CAROTENOID/RETINOID MODULATION OF CELLULAR REDOX STATUS AND CANCER

N-乙酰半胱氨酸（NAC）和4-羟基苯基视黄酰胺（4- HPR）被发现对 雄性TG.AC小鼠中TPA诱导的乳头状突起的多样性。 发现4 -HPR抑制乳头状突起的发生，并且抑制 仅在乳头状突起形成早期观察到。关注- UP实验表明，4-HPR是抗炎的， 在TPA治疗后的早期。我们正在评估 4-HPR刺激细胞凋亡的可能性 炎症细胞从两个独立的实验来看 当喂食以大豆为基础的半纯化饮食时， 在1.5%和3.0%的饮食刺激的多样性， 这些乳头状瘤这是最有趣的，因为NAC是 通常抑制致癌过程-我们有 发现了这种抗氧化剂的矛盾活性。这 当NAC以酪蛋白为基础喂养时， 节食。因此，看起来NAC和 和大豆分离物的一些组分（不存在于大豆分离物中）。 酪蛋白为基础的饮食），其合作，以引起增加的 多发性乳头状瘤第二个目标是测试 假设饮食抗氧化剂的调节在两个 不同的发病阶段会有相反的 对恶性肿瘤形成的最终产量的影响。我们 假设最小化氧化应激（通过饮食 抗氧化剂）在肿瘤的最早阶段（促进） 发病机制将在功能上中和 炎症成分的肿瘤促进，从而最终 导致恶性肿瘤的发生率降低。在 相反，我们预计，最小化氧化应激（因此， 抑制细胞凋亡），特别是在诱导 病变从癌前病变进展到恶性肿瘤， 导致对受损细胞的选择性优势， 最终导致更多的恶性肿瘤因此，我们评估了 该假设使用Tg.AC x p53单倍不足小鼠 用B（a）P局部处理以诱导皮肤致癌作用。 与对照饮食相比，NAC喂养与 降低肿瘤负荷（多重性），但刺激肿瘤 刺激他们发展成恶性肿瘤最后 从这个皮肤癌实验中的偶然观察， NAC喂养与早期死亡率增加有关， 可能是淋巴瘤我们已经开始了一个体内 调查以证实和扩大这一观察。一个 体外类似研究表明，NAC 补充有丝分裂原处理的脾细胞刺激 增殖并抑制凋亡。因此，我们确定了 三种典型的抗氧化剂 肿瘤进展。

Both N-acetyl cysteine (NAC) and 4-hydroxyphenylretinamide (4- HPR) were found to have significant effects on the multiplicity of TPA-induced papillogenesis in male TG.AC mice. 4 -HPR was found to inhibit papillogenesis and the inhibition was only observed if present early in papillogenesis. Follow- up experiments demonstrate that 4-hpr is anti-inflammatory in the early hours after initial TPA treatment. We are evaluating the possibility that 4-HPR stimulates apoptosis of inflammatory cells. It appears from two separate experiments that when fed on top of a soy- based semi-purified diet, NAC at 1.5% and 3.0% of the diet stimulates the multiplicity of these papillomas. This is most interesting because NAC is usually inhibitory to the carcinogenic process- we have identified a paradoxical activity of this antioxidant. This phenomenon does not occur when NAC is fed in casein-based diets. Thus, it appears there is an interaction between NAC and some component(s) of the soy isolate (not occurring in the casein-based diet) which cooperate to cause the increased papilloma multiplicity. A second objective is to test the hypothesis that the modulation of dietary antioxidants at two distinctly different stages of pathogenesis will have opposite effects on the eventual yield of malignant tumor formation. We postulate that minimizing oxidative stress (by dietary antioxidants) in the earliest stages (promotion) of tumor pathogenesis will serve to functionally neutralize the inflammatory component of tumor promotion, thereby eventually translating to a decreased yield of malignant tumors. In contrast, we anticipate that minimizing oxidative stress (thus inhibiting apoptosis) specifically in the period when induced lesions progress from preneoplasia through malignancy will result in a selective advantage for the damaged cells and eventually yield more malignancies. We therefore evaluated this hypothesis using Tg.AC x p53 haploinsufficient mice treated topically with B(a)P to induce skin carcinogenesis. Compared to control diets, NAC feeding was associated with a lower tumor burden (multiplicity) of tumors but stimulated it stimulated their progression to malignancies. Finally, a serendipitous observation from this skin cancer experiment was that NAC feeding was associated with enhanced early deaths, possibly from lymphomas. We have begun an in vivo investigation to confirm and amplify this observation. An analogous investigation in vitro shows that NAC supplementation to mitogen treated splenocytes stimulates proliferation and inhibits apoptosis. Thus we have identified three contexts where the prototypic antioxidant exacerbated tumor progression.