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Abstract
SummaryDevelopment of cancer chemoprevention compounds requires enhanced consideration for toxicity and route of administration because the target population is healthy. The small molecule drug, SHetA2 (NSC 726189), exhibited in vivo chemoprevention activity and lack of toxicity when administered by oral gavage. Our objective was to determine if a dietary formulation of SHetA2 could achieve effective tissue drug levels without toxicity. C57bl/6 J mice were monitored on modified American Institute of Nutrition (AIN)76A diet mixed with SHetA2 in a 3:1 ratio with Kolliphor HS15, a self-emulsifying drug delivery system (SEDDS) to deliver 37.5, 62.5, 125, 187 or 250 mg SHetA2/kg/day. Blood and tissues were evaluated after 1, 3 and 6 weeks. The 187 mg/kg/day dose was identified as optimal based on achievement of maximum blood and tissue drug levels in the effective micromolar range without evidence of toxicity. The 250 mg/kg/day group exhibited lower drug levels and the highest intestinal drug content suggesting that an upper limit of intestinal absorption had been surpassed. Only this highest dose resulted in liver and kidney function tests that were outside of the normal range, and significant reduction of cyclin D1 protein in normal cervical tissue. SHetA2 reduced cyclin D1 to greater extents in cancer compared to non-cancer cell cultures. Given this differential effect, optimal chemoprevention without toxicity would be expected to occur at doses that reduced cyclin D1 in neoplastic, but not in normal tissues. These findings support further development of SHetA2 as a chemoprevention agent and potential food additive.
Highlights
Current therapeutic strategies for gynecologic cancers incorporate various combinations of surgery, radiation, chemotherapy and molecularly-targeted drugs, which commonly cause severe patient morbidity [1, 2]
An orally-available chemoprevention compound that exhibits no evidence of toxicity in large population-based studies could be considered for use as a food additive
The objective of this study was determine if various doses of SHetA2 could be administered in a dietary formulation containing Kolliphor HS15 to achieve chemoprevention-effective serum and tissue drug levels without toxicity
Summary
Current therapeutic strategies for gynecologic cancers incorporate various combinations of surgery, radiation, chemotherapy and molecularly-targeted drugs, which commonly cause severe patient morbidity [1, 2]. Only minimal-to-no toxicity will be acceptable to the target population. Patients undergoing secondary cancer prevention schemes after primary therapy are likely to accept a low level of toxicity to reduce cancer recurrence. The approach of using natural or synthetic compounds to prevent cancer (chemoprevention) has been proven effective in multiple experimental models and clinical trials, side effects caused by long-term continuous use of chemoprevention agents, such as selective estrogen response modulators (SERMS), have limited their acceptability in healthy individuals [3, 4]. An orally-available chemoprevention compound that exhibits no evidence of toxicity in large population-based studies could be considered for use as a food additive
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