Study may aid pancreatic cancer patients' response to chemo drugs

Nov 1 2007

Pancreatic cancer patients face the worst survival rates compared to all other forms of human cancer as the disease is nearly impossible to diagnose at an early stage when successful treatments might be possible.

Owing to late stage diagnosis, the remaining clinical options are limited to chemotherapeutic approaches involving the use of such drugs as gemcitabine and 5-fluorouracil (5-FU). The popular chemotherapeutic agents have produced limited clinical success and Northeastern University professor Robert B. Campbell wanted to know why.

Campbell and his graduate student investigated whether or not mucin overexpressed on the surface of human pancreatic tumor cells might act as a physical barrier, limiting the drug's effectiveness.

The article discussing the experiment, titled “Mucin Impedes Cytotoxic Effect of 5-FU against Growth of Human Pancreatic Cancer Cells; Overcoming Cellular Barriers for Therapeutic Gain” is published in this month's issue of The British Journal of Cancer.

“In order to improve treatment approaches, we must consider the biology of pancreatic tumors at the molecular, cellular and physiological levels,” said Dr. Campbell, Assistant Professor of Pharmaceutical Sciences at the Northeastern's Bouvé College of Health Sciences. “Our experimental findings in this study suggest that mucin is in fact a cellular barrier limiting chemotherapeutic action of 5-FU against human pancreatic cancer cells, making 5-FU less effective.”

Normal epithelial cells are covered with mucin. In cancerous tumor cells, mucin is overexpressed on the cell's surface. Dr. Campbell and his Ph.D., student Mr. Ashish V. Kalra were probing the effects of a single mucin variety, called MUC1, which is present on the surface of both normal epithelial cells and pancreatic tumor cells and is responsible for the overabundance of mucin on the latter. In order to find out whether or not mucin influenced the intracellular uptake of 5-FU, the researchers used inhibitors to limit the amount of MUC1 and reduce the mucin glycation mesh surrounding cells. Campbell and Kalra observed that the exposure to inhibitors did not harm the healthy physiology of cells, however, the reduction of mucin mesh on the tumor cells enhanced the cell killing effect of 5-FU.

“The exact mechanism is not known, but we speculate that the inhibition of mucin may reduce the mucin mesh,” said Kalra. The authors speculate that “this reaction may facilitate the diffusion of drugs across the compromised mucus layer, improve intracellular drug uptake and enhance the effects of chemotherapeutic drugs, such as 5-FU.”

Campbell and Kalra suggest that inhibiting the mucin on the surface of pancreatic tumor cells and therefore limiting the barrier that stands in the way of the chemotherapeutic agents, may also lead to the need for smaller amounts of drugs to get the same results. The researchers also say that investigations into the role of mucin during chemotherapy in preclinical models are necessary to better understand the clinical implications of their experimental findings.