating genes that control angiogenesis, meta-stasis and resistance to oxidative stress. It also controls the switch to anaerobic metabolism, which can maintain cell NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript viability under hypoxic conditions. Further, HIF1 activity can promote treatment resistance by promoting endothelial and tumour cell survival after cytotoxic therapy. The mechanisms that control HIF1 activity are complex and are influenced by microenvironmental factors involving hypoxia, oxidative and nitrosative stress.In this Review we will discuss four important and interrelated aspects of tumour hypoxia. First, we will define the hypoxic response, discussing its relevance in influencing tumour cell survival, behaviour and angiogenesis. We will examine the physiological factors that contribute to hypoxia, emphasizing a perspective based on spatial and temporal dysfunction of tumour microcirculation. The question of whethe...

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Section: Kineticsmentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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“…Experiments conducted in mammalian cells of different origin showed that prolonged hypoxia causes accumulation in the G 1 -phase of the cell cycle and inhibition of DNA replication, effects reversible upon reoxygenation (Amellem and Pettersen, 1991;Giaccia, 1996;Krtolica and Ludlow, 1996;Schmaltz et al, 1998). In experimental tumors, the fraction of proliferating cells and/or the rate of cell proliferation decreased as the distance from the vasculature increased (Tannock, 1968;Minchinton et al, 1990;Rodriguez et al, 1994). This can result in a loss of efficacy of most anticancer agents, which are primarily effective against rapidly dividing cells.…”

Section: Chemoresistancementioning

confidence: 99%

How to overcome (and exploit) tumor hypoxia for targeted gene therapy

Greco

Marples

Joiner

et al. 2003

Journal Cellular Physiology

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Tumor hypoxia has long been recognized as a critical issue in oncology. Resistance of hypoxic areas has been shown to affect treatment outcome after radiation, chemotherapy, and surgery in a number of tumor sites. Two main strategies to overcome tumor hypoxia are to increase the delivery of oxygen (or oxygen-mimetic drugs), or to exploit this unique environmental condition of solid tumors for targeted therapy. The first strategy includes hyperbaric oxygen breathing, the administration of carbogen and nicotinamide, and the delivery of chemical radiosensitizers. In contrast, bioreductive drugs and hypoxia-targeted suicide gene therapy aim at activating cytotoxic agents at the tumor site, while sparing normal tissue from damage. The cellular machinery responds to hypoxia by activating the expression of genes involved in angiogenesis, anaerobic metabolism, vascular permeability, and inflammation. In most cases, transcription is initiated by the binding of the transcription factor hypoxia-inducible factor (HIF) to hypoxia responsive elements (HREs). Hypoxia-targeting for gene therapy has been achieved by utilizing promoters containing HREs, to induce selective and efficient transgene activation at the tumor site. Hypoxia-targeted delivery and prodrug activation may add additional levels of selectivity to the treatment. In this article, the latest developments of cancer gene therapy of the hypoxic environment are discussed, with particular attention to combined protocols with ionizing radiation. Ultimately, it is proposed that by adopting specific transgene activation and molecular amplification systems, resistant hypoxic tumor tissues may be effectively targeted with gene therapy.

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“…In such a situation, increasing the oxygen carrying capacity of the blood would not be an effective method of reoxygenation. There is now clear evidence that radiobiological hypoxia in at least two experimental tumours can result from transient fluctuations in microregional blood flow Chaplin et al, 1986;Trotter et al, 1989;Chaplin et al, 1989;Minchinton et al, 1990). If (Horsman et al, 1987;Horsman et al, 1988;Horsman et al, 1989), have indicated that its activity, at least in part, results from its ability to reduce the occurrence of acute hypoxia within a solid tumour (Teicher et al, 1989 (Chaplin et al, 1983) using 270 kVp X-rays at a dose rate of 2.9Gy min-'.…”

mentioning

confidence: 99%

Nicotinamide, Fluosol DA and Carbogen: a strategy to reoxygenate acutely and chronically hypoxic cells in vivo

Chaplin

Horsman²,

Aoki³

1991

Br J Cancer

Self Cite

106

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Intermittent blood flow in the KHT sarcoma--flow cytometry studies using Hoechst 33342

Cited by 48 publications

References 23 publications

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

How to overcome (and exploit) tumor hypoxia for targeted gene therapy

Nicotinamide, Fluosol DA and Carbogen: a strategy to reoxygenate acutely and chronically hypoxic cells in vivo

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