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.


CONCLUSIONS
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.
Rezaï
Keyvan
K
Department of Clinical Hematology, Institut Curie, Paris, France. k.rezai@stcloud-huguenin.org
Lokiec
François
F
Grandjean
Isabelle
I
Weill
Sophie
S
de Cremoux
Patricia
P
Bordier
Vincent
V
Ekue
Richard
R
Garcia
Mickael
M
Poupon
Marie-France
MF
Decaudin
Didier
D
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001549:Benzamides; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004357:Drug Synergism; D005047:Etoposide / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000068877:Imatinib Mesylate; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D005047:Etoposide; D000068877:Imatinib Mesylate; D007069:Ifosfamide