Pretreatment with Rituximab Enhances Radiosensitivity of Non-Hodgkin's Lymphoma Cells

Abstract

The present study examines the effects of ionizing radiation in combination with rituximab (RTX), a chimeric human anti-CD20 monoclonal antibody, on proliferation, cell cycle distribution and apoptosis in B-lymphoma RL and Raji cells. Exposure to ionizing radiation (9 Gy) induced cell growth delay and apoptosis in RL cells, whereas Raji cells showed moderate radio-resistance. The simultaneous exposure of lymphoma cells to ionizing radiation and RTX (10 microg/mL) markedly enhanced apoptosis and cell growth delay in RL and Raji cells. Cooperative antiproliferative and apoptotic effects of RTX and radiation were achieved through the inhibition of c-myc and bcl-XL expression. Furthermore, RTX-modulated expression of cell cycle regulating proteins, such as p53, p21/WAF1, p27/KIP1, contributed to the development of radiation-induced cell killing and growth arrest. Each NHL cell line that underwent apoptosis induced by combination treatment revealed enhanced caspase-3 and poly (ADP-ribose) polymerase (PARP) cleavage as compared to only irradiated cells. These findings show that rituximab synergistically enhances radiation-induced apoptosis and cell growth delay through the expression of proteins involved in the programmed cell death and cell cycle regulation pathways.

Preclinical and clinical evaluation of epratuzumab (anti-CD22 IgG) in B-cell malignancies

“…The mechanisms responsible for its activity are under intense study and debate, with antibody-dependent cellular cytotoxicity (ADCC), complement-mediated cytotoxicity and direct induction of apoptosis all implicated (Golay et al, 2000;Harjunpaa et al, 2000;Maloney et al, 2002;Johnson and Glennie, 2003). Although it was initially approved as a monotherapy, it is clear that it can enhance the antitumor effects of chemotherapy (Chow et al, 2002;Jazirehi et al, 2005) or radiation (Skvortsova et al, 2005). Virtually all indolent and aggressive B-cell NHL patients receive rituximab as part of their initial therapy, as well as at relapse.…”

"Estudo de marcação com Iodo-131 de anticorpo monoclonal anti-CD20 usado na terapia de linfoma não-Hodgkin"

“…Finalmente, Behr e colaboradores [58], demonstraram num ensaio clínico a capacidade em potencial desse anticorpo anti-CD20 marcado com iodo-131, na indução de remissões duráveis após tratamento com atividade alta ou terapêutica [58]. Skivortsova e colaboradores [35] realizaram estudo onde avaliaram os efeitos de radiação ionizante em combinação com a Rituximab (Mabthera ® ), sobre a proliferação, distribuição do ciclo celular e apoptoses em células de modelo tumoral de linfomas-B (células Rajji e Daudi). Constataram que a exposição dessas células à radiação ionizante de aproximadamente 9Gy induziu o retardamento de crescimento celular e apoptose em células Daudi, enquanto que, as células Rajji demonstraram-se moderadamente radio-resistente.…”

“…Observaram que a exposição simultânea dessas células à radiação ionizante e Rituximab (10mg/ml) intensificou significativamente as apoptoses e retardamento no crescimento celular dessas células. Constataram também que o efeito antiproliferativo e apoptótico tanto do Rituximab como da radiação são cooperativos [35,89]. Contudo, as descobertas de Skivortsova e colaboradores [35] confirmaram o que já foi relatado em outros trabalhos de que Rituximab é capaz de intensificar sinergisticamente a apoptose radio -induzida e retardamento do crescimento celular através de bloqueio protéico envolvido tanto na morte programada como na regulação das etapas do ciclo celular [35,89].…”

“…Uma vantagem evidente é que com RIT, os efeitos anti-tumor destes Acms, os mecanismos tanto biológico e imunológico, como apoptose, ADCC e CDC, em conjunto com os efeitos da radiação, exercem papel importante nas respostas anti-tumorais observadas [4,16,17,28,29,32,35].…”

Czy należy stosować radioterapię w nieziarniczym rozlanym chłoniaku z dużych komórek B? Głos na tak

“…Skuteczność dawek nawet tak niskich jak 1 Gy oraz wysoki udział całkowitych remisji po konwencjonalnie frakcjonowanych dawkach całkowitych wynoszących 20-40 Gy sugerowały wysoką skuteczność tej metody, chociaż badania na liniach komórkowych chłonia-ków wykazywały ich zróżnicowaną promieniowrażliwość i brak zależności od dawki całkowitej. W ostatnich latach odkryto możliwość zwiększenia wrażliwości komórek chło-niaków na promieniowanie jonizujące przez wcześniejsze lub równoczasowe podanie rytuksymabu [6]. Wydaje się, że w NHL tak jak w innych promieniowrażliwych nowotworach złośliwych szansa na uzyskanie remisji i kontroli miejscowej zależy od dawki biologicznej, objętości napromienianej masy guzowo-węzłowej oraz rodzaju odpowiedzi na chemioterapię (o ile była podawana).…”