In vivo establishment and characterization of a paclitaxel-resistant human ovarian cancer cell line showing enhanced growth properties and drug-resistance only in vivo

Abstract

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.