Second-generation taxanes effectively suppress subcutaneous rat lymphoma: role of disposition, transport, metabolism, in vitro potency and expression of angiogenesis genes
| Autor: | Vlasta Němcová, Pavel Soucek, Ivan Gut, Jiří Hrdý, Otová B, Radka Vaclavikova, Stanislav Horský, Jana Vobořilová, Ilaria Zanardi, Iwao Ojima, Marie Ehrlichová, Jan Kovář |
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| Rok vydání: | 2011 |
| Předmět: |
Male
ATP Binding Cassette Transporter Subfamily B Lymphoma Angiogenesis Antineoplastic Agents Pharmacology Fibroblast growth factor Rats Sprague-Dawley chemistry.chemical_compound In vivo Animals Cytochrome P-450 CYP3A Pharmacology (medical) Receptor Neovascularization Pathologic biology Membrane Proteins In vitro Rats Tumor Burden Gene Expression Regulation Neoplastic Oncology Paclitaxel chemistry Fibroblast growth factor receptor Area Under Curve biology.protein Female Taxoids Platelet-derived growth factor receptor |
| Zdroj: | Investigational New Drugs. 30:991-1002 |
| ISSN: | 1573-0646 0167-6997 |
| Popis: | The study investigated possible mechanisms by which second-generation taxanes, established as significantly more effective than paclitaxel in vitro, suppress a rat lymphoma model in vivo. The studied mechanisms included taxane pharmacokinetics, expression of genes dominating their metabolism (Cyp3a1/2) and transport (Abcb1) and genes controlling tumour angiogenesis (growth factors and receptors). SB-T-1214, SB-T-12854 and IDN5109 suppressed rat lymphoma more effectively than paclitaxel, SB-T-12851, SB-T-12852, SB-T-12853 or IDN5390 as well as P388D1 leukaemia cells in vitro. The greater anti-lymphoma effects of SB-T-1214 in rats corresponded to a higher bioavailability than with SB-T-12854, and lower systemic toxicity of SB-T-1214 for rats reflected its lower cytotoxicity for P388D1 cells in vitro. Suppression of Abcb1 and CYP3a1 expression by SB-T-1214 and IDN5109 could partly explain their anti-lymphoma effects, but not that of SB-T-12854. Growth factors genes Egf, Fgf, Pdgf, and Vegf associated with tumour angiogenesis had significantly lower expression following treatment with anti-lymphoma effective IDN5109 and their receptors were unaffected, whereas inefficient IDN5390 increased expression of the most important Vegf. The effective SB-T-12854 inhibited Egf, Egfr, Fgfr and Pdgfr expression, while the ineffective SB-T-12851, SB-T-12852 and SB-T-12853 inhibited only Egf or Egfr expression. Vegfr expression was inhibited significantly by SB-T-12851 and SB-T-12854, but effect of SB-T-12851 was compromised by induced Vegf expression. The very effective SB-T-1214 decreased the expression of Vegf, Egf and all receptors most prominently indicating the possible supporting role of these genes in anti-lymphoma effects. In conclusion, SB-T-1214, SB-T-12854 and IDN5109 are good candidates for further study. |
| Databáze: | OpenAIRE |
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