Surbone Anna, Fuso Luca, Passera Roberto, Ferrero Annamaria, Marchese Cristiana, Martino Cosimo, Luchin Annalisa, Di Renzo Maria Flavia, Zola Paolo
Unit of Gynecologic Oncology, Department of Gynecology and Obstetrics of the University of Torino at Azienda Ospedaliera Ordine Mauriziano, Largo Turati 62, Turin, Italy.
BMC Res Notes. 2012 Sep 23;5:517. doi: 10.1186/1756-0500-5-517.
Hepatocyte Growth Factor (HGF) enhances cytotoxicity of paclitaxel (PTX) and cisplatin (CDDP) in human ovarian cancer cells. Because of potential pitfalls of HGF exogenous administration, we investigated whether HGF serum concentration might be alternatively raised in vivo by administering low molecular weight heparin (LMWH).
The main HGF pharmacokinetic parameters were evaluated following acute and chronic LMWH treatment. First, women, operated on for gynaecological tumors, were treated with a single dose of calcium nadroparin and studied for 12 hours. Next, women operated on for benign or malignant gynaecological tumors were treated daily with calcic nadroparin for one month. Subsequently, the biological activity of the measured HGF serum levels was tested in assays of ovarian cancer cell sensitization to drugs.
In the short-term treated group, median HGF AUCss, Cmax and Caverage were about four-fold that of the control group, whereas Cmin was three-fold. In the patients treated chronically median HGF serum levels rose about six-fold in the first week, and decreased but remained significantly higher after one month. The pharmacokinetic of nadroparin-dependent HGF increase were similar in the two groups. The HGF concentrations measured after both acute and chronic treatment were found to be effective in sensitising ovarian cancer cells to chemotherapeutics.
This study raises the possibility of using LMWH to increase HGF serum concentration and to take advantage of its biological activities. In particular, nadroparin might be used as a chemo-potentiating agent in epithelial cell ovarian carcinoma through its action on HGF serum concentration.
ClinicalTrials.gov ID: NCT01523652.
肝细胞生长因子（HGF）可增强紫杉醇（PTX）和顺铂（CDDP）对人卵巢癌细胞的细胞毒性。由于外源性给予HGF存在潜在风险，我们研究了给予低分子量肝素（LMWH）是否可在体内使HGF血清浓度升高。
在急性和慢性LMWH治疗后评估主要的HGF药代动力学参数。首先，对接受妇科肿瘤手术的女性给予单剂量那屈肝素钙治疗，并进行12小时的研究。接下来，对接受良性或恶性妇科肿瘤手术的女性每天给予那屈肝素钙治疗1个月。随后，在卵巢癌细胞对药物的敏感性测定中测试所测HGF血清水平的生物活性。
在短期治疗组中，HGF的中位AUCss、Cmax和Caverage约为对照组的4倍，而Cmin为3倍。在长期治疗的患者中，HGF血清中位水平在第一周升高约6倍，1个月后下降但仍显著高于对照组。两组中那屈肝素依赖性HGF升高的药代动力学相似。急性和慢性治疗后测得的HGF浓度均被发现可有效使卵巢癌细胞对化疗药物敏感。
本研究提出了使用LMWH提高HGF血清浓度并利用其生物活性的可能性。特别是，那屈肝素可能通过其对HGF血清浓度的作用，用作上皮性卵巢癌的化疗增效剂。
ClinicalTrials.gov标识符：NCT01523652。
