Abstract B9: Role of disposition, transport, in vitro efficiency and expression of relevant genes in the effects of novel taxanes on subcutaneous lymphoma in Sprague-Dawley/Cub rats
Authors: Gut Ivan , Vaclavikova Radka , Ehrlichova Marie , Ojima Iwao , Otova Berta , Hrdy Jiri , Kovar Jan , Voborilova Jana , Nemcova Vlasta , Zanardi Ilaria 
Published: June 2012

Novel taxoids SB-T-1214, SB-T-12851, SB-T-12852, SB-T-12853, SB-T-12854 and IDN-5109 proved to be more effective than paclitaxel in vitro in MDA-MB-435 cell line, but especially in NCI/ADR-RES cell line, highly expressing ABCB1. Thus, their effects in vivo are of considerable interest, because they could overcome drug-resistance due to high ABCB1 and CYP3A expressions which may limit effects of paclitaxel.

Purposes of the study: To investigate if some of the novel taxanes synthesized at Stony Brook exert significant effects on the genetically well defined lymphoma in Sprague-Dawley/Cub rats, for which paclitaxel is ineffective.

Experimental procedures: The rats were kept in standard laboratory conditions and the drugs were administered i.p. under conditions approved by Ethical Committee, Charles University Prague. The intravital area of subcutaneous lymphoma was measured by palpation and their weight during post-mortem examination. Drug blood levels were determined by HPLC. Quantitative expressions of mRNAs of Abcb1, Cyp3a, Egf, Fgf, Pdgf and Vegf and their receptors Egfr, Fgfr, Pdgfr and Vegfr were made by real-time PCR system using reaction mixtures of Applied Biosystems. Effects were also compared with in vitro efficiency of the drugs in P388D1 lymphoma line.

Summary of new and unpublished data: IDN-5109, SB-T-1214 and SB-T-12854 were the most effective drugs against the subcutaneous lymphoma. The higher effects of SB-T-1214 than SB-T-12854 are ascribed to 3.3-higher blood levels, as well as to the fact that systemic toxicity of SB-T-1214 is significantly lower than that of SB-T-12854. Expression of Abcb1 and Cyp3a1 in lymphomas after treatment with the drugs does not correspond to their anti-lymphoma effects. However, the anti-lymphoma activities of IDN-5109, SB-T-1214 and SB-T-12854 corresponded to their effects on growth factors and their receptors, especially Vegf and Vegfr. The result is consistent with the reported effect of paclitaxel on growth factors and tumor angiogenesis, and these effects could be an important factor for their activities in addition to the proved effects on mitosis and apoptosis. Higher in vitro activities of the novel taxanes than paclitaxel in P388D1 cell line correspond to their higher efficacies on the subcutaneous lymphoma in vivo as compared with paclitaxel.

Conclusions: IDN-5109, already proved effective against various tumors and presently in Phase II clinical studies, as well as novel taxanes SB-T-1214 and SB-T-12854, are found to be effective against non-Hodgkin type rat lymphoma. These taxanes could be efficacious against paclitaxel-resistant tumors, due to the fact that they are not subjected to drug-resistance caused by high ABCB1 expression and are potentially effective against tumor angiogenesis.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B9.