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.
Némati
Fariba
F
Laboratory of Pre-clinical Investigations, Institut National de la Santé et de la Recherche Médicale Unité 668, Institut Pasteur, Paris, France.
Mathiot
Claire
C
Grandjean
Isabelle
I
Lantz
Olivier
O
Bordier
Vincent
V
Dewulf
Sébastien
S
Ekue
Richard
R
Di Santo
James P
JP
Poupon
Marie-France
MF
Decaudin
Didier
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001549:Benzamides; D004347:Drug Interactions; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000821:virology; D005260:Female; D004854:Herpesvirus 4, Human / Q000472:pathogenicity*; D006801:Humans; D000068877:Imatinib Mesylate; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use; D000069283:Rituximab; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000069283:Rituximab; D000068877:Imatinib Mesylate