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STI571 Enhances the Therapeutic Index of Epothilone B by a Tumor-selective Increase of Drug Uptake

Ludwig Institute for Cancer Research, SE-751 24 Uppsala, Sweden [K. P., C-H. H., A. Ö.]; Novartis Pharma AG, Basel, Switzerland [M. S., E. B., P. M., M. W.]; Novartis Pharma S.A.S., Rueil-Malmaison, France [M. H.]; and Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden [K. R.]

Purpose: The purpose is to investigate whether STI571, through platelet-derived growth factor receptor inhibition, enhances the therapeutic response to the chemotherapeutic drug epothilone B (EPO906) and, if so, to analyze the mechanism(s) underlying the effect.

Experimental Design: SCID mice with s.c. human anaplastic thyroid carcinomas were treated with different doses of EPO906 alone or in combination with STI571 and with different timing of STI571 and EPO906 administration. Tumor growth, tumor interstitial fluid pressure (IFP), and uptake of EPO906 in tumors and normal organs were monitored.

Results: STI571 potentiated the therapeutic effect of EPO906. Tumors subjected to combination treatment were >40% smaller than those subjected to monotreatment with EPO906. The improved efficacy was matched by reduced tumor IFP and a 3-fold increase in the tumor levels of EPO906. No significant increase of EPO906 levels was seen in liver, kidney, or the intestinal tract. Cotreatment did not reduce the tolerability of EPO906, as determined by measuring body weight throughout treatment. STI571-induced reduction in tumor IFP and increase in tumor uptake required a minimum of three daily doses of STI571 and was not observed 3 days after last treatment with STI571. The enhancement of EPO906 therapeutic efficacy was only observed when STI571 was scheduled in a manner associated with reduced tumor IFP and increased tumor uptake of EPO906.

Conclusions: We conclude that STI571 increases the therapeutic index of EPO906 by selectively increasing the EPO906 uptake in tumors. The correlations between STI571 effects on tumor IFP and tumor drug uptake of EPO906 suggest a causal relationship between these phenomena. The study thus validates STI571 for combination treatment to enhance the therapeutic index of EPO906 in particular and, possibly, of chemotherapeutics in general.

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