Cur­rent treat­ments for pan­cre­atic cancer have failed to effec­tively manage the dis­ease and improve the grim sur­vival rate. A North­eastern Uni­ver­sity study found that the thick layer of mucin cov­ering the tumor cells acts as a bar­rier to chemotherapy drugs, thus it is respon­sible for the dimin­ished anti-​​tumor effect of pop­ular treat­ment drugs such as 5-​​FU (fluorouracil).

Pro­fessor Robert B. Camp­bell and his Ph.D. stu­dent Ashish V. Kalra have found not only that reducing the mucin on the tumor cell’s sur­face increases the effect of 5-​​FU sig­nif­i­cantly, it may also con­tribute to a decrease in the amount of drug needed to get the same ther­a­peutic result.

We are beating down the bar­rier that stands in the way of effec­tive cancer treat­ment,” said Camp­bell, Assis­tant Pro­fessor of Phar­ma­ceu­tical Sci­ences at Northeastern’s Bouvé Col­lege of Health Sci­ences. “Our goal is to help improve the effi­cacy of drugs and limit the amount of these toxic drugs needed for treatment.”

This is the second phase of Campbell’s and Kalra’s study of the bio­log­ical attrib­utes of pan­cre­atic tumor cells and the role cel­lular bar­riers play in lim­iting the effec­tive­ness of drugs. During Phase I, the researchers found that extracellular-​​bound mucin was impeding the cyto­toxic effect of 5-​​FU against the growth of pan­cre­atic cancer cells in vitro.

In Phase II, they con­firmed that the mucin gly­ca­tion mesh pro­duced during the normal devel­op­ment of pan­cre­atic tumors limits the overall effec­tive­ness of 5-​​FU in vivo. They also showed that the con­cen­tra­tion of 5-​​FU taken up by the target cell was 5~fold greater when the for­ma­tion of the gly­ca­tion mesh was inhib­ited, fur­ther sup­porting the bar­rier effect of mucin.

We knew from the first study that the ability of pan­cre­atic cancer cells to respond to 5-​​FU treat­ment in vitro can be enhanced by inhibiting mucin o-​​glycosylation,” said Camp­bell. “This time, we found that the overall tumor response to 5-​​FU in mice that received intra­tu­moral injec­tions of the mucin O-​​glycosylation inhibitor was greater than the saline con­trol group.”

In addi­tion to the enhanced cell killing effect of 5-​​FU in a reduced extra­cel­lular mucin envi­ron­ment, Camp­bell and Kalra also con­firmed that the expo­sure to mucin inhibitors did not harm the via­bility and mor­phology of the pan­cre­atic cancer cells.

Improving effi­cacy of chemother­a­peutic drugs plus reducing tox­i­city in pan­cre­atic cancer patients by lim­iting the amount of drugs needed to get the same results are hugely impor­tant steps toward effec­tive treat­ment of pan­cre­atic cancer,” added Camp­bell. “These find­ings also have the poten­tial to improve the effec­tive­ness of other con­ven­tional chemother­a­peutic drugs.”

Campbell’s and Kalra’s find­ings are dis­cussed in an article titled “Mucin over­ex­pres­sion limits the effec­tive­ness of 5-​​FU by reducing intra­cel­lular drug uptake and anti­neo­plastic drug effects in pan­cre­atic tumors” pub­lished in this month’s issue of the Euro­pean Journal of Cancer.

The article dis­cussing Phase I of the study appeared in the October ’07 issue of the British Journal of Cancer.