Bennett James A, DeFreest Lori, Anaka Ikenna, Saadati Hamid, Balulad Sujata, Jacobson Herbert I, Andersen Thomas T
Center for Immunology and Microbial Diseases, Albany Medical College, Albany, NY 12208, USA.
Breast Cancer Res Treat. 2006 Jul;98(2):133-41. doi: 10.1007/s10549-005-9140-5. Epub 2006 Mar 15.
We have synthesized a cyclic nonapeptide (AFPep) that is effective, after being administered by parenteral routes, for the treatment or the prevention of breast cancer. To test the hypothesis that AFPep remains safe and efficacious after oral administration, three different whole-animal bioassays were utilized, and the mechanism by which AFPep functions was investigated.
Using a human breast cancer xenograft model in mice for therapeutic activity, a carcinogen-induced breast cancer model in rats for prevention efficacy, and a mouse uterus growth inhibition model of anti-estrogenic activity, AFPep was administered by oral gavage (p.o.) and its effects compared to those following intraperitoneal (i.p.) and subcutaneous (s.c.) administration. Toxicity studies evaluated body weights and organ weights in mice and rats receiving AFPep. Preliminary mechanistic studies were carried out in T47D human breast cancer cells growing in culture and evaluated the effect of AFPep on estrogen-stimulated cell growth, phosphorylation of the estrogen receptor (ER), and on level of ER-related kinases.
Orally administered AFPep stopped the growth of human tumor xenografts in mice, decreased the incidence and multiplicity of breast cancers in carcinogen-exposed rats, and inhibited the estrogen-stimulated growth of mouse uteri. In each of these systems, orally administered AFPep produced an effect similar to that obtained for AFPep administered by either i.p or s.c. routes. In rodents, no evidence of toxicity was seen for the peptide, even at very high doses. In culture, AFPep inhibited the estrogen-stimulated growth, but not the basal growth, of T47D cells, and it inhibited the estrogen-stimulated phosphorylation of Serine 118 in the ER of these cells, which was not explainable by early changes in ER-related kinases.
Chronic oral administration of AFPep appears to be safe and effective for the treatment or prevention of breast cancer in animal models.
我们合成了一种环九肽（AFPep），经肠胃外途径给药后，它对乳腺癌的治疗或预防有效。为了验证AFPep口服后仍安全有效的假设，我们采用了三种不同的整体动物生物测定法，并研究了AFPep发挥作用的机制。
利用小鼠人乳腺癌异种移植模型评估治疗活性，利用大鼠致癌物诱导的乳腺癌模型评估预防效果，利用小鼠子宫生长抑制模型评估抗雌激素活性，通过灌胃（口服）给予AFPep，并将其效果与腹腔注射（i.p.）和皮下注射（s.c.）后的效果进行比较。毒性研究评估了接受AFPep的小鼠和大鼠的体重及器官重量。在培养的T47D人乳腺癌细胞中进行了初步的机制研究，评估了AFPep对雌激素刺激的细胞生长、雌激素受体（ER）磷酸化以及ER相关激酶水平的影响。
口服AFPep可抑制小鼠人肿瘤异种移植的生长，降低致癌物暴露大鼠乳腺癌的发病率和多发性，并抑制雌激素刺激的小鼠子宫生长。在上述每个系统中，口服AFPep产生的效果与腹腔注射或皮下注射AFPep所获得的效果相似。在啮齿动物中，即使给予非常高的剂量，也未发现该肽有任何毒性迹象。在培养中，AFPep抑制了T47D细胞雌激素刺激的生长，但不抑制其基础生长，并且抑制了这些细胞中ER丝氨酸118位点的雌激素刺激的磷酸化，这无法用ER相关激酶的早期变化来解释。
在动物模型中，长期口服AFPep似乎对乳腺癌的治疗或预防是安全有效的。
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