Pancreatic
adenocarcinoma is one of the most incurable and least understood of all human
cancers. It is the fourth leading cause of
cancer-related mortality in males (after lung, prostate, and colon) and in females (after lung, breast, and colon) in the United States with <2-3% of patients surviving >5 years. In an attempt to search for more effective
therapies for this disease, we report here, for the first time, an effective treatment, the combination of
gemcitabine and
auristatin-
phenethylamine (PE), against an orthotopic implantation of a human pancreatic
adenocarcinoma cell line (HPAC) in severe combined immunodeficient (SCID) mice.
Tumor implantation was performed by injecting 100 microl of the HPAC cell
suspension (1 x 10(6) cells) directly into the pancreas of 5-week-old SCID mice. After implantation,
tumor formation was checked twice a week. All palpable
tumors were detected within 21 days (100% take rate), and
tumors were confirmed histologically to be pancreatic
adenocarcinoma. For the subsequent efficacy trial,
tumor-bearing SCID mice were randomized into four groups with five mice in each group. One served as a control, the second received
gemcitabine alone (2.5 mg/kg/injection i.p.), the third received
auristatin-PE alone (2.0 mg/kg/injection i.v.), and the fourth group received the combination of
gemcitabine (i.p.) and
auristatin-PE (1.5 mg/kg/injection i.v.). All animals were euthanized 7 days after the completion of their treatments, and the pancreases were resected. Histological examination revealed the
tumors to be
adenocarcinoma. The
tumors were composed of diffuse sheets of cells interrupted by glandular spaces containing secretory material. Cytologically, the
tumor cells were large, pleomorphic, and hyperchromatic. Many cells contained intracellular lumina containing
mucin. Immunohistochemical studies showed strong p21WAF1 (p21) expression but no immunoreactivity with p53 and Her-2/neu
antibodies. The mean pancreatic weight in the
gemcitabine/
auristatin-PE combination group was significantly (P = 0.014) lower (0.84 +/- 0.639 g) when compared with those of the control (2.91 +/- 1.19 g) and
gemcitabine alone (1.84 +/- 0.796 g; P = 0.064) groups. In addition, the mean weight in the combination group approached statistical significance when compared with the
auristatin-PE group alone (1.16 +/- 0.635 g; P = 0.028). We conclude that the combination of
gemcitabine and
auristatin-PE is an effective treatment against HPAC
tumors in this xenograft model and more effective than treatment with either
gemcitabine or
auristatin-PE alone and could be considered for future animal studies with
pancreas cancer and/or for human clinical trials.