Avtor/Urednik		Jezeršek-Novaković, Barbara; Kotnik, Vladimir; Južnič-Šetina, Tanja; Vovk, Marjeta; Novaković, Srdjan
Naslov		Testing of mechanisms of action of rituximab and clinical results in high-risk patients with aggressive CD20+ lymphoma
Prevedeni naslov		Ugotavljanje mehanizmov delovanja rituksimaba in klinični rezultati pri vsioko rizičnih bolnikih z agresivnimi CD20+ limfomi
Tip		članek
Vir		Radiol Oncol
Vol. in št.		Letnik 41, št. 1
Leto izdaje		2007
Obseg		str. 23-32
Jezik		eng
Abstrakt		Background. Rituximab has been applied successfully in the treatment of indolent and aggressive CD20 positive B cell lymphomas, yet the exact in vivo mechanisms of its action have not been unambiguously explained. This study was therefore aimed to confirm the presumed major mechanisms of action of rituximab and concomitantly to assess the effectiveness of first-line chemoimmunotherapy in high-risk patients with aggressive CD20 lymphomas. Patients, materials and methods. The activity of rituximab was tested in vitro on Raji and SU-DHL-4 cells using the cell proliferation assay and flow cytometry. In the clinical part of the study, 20 high-risk patients with aggressive CD 20 lymphomas were treated with R-CHOP. Results. Only complement-mediated cytotoxicity was observed under the in vitro applied experimental conditions. Neither the direct apoptotic effect nor the antibody-dependent cell-mediated cytotoxicity was detected probably due to a too low concentration of rituximab and a too low ratio of cytotoxic lymphocytes to tumor cells. The treatment outcome in patients was excellent since complete remissions were achieved in 90% of poor-risk patients at the end of primary treatment and 80% of patients were disease free at 18.5 months median observation period. Conclusions. According to our results, the complement-dependent cytotoxicity is an important mechanism of rituximab action in vitro. To achieve direct apoptosis, higher concentrations than 20 micro g/ml of rituximab should be used, while for an effective antibody-dependent cell-mediated cytotoxicity, the ratio of cytotoxic lymphocytes to tumor cells should be higher than 1:1. In the high- risk patients with aggressive CD20 lymphomas, the addition of rituximab to CHOP substantially improves the therapeutic results.
Izvleček		Izhodišča. Rituksimab se je izkazal kot učinkovito zdravilo pri zdravljenju bolnikov z indolentnimi in agresivnimi CD20 pozitivnimi B celičnimi limfomi, vendar natančnih mehanizmov njegovega delovanja in vivo še ne poznamo v celoti. To raziskavo smo zato usmerili v potrjevanje domnevnih glavnih mehanizmov delovanja rituksimaba in hkrati želeli oceniti učinkovitost prvega zdravljenja visoko rizičnih bolnikov z agresivnimi CD20 limfomi s kemoimunoterapijo. Bolniki, materiali in metode. Delovanje rituksimaba smo preučevali in vitro na Raji in SUDHL-4 celicah s testom pomnoževanja celic in s pretočno citometrijo. V kliničnem delu raziskave smo 20 visoko rizičnih bolnikov z agresivnimi CD20 limfomi zdravili s kemoimunoterapijo R-CHOP. Rezultati. V in vitro pogojih smo ugotavljali le s komplementom posredovano citotoksično delovanje rituksimaba. Pri tem pa nismo dokazali niti direktnega apoptotičnega delovanja niti s protitelesi posredovane celične citotoksičnosti verjetno zaradi prenizke koncentracije rituksimaba oziroma neustreznega razmerja med citotoksičnimi limfociti in tumorskimi celicami. Klinični rezultati zdravljenja z R-CHOP so bili odlični, saj smo popolno remisijo ob koncu primarnega zdravljenja dosegli pri 90% visoko rizičnih bolnikov. Poleg tega se pri 80% bolnikov bolezen v medianem času opazovanja 18,5 mesecev ni ponovila. Zaključki. Glede na naša opažanja je s komplementom posredovana citotoksičnost pomemben mehanizem delovanja rituksimaba in vitro. Za direktno sprožitev apoptoze so potrebne višje koncentracije rituksimaba od 20 μg/ml, medtem ko je za učinkovito od protiteles odvisno celično citotoksičnost potrebno razmerje med citotoksičnimi limfociti in tumorskimi celicami, ki je večje od 1:1. Pri bolnikih z visoko rizičnimi agresivnimi CD20 limfomi dodatek rituksimaba k CHOP kemoterapiji pomembno izboljša učinek zdravljenja.
Deskriptorji		LYMPHOMA, B-CELL ANTIGENS, CD20 ANTIBODIES, MONOCLONAL MONOCYTES CELL SURVIVAL FLOW CYTOMETRY APOPTOSIS DISEASE-FREE SURVIVAL