Melisi Davide, Caputo Rosa, Damiano Vincenzo, Bianco Roberto, Veneziani Bianca Maria, Bianco A Raffaele, De Placido Sabino, Ciardiello Fortunato, Tortora Giampaolo
Cattedra di Oncologia Medica, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Università di Napoli Federico II, Naples, Italy.
Endocr Relat Cancer. 2005 Dec;12(4):1051-8. doi: 10.1677/erc.1.01061.
Biphosphonates (BPs) are widely used to inhibit osteoclastic activity in malignant diseases such as bone metastatic breast and prostate carcinoma. Recent studies reported that BPs could also cause a direct antitumor effect, probably due to their ability to interfere with several intracellular signalling molecules. The enzyme cyclooxygenase-2 (COX-2) and the epidermal growth factor receptor (EGFR) play an important role in the control of cancer cell growth and inhibitors of COX-2 and EGFR have shown antitumor activity in vitro and in vivo in several tumor types. We, and others, have previously shown that EGFR and COX-2 may be directly related to each other and that their selective inhibitors may have a cooperative effect. In the present study we have evaluated the combined effect of zoledronic acid, the most potent nitrogen-containing BP, with the COX-2 inhibitor SC-236 and the selective EGFR-tyrosine kinase inhibitor gefitinib, on breast and prostate cancer models in vitro and in xenografted nude mice. We show that combination of zoledronic acid with SC-236 and gefitinib causes a cooperative antitumor effect accompanied by induction of apoptosis and regulation of the expression of mitogenic factors, proangiogenic factors and cell cycle controllers both in vitro and in xenografted nude mice. The modulatory effect on protein expression and the inhibitory effect on tumor growth is much more potent when the three agents are used together. Since studies are ongoing to explore the antitumor effect of zoledronic acid, our results provide new insights into the mechanism of action of these agents and a novel rationale to translate this feasible combination treatment strategy into a clinical setting.
双膦酸盐（BPs）被广泛用于抑制恶性疾病（如骨转移性乳腺癌和前列腺癌）中的破骨细胞活性。最近的研究报道，双膦酸盐还可能产生直接的抗肿瘤作用，这可能是由于它们干扰多种细胞内信号分子的能力。环氧合酶-2（COX-2）和表皮生长因子受体（EGFR）在癌细胞生长控制中起重要作用，COX-2和EGFR的抑制剂已在几种肿瘤类型的体外和体内显示出抗肿瘤活性。我们和其他人之前已经表明，EGFR和COX-2可能直接相互关联，并且它们的选择性抑制剂可能具有协同作用。在本研究中，我们评估了最有效的含氮双膦酸盐唑来膦酸与COX-2抑制剂SC-236和选择性EGFR酪氨酸激酶抑制剂吉非替尼联合应用于体外乳腺癌和前列腺癌模型以及异种移植裸鼠的效果。我们发现，唑来膦酸与SC-236和吉非替尼联合使用会产生协同抗肿瘤作用，同时在体外和异种移植裸鼠中诱导细胞凋亡，并调节促有丝分裂因子、促血管生成因子和细胞周期调控因子的表达。当三种药物一起使用时，对蛋白质表达的调节作用和对肿瘤生长的抑制作用要强得多。由于正在进行探索唑来膦酸抗肿瘤作用的研究，我们的结果为这些药物的作用机制提供了新的见解，并为将这种可行的联合治疗策略转化为临床应用提供了新的理论依据。
