Research Interests:

A common focus of our group is to understand and manipulate the factors that impact on tumor cell response to treatment in order to improve therapy outcome.

Tumour hypoxia or lack of oxygen is known to adversely affect prognosis, as hypoxic cells in solid tumors are more likely to be aggressive, metastatic, and resistant to treatment. An important goal would be achieved if detection of hypoxic cells in solid tumors could be performed routinely in high risk tumor types. Towards this end, we have developed and applied several different methods for detecting hypoxic cells, first in model systems and recently in the clinic. These include methods based on differences in radiation-induced DNA damage, probes that bind specifically to hypoxic cells, and most recently, endogenous hypoxia markers.

Irradiated cells show clusters of RPA molecules involved in the process of DNA repair. Using a single cell gel electrophoresis method called the comet assay, damaged nuclei show long tails containing fragmented DNA

DNA damage and repair are critical components of overall tumor response to therapy. Individual differences in susceptibility or repair capacity are likely to contribute to differences in tumor response to both drugs and radiation. Even within a single tumor, heterogeneity in response to treatment can lead to selection of resistant cells. We have developed the comet assay as a method of measuring response of tumor cells to DNA damaging agents. This single cell gel electrophoresis method offers an opportunity to identify non-responding tumor cells in samples obtained from a single fine needle aspirate biopsy. In addition to the comet assay, immunohistochemical evaluation of components of DNA repair complexes (γH2AX, RPA, BRCA1) are being examined as a way to identify radioresistant tumors and genetically unstable progeny of irradiated cells.

Growth of cells in close contact with other cells leads to a unique form of drug and radiation resistance called "the contact effect". The mechanism behind this effect is largely unknown, but may involve changes chromatin organization and cell signaling. We are particularly interested in resistance to the anticancer drug etoposide that develops rapidly when many cell types are grown as multicell spheroids or tumors. This resistance is associated with a change in the subcellular location and phosphorylation of the target enzyme, topoisomerase II. Results from differential display point to increases in calcium binding activity that may be involved in etoposide resistance. Ongoing experiments are evaluating calcium levels using flow cytometry and measuring sensitivity of cells transfected with a gene involved in calcium binding and metastasis.

These studies are funded by the  National Cancer Institute of Canada (with funds provided by the Canadian Cancer Society), and the  Canadian Institutes of Health Research.

Senior Scientist, Emeritus

Research Associates

Judit P. Banáth, Ph.D.

Research Assistants

Nancy LePard, B.Sc.

Administration

Wil Cottingham (E-mail:  wcotting@bccancer.bc.ca)