AN ORTHOTOPIC MODEL OF HUMAN PANCREATIC-CANCER IN SEVERE COMBINED IMMUNODEFICIENT MICE - POTENTIAL APPLICATION FOR PRECLINICAL STUDIES

Pancreatic adenocarcinoma is one of the most incurable and least under stood of all human cancers. It is the fourth leading cause of cancer-r elated mortality in males (after lung, prostate, and colon) and in fem ales (after lung, breast, and colon) in the United States with <2-3% o f patients surviving >5 years, In an attempt to search for more effect ive therapies for this disease, we report here, for the first time, an effective treatment, the combination of gemcitabine and auristatin-ph enethylamine (PE), against an orthotopic implantation of a human pancr eatic adenocarcinoma cell line (HPAC) in severe combined immunodeficie nt (SCID) mice, Tumor implantation was performed by injecting 100 mu l of the HPAC cell suspension (1 x 10(6) cells) directly into the pancr eas of 5-week-old SCID mice. After implantation, tumor formation was c hecked twice a week, All palpable tumors were detected within 21 days (100% take rate), and tumors were confirmed histologically to be pancr eatic adenocarcinoma, For the subsequent efficacy trial, tumor-bearing SCID mice were randomized into four groups with five mice in each gro up, 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 m g/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 treatment s, 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 m aterial, Cytologically, the tumor cells were large, pleomorphic, and h yperchromatic, Many cells contained intracellular lumina containing mu cin, Immunohistochemical studies showed strong p21(WAF1) (p21) express ion but no immunoreactivity with p53 and Her-2/neu antibodies, The mea n 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 (1.8 4 +/- 0.796 g; P = 0.064) groups, In addition, the mean weight in the combination group approached statistical significance when compared wi th the auristatin-PE group alone (1.16 +/- 0.635 g; P = 0.028), We con clude that the combination of gemcitabine and auristatin-PE is an effe ctive treatment against HPAC tumors in this xenograft model and more e ffective than treatment with either gemcitabine or auristatin-PE alone and could be considered for future animal studies with pancreas cance r and/or for human clinical trials.