Investigation of Novel Cytostatic Therapy for HCV Induced Liver Cancer
Current non-surgical cancer therapies are mostly non-specific cytotoxic drugs with limited specificity, which enhance both genetic instability and the rapid evolution of therapy resistance in any surviving tumour cells. Cytostatic therapy may circumvent this problem by removing the evolutionary pres...
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| Format: | Dissertation |
| Language: | English |
| Published: |
ProQuest Dissertations & Theses
01-01-2016
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| Online Access: | Get full text |
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| Summary: | Current non-surgical cancer therapies are mostly non-specific cytotoxic drugs with limited specificity, which enhance both genetic instability and the rapid evolution of therapy resistance in any surviving tumour cells. Cytostatic therapy may circumvent this problem by removing the evolutionary pressure and preventing the accumulation of therapy induced genetic instability.Previous work has shown that the Rho Kinase (ROCK) inhibitor Y27632, and its structural analogue YA1, can persistently suppress the growth of transformed murine NIH3T3 cell colonies without cell killing when these were co-cultured with non- transformed NIH3T3 cells. In order to test whether this effect could be reproduced with transformed human cells, a cell culture model was developed where immortalised human hepatocytes were transformed by ectopic expression of the HCV Core and NS4B open reading frames (ORFs)We found that Y27632 and YA1 significantly reduced colony formation in cultures of these cells. We postulated that transient blockade of kinases can induce a persistent inhibition of non-contact inhibited transformed colony formation and can also remove pre- formed colonies. Since supplementation with Zinc has been shown to improve HCV related liver pathology, the effect of its addition to these cultures was initially investigated. This showed that Zinc down-regulated expression of both HCV ORF's but did not suppress the growth of transformed colonies, indicating that the transformed phenotype was not dependent on continued expression of either viral ORFThese compounds with this property may thus provide a novel strategy for viral associated liver cancer cytostatic therapy. |
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| ISBN: | 9798496577519 |