Efficacy Of Diethyldihydroxyhomospermine Against Human Pancreatic Adenocarcinoma Using Orthotopic Implantation Of Human Pancreatic L3.6pl Cells Into The Pancreas Of Nude Mice

Purpose: To determine the anti-neoplastic effects of (S,S)N1,N14-diethyl-3,12-dihydroxyhomospermine ([HO]2DEHSPM, SUN-101) after subcutaneous (s.c.) administration after orthotopic transplantation of human pancreatic cancer cells (L3.6pl) in the pancreas of nude mice. Methods: L3.6pl cells were injected into the pancreas of nude mice and seven to ten days later the treatment groups were: Study 1: mice (n=10/group) with saline (control), SUN-101 (25 mg/kg), SUN-101 (50 mg/kg), and SUN-101 (100 mg/kg) QD for 4 to 6 weeks. Study 2: mice (n=10/group) with saline (control), SUN-101 (25 mg/kg, QD), SUN-101 (25 mg/kg three times a week, QOD), SUN-101 (15 mg/kg, QOD), and SUN-101 (5 mg/kg, QOD) for 4 to 6 weeks Study 3: mice (n=10/group) with saline (control), Gemzar (100 mg/kg, intraperitoneal (i.p.), twice a week), SUN-101 (25 mg/kg, QOD), and Gemzar plus SUN-101 for 4 to 6 weeks. Results: In study 1, the optimal dose of SUN-101 was determined to be 25 mg/kg QD. This dose reduced up to 82.9% the weight of human pancreatic tumors in mice. Treatment with 50 and 100 mg/kg doses resulted in decreased body weight and proved to be toxic in mice. Histologic changes in the liver included hepatocyte reparative change and in the exocrine pancreas included a mild decrease of cytoplasmic granules in the epithelium of the pancreatic acini. In study 2, the optimal dose of 25 mg/kg administrated QOD was less toxic than daily 25 mg/kg administrations. The pancreatic weight and volume were decreased (47.8% and 66.6%, respectively) with 25 mg/kg administrated QOD and dose related decreases were observed at the 15 mg/kg QOD (20.1% and 52.6%, respectively). No decrease in tumor weight or volume was noted with 5 mg/kg administrated QOD. In study 3, the treatment of Gemzar, SUN-101, and Gemzar plus SUN-101 resulted in 18.7%, 35.6%, and 42.4% decreases in the body weight, respectively. Compared with tumor-bearing control, the treatment of Gemzar, SUN-101, and Gemzar plus SUN-101 resulted in 24.7%, 58.8%, and 67.2% decreases in the pancreas weight, respectively, and 37.8%, 58.4%, and 72.9% decreases in the tumor volumes, respectively. The incidence of liver metastasis was also decreased with SUN-101, Gemzar, and combination of Gemzar plus SUN-101. Conclusions: SUN-101 administered QD or QOD 25 mg/kg inhibited the growth of human pancreatic carcinoma in mice. SUN-101 demonstrated higher toxicity including disruption of the digestive process at daily 50 and 100 mg/kg doses. Co-administration of SUN-101 with gemcitabine appeared to have an additive or synergistic effect on reduction in the pancreatic tumor. Citation Format: Ajit K. Shah, Michael T. Cullen, Cheryl H. Baker. Efficacy of diethyldihydroxyhomospermine against human pancreatic adenocarcinoma using orthotopic implantation of human pancreatic L3.6pl cells into the pancreas of nude mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3128. doi:10.1158/1538-7445.AM2014-3128