Adenocarcinoma of the pancreas is one of the least understood and most incurable malignancies. Almost all patients with this disease die within 1 year of diagnosis. To facilitate development of novel radiopharmaceuticals for diagnostic and therapeutic uses, in vivo models are need that closely mimic the natural biological behaviour of pancreatic carcinomas in humans. This work aimed to establish an in vivo model of human pancreatic cancer for t his purpose and to evaluate the potential of the pancreatic carcinoma-affine L-p-amino-3-[ 123 I]Iodo-phenylalanine (IAPA) and L-p-[ 123 I]Iodo-phenylalanine (IPA) preclinically.
The human pancreatic carcinomas, PaCa44 and PanC1 (1-2 x 10 6 cells in 10-30 microL PBS), were implanted either subcutaneously into the flank or orthotopically into the pancreas of anesthesized severe combined immunodeficient (SCID) mice. The size of sc. tumor was recorded twice weekly using linear calipers. Additionally, tumor formation was monitored noninvasively by MRI, using a small animal magnetic resonance tomograph, as well as histopathologically after biodistribution and SPET studies with IPA and IAPA.
All animals developed a pancreatic tumor within 3.5 weeks. The tumor was clearly demonstrated in all animals with subcutaneous implantation by MRI, as well as 90%, and 60% of the orthotopic implanted PaCa44 and PanC1 cells, respectively. No invasion or metastases could be demonstrated by heterotropic-implanted tumors. Tumor growth and spread following orthotopic implantation resembled the situation in human, including invasion into adjacent organs and metastases formation in different sites in the abdomen, especially in mice bearing PaCa44 cells.
Biodistribution study followed i.v. application revealed that IPA and IAPA were excreted by urine. Moreover, both radioligands showed high tumor uptake. Radioactivity accumulation in tumor, 60 and 240 min p.i. amounted 8,6 and 6,1 %I.D./g for IAPA, and 12 and 16,7 %I.D./g for IPA, respectively, with tumor-to-organ ratios of 1,1 -4,2 (Tu/blood), 1,4 -5,4 (Tu/Liver), 2,1 -5,5 (Tu/spleen) and 3,3 -11,7 (Tu/Muscle). In comparison tumor uptake following FDG injection was 15,5 and 3,5 %I.D./g. However, organ uptakes in both implantations provided evidence that the orthotopic transplant model more than the heterotopic one appropriately reflects the entire process of human pancreatic cancer.
The present cancer model is a powerful tool for biological studies of human pancreatic tumor and for preclinical evaluations of radiopharmaceuticals. Moreover, results of biodistribution studies suggest that IAPA and IPA are very interesting candidates as radiotracers for noninvasive imaging of pancreatic carcinomas by SPET.