INITIAL STUDIES OF MONOCLONAL-ANTIBODY PAM4 TARGETING TO XENOGRAFTED ORTHOTOPIC PANCREATIC-CANCER

To resemble the clinical presentation of pancreatic: cancer in an anim al model more closely, we developed an orthotopic xenograft of CaPan-1 human pancreatic cancer in athymic nude mice, Within 3 weeks after im plantation into the body and head of the pancreas, animals had palpabl e tumors, By 8 weeks, metastases to the liver and spleen were observed , and at 10-14 weeks, ascites formation, with and without seeding of t he diaphragm, and jaundice were evident, Thus, this tumor model exhibi ted many of the most common features of human pancreatic cancer, Radio labeled monoclonal antibody PAM4 showed specific localization of the p rimary orthotopic and metastatic tumors, On day 3, PAM4 accumulation w ithin the primary tumor (0.5 g) was 11.3 +/- 5.1% injected dose/g with a localization index of 11.3 +/- 4.0. The estimated tumor:blood radia tion dose ratio for PAM4 was 4:1, whereas a nonspecific antibody (Ag8) would provide only 40% of the blood dose to the tumor, Based on these observations, animals bearing 4-week-old orthotopic tumors (estimated volume, 0.25 cm(3)) were administered either I-131-labeled PAM4, 350 mu Ci, or nonspecific Ag8, 350 mu Ci, and compared with an untreated c ontrol group, Radiolabeled PAM4 provided a significant (P < 0.001) inc rease in survival time with less morbidity compared with the untreated control group, whereas nonspecific Ag8 was not significantly differen t from the control group, These studies provide a rationale for initia ting a Phase I clinical study for detection and therapy of pancreatic cancer with PAM4.