Impact of imatinib on the pharmacokinetics and in vivo efficacy of etoposide and/or ifosfamide.

BACKGROUND: Using a human small cell lung cancer (SCLC) xenografted in nude mice, we have previously reported enhanced tumor growth inhibition following chemotherapy in combination with imatinib (STI571). We therefore investigated the in vivo impact of imatinib on the pharmacokinetics and efficacy of chemotherapy. METHODS: Two different human tumors were used: SCLC6 small cell lung cancer xenografted in nude mice, and LY-3 EBV-associated human B-cell lymphoma xenografted in SCID mice. Plasma, urine, and fecal concentrations of etoposide (VP16) were determined by a validated high performance liquid chromatography method. Plasma concentrations of ifosfamidewere determined by a validated gas chromatography assay with nitrogen-phosphorus detection. RESULTS: Slight tumor growth inhibition was induced by imatinib administered alone in one in vivo EBV-associated B-cell lymphomatous xenograft. In contrast, an increase of the chemotherapy-induced antitumor effect was observed in the lymphoma model but not in a small cell lung cancer model when mice bearing human xenografted tumors were treated concomitantly by imatinib and chemotherapy. This antitumor effect was not influenced by concomitant administration of fluconazole. The AUC0-3 h (Area Under the concentration-time Curve) of etoposide was increased when mice were treated with etoposide + imatinib due to decreased fecal excretion. In contrast, imatinib did not appear to influence the urinary excretion of etoposide, and concomitant administration of the CYP3A4 inhibitor, fluconazole, with imatinib did not modify the pharmacokinetics of etoposide plus imatinib alone. CONCLUSION: Altogether, these results therefore justify further prospective phase I and II clinical trials with combinations of etoposide-based chemotherapy and imatinib in patients with certain cancers, such as malignant lymphoma, with careful toxicologic monitoring.

Imatinib mesylate reduces rituximab-induced tumor-growth inhibition in vivo on Epstein-Barr virus-associated human B-cell lymphoma.

We have reported earlier an increase of tumor-growth inhibition following chemotherapy combined with concomitant administration of imatinib mesylate. Conversely, the combination of imatinib and rituximab has been reported in very few cases of patients and remains controversial. To explore this particular combination of targeted therapies, we therefore investigated the in-vivo impact of rituximab plus imatinib on B-cell lymphoproliferation. Combination of the tyrosine kinase inhibitor imatinib mesylate (STI571) and the anti-CD20 monoclonal antibody rituximab was evaluated on an Epstein-Barr virus-associated B-cell lymphoproliferative disorder xenografted into severe combined immunodeficient or Rag2/gammac-/- (B-, T- and NK-) mice. Using severe combined immunodeficient mice, we found that STI571 diminished the efficacy of rituximab to inhibit tumor growth in vivo. Using alymphoid Rag2/gammac-/- mice, we showed that the effect of STI571 was not dependent on the presence of natural killer cells. In contrast, serum complement administered after STI571 treatment reversed this inhibitory effect. Finally, using nonimmunodeficient mice, we observed an in-vivo decrease of CD4-positive T-cells and mature B-cell lymphocytes after imatinib administration. We found that STI571 decreased the in-vivo efficacy of rituximab via serum protein components that could influence complement-dependent cytotoxicity. In contrast, this effect was not dependent on the presence of natural killer cells.