Okugawa Kaoru, Kobayashi Hiroaki, Hirakawa Toshio, Sonoda Takanori, Ogura Tomonori, Nakano Hitoo
Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, 812-8582, Fukuoka, Japan.
J Cancer Res Clin Oncol. 2004 Mar;130(3):178-86. doi: 10.1007/s00432-003-0516-9. Epub 2003 Dec 4.
In order to establish a more faithful model of clinically recurrent ovarian cancer after paclitaxel-based chemotherapy, a paclitaxel-resistant human ovarian cancer cell line was established in vivo, and its biological profiles were compared with the conventional in vitro established drug-resistant cell line.
An in vivo paclitaxel-resistant subline (OM1/Tvivo) was established from the parental human ovarian cancer cell line (OVMG1) by repeated paclitaxel administration into tumor-bearing mice. As a control, the in vivo drug-sensitive subline (OM1/Cvivo) was made in the same manner, without paclitaxel. An in vitro paclitaxel-resistant subline (OM1/Tvitro) was established by exposure to stepwise increased concentrations of the drug in a cell culture medium. Chromosomal analysis, evaluation of growth, invasiveness and metastasis, in vivo and in vitro drug sensitivity, and a pharmacokinetic study were performed.
Both in vivo sublines confirmed their human origin by G-band chromosomal analysis and showed a similar cell growth rate in cell culture. As for in vivo tumor growth, OM1/Tvivo showed enhanced tumor growth property compared with OM1/Cvivo, while OM1/Tvitro lost tumorigenicity. Both OM1/Tvivo and OM1/Cvivo sublines as well as their parental OVMG1 could not form either invasive or metastatic lesions. Compared with the OM1/Cvivo subline, the OM1/Tvivo tumor showed stable drug-resistance and lower drug distribution after paclitaxel administration into mice, whereas cultured OM1/Tvivo cells lost both completely. On the other hand, an unreasonably higher level of drug-resistance and lower drug concentration was detected in vitro only in OM1/Tvitro cells after exposure to the drug in a culture medium.
These results suggest that the in vivo established paclitaxel-resistant cell line, rather than the conventional in vitro established cell line, is a suitable and faithful model for clinically recurrent tumors showing transformed aggressiveness. The in vivo specific drug-resistant mechanism should involve an interaction between the tumor and host stromal tissue rather than only changes in cellular drug sensitivity. The present study is probably the first report of an in vivo established paclitaxel-resistant human ovarian cancer cell line, and the elucidation of such an in vivo drug-resistance mechanism may be clinically important in preventing or overcoming acquired drug-resistant ovarian cancers recurring after paclitaxel-based chemotherapy.
为建立一种更符合临床紫杉醇化疗后复发性卵巢癌的模型，在体内建立了一种紫杉醇耐药的人卵巢癌细胞系，并将其生物学特性与传统体外建立的耐药细胞系进行比较。
通过向荷瘤小鼠反复给予紫杉醇，从亲代人卵巢癌细胞系（OVMG1）建立体内紫杉醇耐药亚系（OM1/Tvivo）。作为对照，以同样方式建立体内药物敏感亚系（OM1/Cvivo），但不给予紫杉醇。通过在细胞培养基中逐步增加药物浓度建立体外紫杉醇耐药亚系（OM1/Tvitro）。进行了染色体分析、生长、侵袭和转移评估、体内和体外药物敏感性以及药代动力学研究。
两个体内亚系通过G带染色体分析证实了其人类起源，并且在细胞培养中显示出相似的细胞生长速率。关于体内肿瘤生长，与OM1/Cvivo相比，OM1/Tvivo显示出增强的肿瘤生长特性，而OM1/Tvitro失去了致瘤性。OM1/Tvivo和OM1/Cvivo亚系及其亲代OVMG1均不能形成侵袭性或转移性病变。与OM1/Cvivo亚系相比，向小鼠给予紫杉醇后，OM1/Tvivo肿瘤显示出稳定的耐药性和较低的药物分布，而培养的OM1/Tvivo细胞则完全丧失了这两者。另一方面，仅在体外将OM1/Tvitro细胞暴露于培养基中的药物后，检测到不合理的高水平耐药性和较低的药物浓度。
这些结果表明，体内建立的紫杉醇耐药细胞系，而非传统体外建立的细胞系，是显示转化侵袭性的临床复发性肿瘤的合适且可靠模型。体内特定的耐药机制应涉及肿瘤与宿主基质组织之间的相互作用，而非仅仅是细胞药物敏感性的变化。本研究可能是首次报道体内建立的紫杉醇耐药人卵巢癌细胞系，阐明这种体内耐药机制在预防或克服基于紫杉醇化疗后复发的获得性耐药卵巢癌方面可能具有临床重要性。
