論文 - 詳細
| RRC ID | 39828 |
|---|---|
| 著者 | Harada M, Imai J, Okuno S, Suzuki T. |
| タイトル | Macrophage-mediated activation of camptothecin analogue T-2513-carboxymethyl dextran conjugate (T-0128): possible cellular mechanism for antitumor activity. |
| ジャーナル | J Control Release |
| Abstract |
Camptothecin (CPT) analogue T-2513-carboxymethyl (CM) dextran conjugate (T-0128) suppressed human tumor xenografts that were refractory to CPTs. This improvement was explained by its altered pharmacokinetics, but the cellular mechanism of action is still not clear. For this reason, in the present study we examined the determinants of T-0128 action at the cellular level. In vitro tests showed that T-0128 was inactive, indicating that the requirement for its activity lies in the release of linked T-2513, accompanied by the cellular uptake of the conjugate. The accumulation varied between cell lines: tumor cells, including Walker-256 carcinoma and B16 melanoma, showed only a marginal uptake and an undetectable drug release in the medium. In contrast, macrophage-like cells, such as J774.1, internalized T-0128 very efficiently, and liberated T-2513. With regard to the mode of accumulation, fluid-phase pinocytosis seems to be a key factor based on the followings: a similar cell-specificity existed in the uptake of FITC dextran, a marker of fluid-phase pinocytosis. Also, the macrophage uptake of T-0128 increased almost linearly with its medium concentration and was insensitive to dextran sulfate, a ligand for macrophage scavenger receptor. Comparative efficacy studies of T-0128 in the presence and absence of macrophages demonstrated that macrophages increased the efficacy of T-0128. The enhancement could be explained in terms of increases in the amount of released T-2513. Overall, these results lead us to the conclusion that T-0128 acts like a Trojan horse with the help of macrophages: T-0128 is taken up by macrophages in tumor tissues, and the liberated T-2513 kills tumor cells. |
| 巻・号 | 69(3) |
| ページ | 389-97 |
| 公開日 | 2000-12-3 |
| DOI | 10.1016/s0168-3659(00)00320-5 |
| PII | S0168365900003205 |
| PMID | 11102679 |
| MeSH | Animals Antineoplastic Agents, Phytogenic / pharmacology* Biotransformation Cell Line Dextrans / pharmacokinetics Dextrans / pharmacology* Humans Macrophages / metabolism* Mice Prodrugs / pharmacology* Topotecan / analogs & derivatives* Topotecan / pharmacokinetics Topotecan / pharmacology |
| IF | 7.727 |
| 引用数 | 21 |
| WOS 分野 | CHEMISTRY, MULTIDISCIPLINARY PHARMACOLOGY & PHARMACY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | P-815(RCB1167) L929 HUC-F2(RCB0436) |