University of Uppsala Scholarships in Medical Science – Clinical Pharmacology

Inside solid tumors the individual cells often grow in close vicinity to each other and areas with mild to severe oxygen deficit, hypoxia, is formed within the tumor. The hypoxic tumor cells are likely to be less sensitive against traditional treatment options, e.g. several studies have demonstrated hypoxia-related resistance against radiotherapy. Most probably this is also true for several chemotherapeutic treatments.

Aim: To investigate the activity of different anticancer drugs on:

1.        tumor cells cultivated in spheroids, i.e. small micro-tumors (0.1-1 mm) with a hypoxic core

2.        tumor cells cultivated under hypoxic conditions in comparison to normoxic conditions,

with special attention to drugs with potentially increased hypoxic activity and their mechanisms.

Work plan: To generate hypoxic growth environment to the cells the complete experiments, from addition of drug until end of incubation, will be performed in a hypoxic chamber. The cell`s sensitivity towards a panel of standard chemotherapeutic agents will be analyzed with the fluorometric microculture cytotoxicity assay (FMCA), which measures cell viability on the basis of fluorescein diacetate hydrolysis in cells with intact plasma membranes. The mechanistic investigation will be performed using gene expression analysis and specific kits for molecular events. Isolated mRNA from hypoxic vs normoxic cancer cells, with or without drug exposure, will be analyzed with Affymetrix technique using the Uppsala Array
 Platform. Cancer cells in spheroids will be cultivated using commercially available tools, e.g. microtiter plates from Scivax.

Importance: Investigations indicate that the different micro-environment in tumors, including hypoxia, can be related to resistance against both radiation and chemotherapy, and that the conditions provide cellular development against more malignant phenotypes. Each of these factors provide a common clinical problem. This project aims to a mechanistic approach to the problem, find connections and to optimize the combination of drugs especially selected to exert effects in a hypoxic environment.

Competence of the applicant: The applicant should have an academic degree e.g. MSc Pharm, or MSc molecular Biology, or similar. Experience from cell cultivation and working under aseptic condition are considered an additional qualification.

Previous experience in experimental research is a merit. Skills in oral and written english is necessary.

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