published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Development of resistance is the major hindrance to successful chemotherapy treatment in oesophago-gastric (OEG) cancers. Platinum based chemotherapy prolong the survival however only 20 - 30 % of patients survive 5- years since diagnosis of the disease. Therefore understanding of the mechanisms that underlie this phenomenon and identification of novel biomarkers/targets that could predict the response to the treatment and sensitize these tumours to current therapy is needed. We established a panel of human cancer cell lines of oesophagus (OE21 and OE33) and gastric cardia (AGS) resistant to oxaliplatin, cisplatin and docetaxel. To study mechanisms of drug resistance we performed gene expression profiling on resistant and parental lines and differentially expressed genes involved in sphingolipids / lysosomes metabolism have been shown as associated with drug resistance. Selected markers were validated on mRNA and protein levels among the panel of OEG cell lines and clinical specimens. Cellular levels of sphingolipid species were determined in drug sensitive and resistant lines using mass spectrometry. This study revealed a positive correlation between over-expression of sphingosine kinase 1 (SPHK1) and increased levels of sphingosine -1-phosphate (S1P) associated with drug resistance in gastric cancer cell lines. Moreover it showed the predictive value of SPHK1 as high level of this protein correlates with poor survival of OEG cancer patients treated with cisplatin based chemotherapy, in contrast to those patients that received surgery alone. Additionally, lipidomic profiling data showed possibly distinct mechanisms of drug resistance between gastric and oesophageal tumours, indicating that mechanisms of drug resistance are likely cell type, rather than drug specific. In conclusions, this study proofs the clinical relevance of our in vitro experimental models to study mechanisms of drug resistance in OEG tumours and provides the source of novel biomarkers for targeted therapy strategies in this disease.

published_or_final_version / Zoology / Doctoral / Doctor of Philosophy

Thesis (M. Phil.)--University of Hong Kong, 1980. / Also available in electronic format. Also available in print.

Thesis (doctoral)--University of Copenhagen.

Thesis (M. Phil.)--University of Hong Kong, 1997. / Includes bibliographical references (leaf 122-142).

Thesis (M. Med. Sc.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 22-25).

Thesis (Ph. D.)--University of Hong Kong, 1998. / Includes bibliographical references (leaf 119-135).

Thesis (Ph. D.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 205-240).

Thesis (Ph. D.)--University of Hong Kong, 1997. / Includes bibliographical references (leaf 181-226).