The cancer-fighting compound, 12-O-tetradecanoylphorbol-13-acetate and generally known as TPA, is found in an oil drawn from seeds of the skin-irritating shrub, the croton plant (Croton tiglium L.). Croton oil has long been known to oriental herbalists for its purgative qualities.
A report of the new discovery by Allan H. Conney at Rutgers, The State University of New Jersey; his student, Gina Avila; and their colleagues is scheduled to appear in the October 2005 issue of The Journal of Pharmacology and Experimental Therapeutics. The report is currently available online at jpet.aspetjournals.org/cgi/reprint/jpet.105.087585v1.
The American Cancer Society predicts that 32,000 Americans will die of pancreatic cancer in 2005, making it the fourth leading cause of cancer death overall. The pancreas is a multipurpose gland in the abdomen that produces enzymes to aid digestion and hormones, such as insulin, that help balance sugar in the blood.
"Pancreas cancer is a tough one to treat. Treatment options are very limited, and not many people survive. TPA has good potential for therapy so it's definitely worth pursuing," said Conney, State of New Jersey Professor of Chemical Biology, Garbe Professor of Leukemia and Cancer Research, and director of the Susan Lehman Cullman Laboratory for Cancer Research at Rutgers' Ernest Mario School of Pharmacy.
Encouraged by their progress in the laboratory with prostate cancer, the researchers initiated studies with the pancreas using three human pancreatic cancer cell lines with different molecular properties. In laboratory cultures, the scientists applied TPA to cells from these lines and found that growth of the pancreatic cancer cells was inhibited by TPA when used in concentrations that are achievable in humans – levels that should not be toxic to people.
They also tested TPA on the cells in combination with all-trans retinoic acid (ATRA), a vitamin A derivative previously shown to be effective in treating leukemia.
"We had previously demonstrated that ATRA is an effective synergist with TPA in treating prostate cancer in the laboratory so it was logical to test the combination against pancreatic cancer as well," Conney said. "We found that the TPA/ATRA combination in cell culture worked better than the individual compounds alone."
The researchers injected cells from the human cancer cell lines into immunodeficient mice – mice specifically bred so that their immune systems would not reject foreign biological material – to grow pancreatic tumors against which the compounds could be tested. Once the tumors were well established, Conney and his team began treating the mice with TPA alone and in combination with ATRA. They observed inhibition of tumor growth and reduction in tumor size.
The researchers saw a substantial increase in apoptosis (programmed cell death) and a substantial decrease in mitosis (cells reproducing) in the tumors. "We were simultaneously stopping the growth of new cancer cells and killing those already existing," Conney said. "This was most dramatic when we used the TPA/ATRA combination on the tumors."
He added that the increased efficacy of the potent combination would permit even lower doses to be used. "It is this TPA/ATRA combination, with its lower doses and its demonstrated synergy, that we would very dearly like to see move to human clinical trials."
Journal
Journal of Pharmacology and Experimental Therapeutics