Abstract
Numerous human tumor types, including ovarian cancer, display a significant expression of the CD44 family of cell surface proteoglycans. To develop tumor-targeted drugs, we have initially evaluated whether the CD44 ligand hyaluronic acid (HA) could serve as a backbone for paclitaxel (TXL) prodrugs. HA-TXL was prepared by modification of previous techniques. The in vitro cytotoxicity of HA-TXL against the CD44(+) human ovarian carcinoma cell lines SKOV-3ip and NMP-1 could be significantly blocked by preincubation with a molar excess of free HA. Female nude mice bearing intraperitoneal implants of NMP-1 cells were treated intraperitoneally with a single sub-maximum tolerated dose dose of HA-TXL or with multiple-dose regimens of paclitaxel (Taxol; Mead Johnson, Princeton, NJ) to determine the effects of these regimens on host survival and intraperitoneal tumor burden, with the latter being assessed by magnetic resonance imaging. NMP-1 xenografts were highly resistant to Taxol regimens, as host survival was only nominally improved compared to controls (T/C ∼ 120), whereas single-dose HA-TXL treatment significantly improved survival in this model (T/C ∼ 140; P = .004). In both NMP-1 and SKOV-3ip models, MR images of abdomens of HA-TXL-treated mice obtained shortly before controls required humane sacrifice revealed markedly reduced tumor burdens compared to control mice. This study is among the first to demonstrate that HA-based prodrugs administered locoregionally have antitumor activity in vivo.
Original language | English (US) |
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Pages (from-to) | 479-486 |
Number of pages | 8 |
Journal | Neoplasia |
Volume | 9 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2007 |
Keywords
- CD44
- Human ovarian carcinoma
- Hyaluronic acid
- Paclitaxel
- Prodrug
ASJC Scopus subject areas
- Cancer Research
MD Anderson CCSG core facilities
- Research Animal Support Facility
- Small Animal Imaging Facility