The porphyrin-polyamine conjugate SL-11217 is a Potent preventive Agent in the Min Mouse model of Adenomatous Polyposis

RF Jacoby MD^a, B Frydman PhD^b, CE Cole PhD^a, A Valasinas PhD^b, VK Reddy PhD^b, JA Kink PhD^b, LJ Marton MD^b, RA Lubet MD^c

^aUniversity of Wisconsin Comprehensive Cancer Center, Madison, WI, United States, ^bSLIL Biomedical Corp, Madison, WI, United States, ^cDivision of Cancer Prevention and Control, NIH, Bethesda, MD, United States

AIM. Colorectal cancer is the second leading cause of cancer death among men and women in the United States. Familial adenomatous polyposis (FAP) is an inherited polyposis syndrome in humans which is associated with the development of numerous colonic adenomas that progress to adenocarcinomas with age. Because Min mice develop adenomas as a result of inactivation of the same tumor suppressor gene (APC) known to be involved in the pathogenesis of most colon cancer in humans, experiments with the APC/Min mouse model are relevant for the design of chemoprevention drugs for human colon cancer. A new porphyrin-polyamine conjugate (SL-11217) was assessed as a chemopreventive agent to establish its efficacy and safety in this model. METHODS. APC/Min mice (n = 48) were randomized to oral treatment by gavage twice weekly from age 30 to 80 days with SL-11217 dissolved in saline at dosages of 0, 100, 300 and 500 mg/Kg/week. After the 50 days of treatment, the colons and 4-cm segments of the small intestines were examined by an individual unaware of each animal's treatment status. Tumor number, location and diameter were measured after formalin fixation and staining with 0.2% methylene blue. RESULTS. SL-11217 significantly prevented tumors when given orally to recently weaned APC/Min mice, decreasing overall tumor multipicity by 39% as compared to controls ( p<0.001). No additional decrease in tumor numbers were seen at the higher doses, suggesting that doses lower than 100 mg/Kg may also be effective. The agent significantly reduced tumor numbers throughout the entire small intestine, including the proximal region (duodenum). Reduction of tumor multiplicity in the duodenum, jejunum, and ileum were 42%, 38%, and 39%, respectively. No ulcers or lesions attributable to SL-11217 were observed all along the intestine, and mice gained weight normally. The adenomas that developed in the presence of SL-11217 were much flatter and smaller than those in control mice. CONCLUSIONS. SL-11217 at all doses tested was safe and effective in significantly decreasing the number and size of adenomas in all segments of the intestine. Treatment of duodenal adenomas remains an important unsolved clinical challenge because after FAP patients undergo total colectomy, a high risk remains for neoplasia in the periampullary area.Other drugs, including the coxibs, NSAIDs and aspirin, previously evaluated for colon cancer prevention in the Min mouse model and in humans are ineffective for treatment of adenomas in the duodenum.In contrast, in the Min mouse model, SL-11217 is very effective for treatment of adenomas throughout the intestine including the duodenum, suggesting it may be a promising drug for chemoprevention in clinical trials.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 997 (Chemoprevention).