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Title: Distribution of anti-cancer drugs in solid tumours studied by MALDI-MSI
Author: Batubara, Afnan
ISNI:       0000 0004 7224 1815
Awarding Body: Sheffield Hallam University
Current Institution: Sheffield Hallam University
Date of Award: 2015
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Vascular disrupting agents (VDAs) have been used in treatment of many cancers. 5,6 -dimethylxanthenone-4-acetic acid (DMXAA) is a low molecular weight drug of the flavonoid group which has an anti-vascular effect in tumours causing endothelial cell apoptosis and activation of cytokines. A study employing matrix assisted laser desorption ionisation-mass spectrometry (MALDI-MS) imaging to examine LS174T colorectal adenocarcinoma xenografts following administration of DMXAA has been conducted to study the distribution of anti-cancer drugs and to explore markers of efficacy and resistance. Initial work established the limit of detection /quantitation of DMXAA in tissue. The drug limit of detection (LoD) is determined as 10 ng/ml and the drug lower limit of quantitation (LLoQ) is 45 ng/ml. MALDI images were recorded from LS174T colorectal adenocarcinoma xenografts removed from immunodeficient mice following treatment with with 27.5 mg/kg DMXAA. These indicated that the drug was distributed mainly in the centre of tumour 4h post-treatment, whilst it was distributed around the periphery 24h posttreatment. A study of lipid expression in treated tumors demonstrated that washing tissue sections with 150 mM ammonium acetate solution (NH[4]AC) improved the intensity of lipids signals in both negative and positive ion mode. These images also indicated that sphingomyelins (SM) and phosphatidylcholines (PC) lipid species were highly expressed in cancerous tissue. A thin layer chromatography-matrix assisted laser desorption ionisation-mass spectrometry (TLC-MALDI-MS) experiment has been carried out for the analysis of phospholipids extracted from the treated xenograft tumours. The lipid extracts were separated into 6 spots on the TLC plate. These were identified as lysophosphatidylcholines (LPC), sphingomyelins (SM), phosphatidylcholines (PC) and phosphatidylethanolamines (PE). The TLC-MALDI-MS data indicated that LPC were highly expressed in the 4h and 24h post-treated tumour samples compared to the control. An increase in expression of LPC lipids in solid tumours treated with DMXAA has been demonstrated and shown to be localised in the central area of the tumour. Mass spectrometry imaging was also used to characterise proteins and peptide signal in tumours after treatment with DMXAA. Histone H2A peaks at 944 m/z were highly expressed in the region of the tumours. In addition, a characteristic increase in the Hb beta chain at 1274.74 m/z in the 24h post-treated tumour has been seen. The data obtained from PCA has shown that the levels of certain proteins changed over the different tumour time point.
Supervisor: Clench, Malcolm ; Loadman, Paul Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available