Markaverich B M, Gregory R R, Alejandro M, Kittrell F S, Medina D, Clark J H, Varma M, Varma R S
Center for Biotechnology, Baylor College of Medicine, The Woodlands, Texas 77381.
Cancer Res. 1990 Mar 1;50(5):1470-8.
Previous studies in our laboratory demonstrated that methyl p-hydroxyphenyllactate (MeHPLA) is an important cell growth-regulating agent which binds to nuclear type II binding sites in normal and malignant cells. Furthermore, this compound is deficient in a variety of rat and mouse mammary tumors and human breast cancer preparations, and this deficiency correlates with the loss of regulatory control. The present studies were performed to examine the metabolic fate of [3H]MeHPLA in mouse mammary tumors. Stable analogs of this compound such as 4,4'-dihydroxy benzylidene acetophenone were also assessed for nuclear type II site binding affinity and their ability to inhibit mammary cancer cell growth and proliferation in vitro and in vivo. The results demonstrate that mouse mammary tumors contain esterase activity which hydrolyzes MeHPLA to p-hydroxyphenyllactic acid, and this was the only major metabolite detected in these tumor preparations in vitro or in vivo. 4,4'-Dihydroxy benzylidene acetophenone, an esterase-stable MeHPLA analog, was found to bind with high affinity to nuclear type II sites but not the estrogen receptor, was capable of occupying type II sites in cultured MCF-7 cells, and inhibited the proliferation of these cells in concentrations which directly correlated with type II binding site occupancy. Similarly, 4,4'-dihydroxy benzylidene acetophenone administration by silastic implant or injection resulted in a dose-dependent inhibition of the growth of transplantable mammary tumors in mice, suggesting that this stable analog mimicks MeHPLA as a cell growth-regulating agent. Taken together, these results suggest esterase hydrolysis of MeHPLA in mammary tumors may result in a deficiency in this compound which correlates with a loss of regulatory control.
我们实验室之前的研究表明，对羟基苯乳酸甲酯（MeHPLA）是一种重要的细胞生长调节剂，它能与正常细胞和恶性细胞中的II型核结合位点结合。此外，这种化合物在多种大鼠和小鼠乳腺肿瘤以及人类乳腺癌制剂中含量不足，这种不足与调控失控相关。本研究旨在检测[3H]MeHPLA在小鼠乳腺肿瘤中的代谢命运。还评估了该化合物的稳定类似物，如4,4'-二羟基苯亚甲基苯乙酮，对II型核位点的结合亲和力及其在体外和体内抑制乳腺癌细胞生长和增殖的能力。结果表明，小鼠乳腺肿瘤含有酯酶活性，可将MeHPLA水解为对羟基苯乳酸，这是在这些肿瘤制剂的体外或体内检测到的唯一主要代谢产物。4,4'-二羟基苯亚甲基苯乙酮是一种酯酶稳定的MeHPLA类似物，被发现与II型核位点具有高亲和力，但与雌激素受体无亲和力，能够占据培养的MCF-7细胞中的II型位点，并以与II型结合位点占有率直接相关的浓度抑制这些细胞的增殖。同样，通过硅橡胶植入或注射给予4,4'-二羟基苯亚甲基苯乙酮会导致小鼠可移植乳腺肿瘤生长受到剂量依赖性抑制，这表明这种稳定类似物作为一种细胞生长调节剂可模拟MeHPLA。综上所述，这些结果表明乳腺肿瘤中MeHPLA的酯酶水解可能导致该化合物缺乏，这与调控失控相关。
