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The effects of bleomycin, mitomycin C, and cytoskeletal-disrupting drugs on angiogenesis in vitro and haemangioma development in vivo
Thesis (PhD)--University of Pretoria, 2009.
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University of Pretoria
2013
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| _version_ | 1867613456966877184 |
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| access_status_str | Open Access |
| author2 | Pepper, Michael Sean |
| author_browse | Pepper, Michael Sean |
| author_facet | Pepper, Michael Sean |
| collection | Thesis |
| dc_rights_str_mv | ©University of Pretoria 2008 D555/ |
| description | Thesis (PhD)--University of Pretoria, 2009. |
| format | Thesis |
| id | oai:repository.up.ac.za:2263/24472 |
| institution | University of Pretoria (South Africa) |
| last_indexed | 2026-06-10T12:36:26.674Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UPSpace — University of Pretoria Institutional Repository |
| publishDate | 2013 |
| publishDateRange | 2013 |
| publishDateSort | 2013 |
| publisher | University of Pretoria |
| publisherStr | University of Pretoria |
| record_format | dspace |
| source_str | UPSpace — University of Pretoria Institutional Repository |
| spelling | oai:repository.up.ac.za:2263/24472 The effects of bleomycin, mitomycin C, and cytoskeletal-disrupting drugs on angiogenesis in vitro and haemangioma development in vivo Pepper, Michael Sean Davis, P.F. Dippenaar, N.G. peace.mabeta@up.ac.za Mabeta, Peaceful Lucy Cell growth Angiogenesis Cell migration Basic fibroblast growth factor Polyoma middle t oncogene Vascular endothelial growth factor (VEGF) Cytoskeletal-disrupting agents Vascular tumour Haemangioma Bleomycin Haemangioma Endothelial cells UCTD Thesis (PhD)--University of Pretoria, 2009. Angiogenesis, the process of new vessel formation, appears to be a central mechanism that underlies the development of haemangiomas. Recently, intralesional bleomycin injection was used to treat paediatric haemangiomas with very good results. The purpose of this study was to determine whether there was significant systemic circulatory spill-over of bleomycin in haemangioma patients treated with intralesional bleomycin to determine safety of use. Furthermore, in order to elucidate bleomycin’s mechanism of action in inducing haemangioma regression, this study aimed at determining the effects of bleomycin on aspects of angiogenesis, namely, endothelial cell migration, growth and apoptosis, and comparing these effects with those of drugs previously reported to inhibit various aspects of the angiogenic process (mitomycin C, 2-methoxyestradiol, taxol, vincristine, vinblastine, colchicine, nocodazole and cytochalasin D). Lastly, the effects of bleomycin, mitomycin C, 2-methoxyestradiol, taxol, vincristine, vinblastine, colchicine, nocodazole and cytochalasin D were studied in an animal haemangioma model. A rapid and highly sensitive high performance liquid chromatographic (HPLC) method was developed. Blood samples were collected from four haemangioma patients before and after (over a 24 hour period) intralesional bleomycin (IB) therapy. As a control, blood samples were also collected at identical time intervals from four patients undergoing intravenous (IV) bleomycin chemotherapy for various malignant tumours. The HPLC method was used to quantitate bleomycin fractions in patient samples. The mean bleomycin concentration detected in plasma samples obtained from IB treated patients was 0.00 ìg/ml for both bleomycin A<Sub>2 and B2 over the 24-hour period following therapy. Plasma bleomycin A2 and B2 levels of 360.79 and 158.85 ìg/ml respectively were detected in samples obtained from cancer patients treated with bleomycin IV. These findings indicate that the low levels detected may translate to a significantly lesser risk of pulmonary fibrosis following IBI. The effect of drugs on endothelial cell migration was analyzed by wounding a confluent monolayer of cells and determining the number of cells that had migrated from the wound edge. Endothelial cell growth was determined in cells treated with various drug concentrations while apoptosis was examined using hematoxylin and eosin staining, DNA fragmentation assay and acridine orange staining. The effect of test drugs on in vitro angiogenesis was determined on endothelial cells induced to form capillary-like tubes in collagen gel. Test drugs were then evaluated for antitumour activity in an animal haemangioma model. Data demonstrated that test drugs inhibited endothelial cell migration, with the exception of mitomycin C. All test drugs induced a reduction in the percentage of viable endothelial cell in a dose-dependant manner, and also induced endothelial cell apoptosis. The drugs inhibited angiogenesis in vitro and inhibited tumour development in vivo with varying potency. In general, results from this study indicated that there was negligible systemic spill-over of bleomycin following IB administration in patients with haemangiomas, suggesting a much lesser risk of developing bleomycin-induced pulmonary fibrosis. This study also showed that test drugs inhibited angiogenesis in vitro and haemangioma development in vivo in a mouse model. Taken together, these observations demonstrate that bleomycin may inhibit haemangioma growth by inhibiting angiogenesis. In addition, mitomycin C, 2-methoxyestradiol, taxol, vincristine, vinblastine, colchicine, nocodazole and cytochalasin D may have potential in the treatment of haemangiomas of infancy, and should be investigated further in a murine haemangioma model to determine effective dose schedules. Physiology unrestricted 2013-09-06T17:37:53Z 2009-04-07 2013-09-06T17:37:53Z 2008-11-28 2009-04-07 2009-01-22 Thesis 2008 D555/gm G-9725-2014 12791859400 http://hdl.handle.net/2263/24472 http://upetd.up.ac.za/thesis/available/etd-01222009-125003/ ©University of Pretoria 2008 D555/ application/pdf application/pdf application/pdf application/pdf application/pdf application/pdf application/pdf application/pdf application/pdf University of Pretoria |
| spellingShingle | Cell growth Angiogenesis Cell migration Basic fibroblast growth factor Polyoma middle t oncogene Vascular endothelial growth factor (VEGF) Cytoskeletal-disrupting agents Vascular tumour Haemangioma Bleomycin Haemangioma Endothelial cells UCTD The effects of bleomycin, mitomycin C, and cytoskeletal-disrupting drugs on angiogenesis in vitro and haemangioma development in vivo |
| title | The effects of bleomycin, mitomycin C, and cytoskeletal-disrupting drugs on angiogenesis in vitro and haemangioma development in vivo |
| title_full | The effects of bleomycin, mitomycin C, and cytoskeletal-disrupting drugs on angiogenesis in vitro and haemangioma development in vivo |
| title_fullStr | The effects of bleomycin, mitomycin C, and cytoskeletal-disrupting drugs on angiogenesis in vitro and haemangioma development in vivo |
| title_full_unstemmed | The effects of bleomycin, mitomycin C, and cytoskeletal-disrupting drugs on angiogenesis in vitro and haemangioma development in vivo |
| title_short | The effects of bleomycin, mitomycin C, and cytoskeletal-disrupting drugs on angiogenesis in vitro and haemangioma development in vivo |
| title_sort | effects of bleomycin mitomycin c and cytoskeletal disrupting drugs on angiogenesis in vitro and haemangioma development in vivo |
| topic | Cell growth Angiogenesis Cell migration Basic fibroblast growth factor Polyoma middle t oncogene Vascular endothelial growth factor (VEGF) Cytoskeletal-disrupting agents Vascular tumour Haemangioma Bleomycin Haemangioma Endothelial cells UCTD |
| url | http://hdl.handle.net/2263/24472 http://upetd.up.ac.za/thesis/available/etd-01222009-125003/ |