Banzato Alessandra, Bobisse Sara, Rondina Maria, Renier Davide, Bettella Fabio, Esposito Giovanni, Quintieri Luigi, Meléndez-Alafort Laura, Mazzi Ulderico, Zanovello Paola, Rosato Antonio
Department of Oncology and Surgical Sciences, University of Padova, Via Gattamelata 64, I-35128 Padua, Italy.
Clin Cancer Res. 2008 Jun 1;14(11):3598-606. doi: 10.1158/1078-0432.CCR-07-2019.
This study was designed to evaluate the pharmacologic and biological properties of a paclitaxel-hyaluronan bioconjugate (ONCOFID-P) against IGROV-1 and OVCAR-3 human ovarian cancer xenografts following i.p. administration.
In vitro tumor sensitivity to ONCOFID-P was analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, whereas bioconjugate interaction with cells was studied cytofluorimetrically and by confocal microscopy. In vivo toxicity was assessed by a single-dose maximum-tolerated dose, peripheral blood cell count determination and by histologic analysis. Biodistribution of the compound was evaluated with a small animal-dedicated scintigraphy gamma camera following injection of 99mTc-labeled ONCOFID-P. Pharmacokinetic analysis was also carried out. Female severe combined immunodeficiency mice implanted with ovarian cancer cells underwent treatment with ONCOFID-P or free paclitaxel starting from day 7 or 14 after tumor injection, and survivals were compared.
ONCOFID-P interacted with CD44, entered cells through a receptor-mediated mechanism, and exerted a concentration-dependent inhibitory effect against tumor cell growth. After i.p. administration, the bioconjugate distributed quite uniformly within the peritoneal cavity, was well-tolerated, and was not associated with local histologic toxicity. Pharmacokinetic studies revealed that blood levels of bioconjugate-derived paclitaxel were much higher and persisted longer than those obtained with the unconjugated free drug. Intraperitoneal treatment of tumor-bearing mice with the bioconjugate revealed that ONCOFID-P exerted a relevant increase in therapeutic activity compared with free drug.
ONCOFID-P significantly improved results obtained with conventional paclitaxel, in terms of in vivo tolerability and therapeutic efficacy; these data strongly support its development for locoregional treatment of ovarian cancer.
本研究旨在评估腹腔注射紫杉醇-透明质酸生物共轭物（ONCOFID-P）对IGROV-1和OVCAR-3人卵巢癌异种移植瘤的药理和生物学特性。
通过3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐法分析体外肿瘤对ONCOFID-P的敏感性，而通过细胞荧光分析和共聚焦显微镜研究生物共轭物与细胞的相互作用。通过单剂量最大耐受剂量、外周血细胞计数测定和组织学分析评估体内毒性。注射99mTc标记的ONCOFID-P后，用小动物专用闪烁γ相机评估化合物的生物分布。还进行了药代动力学分析。从肿瘤注射后第7天或第14天开始，对植入卵巢癌细胞的雌性严重联合免疫缺陷小鼠用ONCOFID-P或游离紫杉醇进行治疗，并比较生存率。
ONCOFID-P与CD44相互作用，通过受体介导的机制进入细胞，并对肿瘤细胞生长发挥浓度依赖性抑制作用。腹腔注射后，生物共轭物在腹腔内分布相当均匀，耐受性良好，且与局部组织学毒性无关。药代动力学研究表明，生物共轭物衍生的紫杉醇的血药浓度比未共轭的游离药物高得多，且持续时间更长。用生物共轭物对荷瘤小鼠进行腹腔治疗表明，与游离药物相比，ONCOFID-P的治疗活性有显著提高。
在体内耐受性和治疗效果方面，ONCOFID-P显著改善了传统紫杉醇的治疗结果；这些数据有力地支持了其用于卵巢癌局部区域治疗的开发。
