Ellagic acid administered by a novel, sustained drug-delivery system inhibits estrogen-induced mammary carcinogenicity

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Cancer chemoprevention approaches have been used to manipulate tumorigenesis and prevent the transformation of normal/pre-cancerous cells to malignancy. Many compounds that have worked in cell culture studies have failed in animal models and clinical trials due to lack of bioavailability. Besides, the high doses required to elicit biological response can be toxic. We hypothesize that the effective dose of chemopreventive agents administered systemically can be reduced substantially compared with the traditional dietary route. Ellagic acid, a significant component in certain berries, has been tested for chemopreventive responses in various animal models with mixed results. Here we report effectiveness of ellagic acid as a model compound administered by a novel, “Sustained Drug-Delivery” (SDD) system against estrogen-induced ACI rat mammary carcinogenicity. Ellagic acid was administered either in the diet (400 ppm) or by subcutaneous silastic implants (27 mg/implant, 4 implants). Two weeks later, animals were treated with 17ß-estradiol (9 mg) by silastic implant. All groups received diet and water ad libitum. The body weight and diet consumption were recorded weekly. The animals were palpated for mammary tumors, and were euthanized when the largest tumor reached >1 cm. The 1^st tumor in the control group appeared after nearly 84 days. However, the first tumor appearance with ellagic acid implants or ellagic acid-supplemented diet was somewhat delayed by 2 and 3 weeks, respectively. The control group reached 100% tumor incidence after 26 wks, but only 75% or 69% of the animals developed palpable tumors in groups receiving ellagic acid by implants or diet, respectively. Ellagic acid also reduced the tumor burden with both the implant (855 ± 242 mm³) and dietary (599 ± 169 mm³) routes compared with control group (1,522 ± 299 mm³). Similar reductions were also observed in the tumor multiplicity (4.8 ± 0.5 and 4.5 ± 0.4 tumors/rat with implant and diet, respectively versus 8.9 ± 1.2 in the control group). The total amount of ellagic acid administered during the entire duration of the study by diet was 800 mg/rat while the implant route delivered only 1.48 ± 0.87 mg per implant, as determined by HPLC measurement of the material left in implants recovered after termination. Thus, with 4 implants per animal, ~135-fold reduction of the ellagic acid dose produced similar biological responses when delivered by the SDD system. This novel approach thus opens new avenues to test many agents individually and as mixtures for their chemopreventive potential that have been discontinued, either due to lack of bioavailability or toxicity due to high doses. The approach will also apply to potentially chemopreventive, plant-derived minor components that otherwise cannot be investigated in animals due to unavailability of sufficient materials (Supported by the USPHS CA-118114).