Abstract
Colorectal cancer is the second most common cancer in the western world with 1 million new cases worldwide each year. Flexible Heteroarotinoids (Flex‐Hets) are a promising new class of anticancer compounds that regulate cell cycle progression, differentiation and apoptosis, as well as xenograft tumor growth and angiogenesis in many cancer types. The lead Flex‐Het, Sulfur heteroarotinoid A2 (SHetA2), prevents DMBA‐induced transformation in endometrial organotypic cultures in vitro and is currently in preclinical testing in the NCI RAPID program. In this study, the potential in vivo chemopreventive effects of SHetA2 were evaluated in APCmin/+ mice. Six‐week old APCmin/+ mice were assigned to three different treatment groups with normalized distributions of males and females. Drug was dissolved in corn oil (0 ‐ placebo, 30 mg/kg SHetA2, 60 mg/kg SHetA2) and administered by gavage five days per week for 12 weeks. There was no statistically significant difference in body weight between any of the treatment groups and controls. All mice were killed and the total number and size of tumors along the entire length of the intestine and colon were visually counted using a magnified lens. SHetA2‐treated groups exhibited dramatic reductions in the total number of intestinal tumors at both doses (SHetA2 30 mg/kg ‐ 60%, SHetA2 60 mg/kg ‐ 54%, P<0.0001). On average, mice developed about 50 tumors per animal in the small intestine of the control, whereas there were only 20 tumors (SHetA2 30 mg/kg) and 23 tumors (SHetA2 60 mg/kg) in the treatment groups. Neither of the SHetA2 doses administered caused intestinal ulceration or acute toxicity. Both doses reduced the numbers of large (>2 mm), medium (1–2 mm) and small (<1 mm) adenomas. When data were analyzed for colon alone, the mean number of tumors per mouse was 2 in the control group, 0.3 with 30 mg/kg SHetA2, and 0.75 with 60 mg/kg SHetA2. Colon tumor incidences were 70%, 30% and 40% for control, 30 mg/kg SHetA2 and 60 mg/kg SHetA2, respectively. Although SHetA2 at both 30 mg/kg and 60 mg/kg appeared to cause a parallel trend in inhibiting tumor growth, 60 mg/kg concentration did not show greater inhibition than 30 mg/kg. Results from this study, for the first time, indicate that the Flex‐Het, SHetA2, significantly decreases small intestinal and colon tumor formation. Currently, work is in progress to study the molecular and cellular activities involved in SHetA2 chemoprevention activity. (Supported by Kerley‐cade chair endowment, R01‐102947 and R01‐CA‐106713)
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A140.
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