Preclinical assessment of cisplatin-based therapy versus docetaxel-based therapy on a panel of human non-small-cell lung cancer xenografts.

The success of treatment of advanced non-small-cell lung cancer (NSCLC) remains very poor. The aim of this study was, on a series of NSCLC xenografts, to compare the efficacy of standard cisplatin-based or docetaxel-based chemotherapy. Seven human xenografts were obtained from six patients (two xenografts were derived from primary or metastatic tumors of the same patient). Three xenografts were adenocarcinomas and four were squamous cell carcinomas. All xenografts reproduced the same histology as that of the patient's original tumor. Docetaxel, administered as single-agent chemotherapy, induced a significant response in five of the seven NSCLC xenografts (71%), without significant increase after combination with cisplatin, vinorelbine, or gemcitabine. Relative expression of genes putatively involved in drug response was also studied in all xenografts and did not explain the variability of drug sensitivity. In conclusion, this panel of human NSCLC xenografts reliably reproduces the data obtained in patient tumors and the relative sensitivity to docetaxel reported in NSCLC patients.

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.

High efficacy of combined rituximab and gemcitabine on Epstein-Barr virus-associated human B-cell lymphoma obtained after Hodgkin's xenograft in immunodeficient mice.

The objectives were to characterize an Epstein-Barr virus-associated human B-cell lymphoma obtained from Hodgkin's xenograft, and to evaluate the in-vivo combination of rituximab and/or gemcitabine. A lymph node biopsy sample from a patient with Hodgkin's disease was xenografted into Rag gamma(c)(-/-) mice. Immunohistochemical, cytogenetic and genetic analyses were performed on both the human biopsy and xenografted tumor from severe combined immunodeficient mice. Tumor-bearing mice were then treated with rituximab and/or gemcitabine. Histologic features of the patient's biopsy concluded on classical CD15/CD30-positive Hodgkin's disease without expression of Epstein-Barr virus proteins. In contrast, morphologic and immunophenotypic examination of the xenograft showed diffuse proliferation of large B cells with high Epstein-Barr virus protein expression. Comparative genomic hybridization showed a normal pattern in the first case and a gain of chromosomal 12 in the xenografted tumor. Finally, polymerase chain reaction detected an immunoglobulin heavy chain rearrangement in the xenografted tumor. Altogether, these results indicate that the xenograft grew from the patient's Epstein-Barr virus-infected B-lymphoid cells and could be assimilated to posttransplant lymphoproliferative disease. In-vivo treatments of xenografted tumors showed significant tumor growth inhibition induced either by rituximab or gemcitabine alone and an impressive efficacy of combined treatment. This result therefore indicates that combined rituximab and gemcitabine could be an alternative approach in patients with posttransplant lymphoproliferative disease.