Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.554909
Title: The role of hypoxia in the malignant progression of androgen dependent prostate cancer
Author: Ming, Louise
Awarding Body: University of Ulster
Current Institution: Ulster University
Date of Award: 2010
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Abstract:
Androgen ablation therapy is frequently used in locally advanced androgen-dependent prostate cancer, however the cancer often returns with a more aggressive, androgen- independent phenotype. The causes of this are poorly understood, however androgen withdrawal is known to induce hypoxia in androgen-sensitive tissue; this is important as hypoxia is known to drive malignant progression. Tumour oxygenation was measured in LNCaP tumours grown in SCID mice treated with a single dose of three anti-androgens; within 24h all had reduced tumour oxygenation with the greatest reduction caused by bicalutamide (10 mg/kg). LNCaP-Luc tumour-bearing mice were then treated daily with a clinically relevant bicalutamide dose (2mg/kg). Oxygenation showed a profound drop to almost zero by day 7 persisting until day 14 when it started to increase up to day 28. This was confirmed ex vivo using the hypoxic marker G lut-I. LNCaP-Luc tumour fragments implanted in a dorsal skin fold chamber and treated with daily bicalutamide showed a marked loss of small vessels at days 7 and 14, revascularisation was complete within the next week suggesting that vascular changes caused the oxygenation changes. Quantitative PCR showed changes in VEGF, IL8, Runx 2 and androgen receptor expression consistent with the oxygen changes and progression to a more malignant phenotype. A control and treated tumour were excised on day 28 and re-established in vitro; cells from treated tumours were shown to have a more malignant phenotype than vehicle-treated controls. Growth delay studies compared daily bicalutamide and its combination with AQ4N which targets hypoxic cells. Bicalutamide increased tumour growth after 16 days and lung metastasis by day 28; AQ4N (single dose, day 7) blocked these effects. AQ4N alone provided the greatest reduction in metastasis. This study shows that bicalutarnide-induced hypoxia selects for cells that show malignant progression; targeting the pre-existing hypoxic cells may therefore be of greater clinical benefit.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.554909  DOI: Not available
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