title: Second-generation taxanes effectively suppress subcutaneous rat lymphoma: role of disposition, transport, metabolism, in vitro potency and expression of angiogenesis genes.
abstract: 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.
authors: Institute of Biology and Medical Genetics, 1st Faculty of Medicine and General Teaching Hospital Charles University, 128 00, Prague, Czech Republic.
authors: Berta
authors: B
authors: Otová
authors: Iwao
authors: I
authors: Ojima
authors: Radka
authors: R
authors: Václavíková
authors: Jiří
authors: J
authors: Hrdý
authors: Marie
authors: M
authors: Ehrlichová
authors: Pavel
authors: P
authors: Souček
authors: Jana
authors: J
authors: Vobořilová
authors: Vlasta
authors: V
authors: Němcová
authors: Ilaria
authors: I
authors: Zanardi
authors: Stanislav
authors: S
authors: Horský
authors: Jan
authors: J
authors: Kovář
authors: Ivan
authors: I
authors: Gut
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D043823:Taxoids / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D008565:Membrane Proteins; D043823:Taxoids; C095122:multidrug resistance protein 3; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A