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.

Differing Mechanisms of Death Induction by Fluorinated Taxane SB-T-12854 in Breast Cancer Cells

“…SB-T-12854 induced cells death in breast cancer cell lines examined (Figure 2). The taxane has also been shown to be effective in cell death induction in other cancer cell lines (7,42). The effect of SB-T-12854 on the growth and survival of breast cancer cells was similar to the effect of previously studied novel non-fluorinated taxane SB-T-1216 (31,32).…”

Metabolism of TM‐2, a potential antitumor drug, in rats by using LC–MS

“…paclitaxel and docetaxel, limit the effectiveness of these agents in clinical use. Great efforts have been made to develop novel agents with improved cytotoxicity in resistant tumors but reduced toxicity to healthy cells .…”

Drug discovery targeting cell division proteins, microtubules and FtsZ

“…47 It was found that the cell death-inducing effect of these new-generation taxoids is significantly higher than paclitaxel, especially against NCI/ADR cells. Although the effective concentration of new-generation taxoids is much lower than that of paclitaxel, the mechanism leading to apoptosis is essentially the same.…”

“…Caspase-2 may act as the most apical caspase that is responsible for the activation of all other caspases including caspase-9. 47 …”