Tumour Hypoxia: Impact on Biology, Prognosis and Treatment of Solid Malignant Tumours
ABSTRACT Tumour hypoxia is a major constraint for radiotherapy and many types of chemotherapy. A variety of different pathogenetic mechanisms contribute to the development of hypoxia in solid tumours. Hypoxia is associated with unfavourable prognosis, regardless of the treatment modality applied. Two different effects have been considered to explain the deleterious effects of hypoxia on the outcome of tumour patients. The first aspect encompasses the direct interference of hypoxia with antineoplastic treatment modalities. The efficacy of ionizing radiation, but also of a variety of cytotoxic drugs and cytokines rely directly on adequate oxygen tensions. The second aspect concerns the effects of hypoxia on the biology of tumour and stromal cells. Hypoxia is related to malignant progression, increased invasion, angiogenesis and an increased risk of metastasis formation. Possibly, hypoxia is furthermore a stressor which selects cells with increased resistance to apoptosis and thereby indirectly contributes to treatment resistance. This article reviews in brief the specific pathophysiology of tumour oxygenation and its implications for prognosis, tumour treatment and biology.
- SourceAvailable from: Aleksandra M Kubiak
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- "In addition, some solid tumours are found to have necrotic (dead) cores, a direct effect of long-standing tissue hypoxia  . Tumour hypoxia has been demonstrated to reduce the efficacy of many standard cytotoxic drugs used in the treatment of cancer . This is due to ineffective penetration of the drug into the hypoxic mass of the tumour, due to poor vascularisation . "
ABSTRACT: Despite substantial investment in prevention, treatment and aftercare, cancer remains a leading cause of death worldwide. More effective and accessible therapies are required. A potential solution is the use of endospore forming Clostridium species, either on their own, or as a tumour delivery vehicle for anti-cancer drugs. This is because intravenously injected spores of these obligate anaerobes can exclusively germinate in the hypoxic/necrotic regions present in solid tumours and nowhere else in the body. Research aimed at exploiting this unique phenomenon in anti-tumour strategies has been ongoing since the early part of the 20th century. Only in the last decade, however, has there been significant progress in the development and refinement of strategies based on spore-mediated tumour colonisation using a range of clostridial species. Much of this progress has been due to advances in genomics and our ability to modify strains using more sophisticated gene tools.Research in Microbiology 01/2015; 166(4). DOI:10.1016/j.resmic.2014.12.006 · 2.83 Impact Factor
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- "With few exceptions, solid tumors have regions with little or no oxygen   . This is due to poor vascularization and is called hypoxia (low oxygen tension) or anoxia (no oxygen). "
ABSTRACT: The sections in this article areIntroductionThe Role of Oxygen in Photodynamic Therapy: 1O2 GenerationDependence of the Photosensitizing Effect on O2 ConcentrationThe Oxygenation Status in Tumors and Normal TissuesPDT-Induced Reduction of Tumor OxygenationO2 Consumption (Primary Reduction)Vascular Damage (Secondary Reactions)Photosensitizer Photobleaching (Secondary Reactions)Methods to Reduce Tumor Deoxygenation During PDTLow Fluence RatesFractionated Light ExposureOther Methods Changes of Quantum Yields Related to Photosensitizer RelocalizationChanges of Optical Penetration Caused by Changes in O2 ConcentrationConclusion Keywords:photodynamic therapy;oxygen;photosensitization;oxygenation;tumor deoxygenation;cancerHandbook of Biophotonics, 01/2013; , ISBN: 9783527643981
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- "A unique feature of solid cancers is that their rapid growth often results in reduced oxygen availability due to the formation of inadequate or aberrant vasculature . The hypoxic fraction of solid tumors is resistant to radiotherapy  and conventional chemotherapy –, and hypoxia correlates with poor therapeutic outcome , , , . At the molecular level, the transcription factor Hypoxia Inducible Factor-1 (HIF-1) has been identified as the key orchestrator of the biological response to hypoxia due to its transactivation of genes that are involved in many aspects of malignant tumor growth from cell survival and metabolism to angiogenesis and invasion –. "
ABSTRACT: The purpose of the present study was to determine the in vitro and in vivo anti-cancer activity and pharmacological properties of 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, KCN1. In the present study, we investigated the in vitro activity of KCN1 on cell proliferation and cell cycle distribution of pancreatic cancer cells, using the MTT and BrdUrd assays, and flow cytometry. The in vivo anti-cancer effects of KCN1 were evaluated in two distinct xenograft models of pancreatic cancer. We also developed an HPLC method for the quantitation of the compound, and examined its stability in mouse plasma, plasma protein binding, and degradation by mouse S9 microsomal enzymes. Furthermore, we examined the pharmacokinetics of KCN1 following intravenous or intraperitoneal injection in mice. Results showed that, in a dose-dependent manner, KCN1 inhibited cell growth and induced cell cycle arrest in human pancreatic cancer cells in vitro, and showed in vivo anticancer efficacy in mice bearing Panc-1 or Mia Paca-2 tumor xenografts. The HPLC method provided linear detection of KCN1 in all of the matrices in the range from 0.1 to 100 µM, and had a lower limit of detection of 0.085 µM in mouse plasma. KCN1 was very stable in mouse plasma, extensively plasma bound, and metabolized by S9 microsomal enzymes. The pharmacokinetic studies indicated that KCN1 could be detected in all of the tissues examined, most for at least 24 h. In conclusion, our preclinical data indicate that KCN1 is a potential therapeutic agent for pancreatic cancer, providing a basis for its future development.PLoS ONE 09/2012; 7(9):e44883. DOI:10.1371/journal.pone.0044883 · 3.23 Impact Factor