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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Inhibitory Effects of 12-O-Tetradecanoylphorbol-13-acetate Alone or in Combination with All-trans Retinoic Acid on the Growth of Cultured Human Pancreas Cancer Cells and Pancreas Tumor Xenografts in Immunodeficient Mice

Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey (G.E.A., X.Z., X.X.C., A.D.R., A.H., R.L.C., Y.P.L., Y.R.L., A.H.C.); Cancer Institute of New Jersey, New Brunswick, New Jersey (A.B.R., W.J.S., A.H.C.); Center for Advanced Biotechnology and Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School and Rutgers, The State University of New Jersey, Piscataway, New Jersey (J.S., A.B.R.); Division of Biometrics, School of Public Health, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey (W.J.S., Y.L.); and Department of Biology, Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana (P.C.)

Treatment of cultured PANC-1, MIA PaCa-2, and BxPC-3 human pancreatic adenocarcinoma cells with 0.1 to 1.6 nM 12-O-tetradecanoylphorbol-13-acetate (TPA) for 96 h inhibited the proliferation of these cells in a dose-dependent manner, and PANC-1 and MIA PaCa-2 cells were more sensitive to TPA than BxPC-3 cells. Inhibition of proliferation by TPA in PANC-1 cells was associated with an increase in the level of p21, but this was not observed in MIA PaCa-2 or BxPC-3 cells. The TPA-induced increase of p21 in PANC-1 cells was blocked by bisindolylmaleimide or rottlerin (inhibitors of protein kinase C). Studies in NCr-immunodeficient mice with well established PANC-1 tumor xenografts indicated that daily i.p. injections of TPA strongly inhibited tumor growth, increased the percentage of caspase-3-positive cells, and decreased the ratio of mitotic cells to caspase-3-positive cells in the tumors. Studies with BxPC-3 tumors in NCr mice receiving daily i.p. injections of vehicle, TPA, all-trans retinoic acid (ATRA), or a TPA/ATRA combination showed that TPA had an inhibitory effect on tumor growth, but treatment of the animals with the TPA/ATRA combination had a greater inhibitory effect on tumor growth than TPA alone. Treatment with the TPA/ATRA combination resulted in a substantially decreased ratio of the percentage of mitotic cells to the percentage of caspase-3-positive cells in the tumors compared with tumors from the vehicle-treated control animals. The inhibitory effects of TPA on tumor growth occurred at clinically achievable blood levels.

Address correspondence to: Dr. Allan H. Conney, Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854. E-mail: aconney{at}rci.rutgers.edu