Markaverich B, Schauweker T, Gregory R, Varma R, Varma M, Kittrell F, Medina D
BAYLOR COLL MED,TEXAS MED CTR,DEPT CELL BIOL,HOUSTON,TX 77030.
Int J Oncol. 1993 Mar;2(3):385-92. doi: 10.3892/ijo.2.3.385.
Methyl p-hydroxyphenyllactate (MeHPLA) is an endogenous ligand for nuclear type II sites which apparently regulates cellular growth and proliferation through this binding interaction. Occupancy of type II sites by MeHPLA agonists such as dihydroxybenzylidene acetophenone (DHBA), 2,6-bis ([3,4-dihydroxyphenyl]-methylene) cyclohexanone (BDHPC) and 2,6-bis ([3-methoxy-4-hydroxyphenyl]-methylene)cyclohexanone (BMHPC) is directly correlated with the inhibition of malignant cell proliferation. Most importantly, these compounds inhibit mammary tumor growth in vivo with minimal non-specific cytotoxicity. Therefore, combination therapy with MeHPLA agonists plus standard anti-neoplastic agents such as 5-Fluorouracil (FU) may result in tumor growth inhibition with minimal non-specific cytotoxicity. The results of these studies demonstrated that low doses of BMHPC (2 mug/mL) and FU (0.2 mug/mL) failed to significantly affect MCF-7 human breast cancer cell proliferation. However, combination therapy with these sub-inhibitory doses of BMHPC plus FU resulted in significant inhibition of cell proliferation in vitro, suggesting that BMHPC acts in an additive or synergistic fashion with FU to inhibit MCF-7 cell proliferation. Similarly, when orally administered to mice at a dose level of 50 mug/mL drinking water, neither BMHPC or FU alone substantially inhibited the growth of estrogen-independent transplantable mammary tumors. However, combination therapy with BMHPC plus FU antagonized tumor growth and no significant treatment effects were observed on fluid consumption or the body weights of these animals. These results demonstrate that MeHPLA agonists such as BMHPC are capable of acting additively or synergistically with FU to maintain therapeutic response with reduced non-specific systemic toxicity.
对羟基苯乳酸甲酯（MeHPLA）是核II型位点的内源性配体，它显然通过这种结合相互作用调节细胞生长和增殖。MeHPLA激动剂如二羟基苯亚甲基苯乙酮（DHBA）、2,6-双（[3,4-二羟基苯基] -亚甲基）环己酮（BDHPC）和2,6-双（[3-甲氧基-4-羟基苯基] -亚甲基）环己酮（BMHPC）占据II型位点与恶性细胞增殖的抑制直接相关。最重要的是，这些化合物在体内抑制乳腺肿瘤生长，且非特异性细胞毒性最小。因此，MeHPLA激动剂与标准抗肿瘤药物如5-氟尿嘧啶（FU）联合治疗可能以最小的非特异性细胞毒性抑制肿瘤生长。这些研究结果表明，低剂量的BMHPC（2微克/毫升）和FU（0.2微克/毫升）未能显著影响MCF-7人乳腺癌细胞增殖。然而，这些亚抑制剂量的BMHPC与FU联合治疗在体外导致细胞增殖的显著抑制，表明BMHPC与FU以相加或协同方式作用以抑制MCF-7细胞增殖。同样，当以50微克/毫升饮用水的剂量水平口服给予小鼠时，单独的BMHPC或FU均未显著抑制雌激素非依赖性可移植乳腺肿瘤的生长。然而，BMHPC与FU联合治疗拮抗肿瘤生长，并且未观察到对这些动物的液体消耗或体重有显著的治疗效果。这些结果表明，诸如BMHPC的MeHPLA激动剂能够与FU以相加或协同方式作用，以维持治疗反应并降低非特异性全身毒性。
