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Molecular mechanisms of resistance to Rituximab and pharmacologic strategies for its circumvention.

Stolz, Claudia LU and Schuler, Martin (2009) In Leukemia & lymphoma 50. p.873-885
Abstract
The introduction of Rituximab has greatly improved therapeutic options for patients with B-cell non-Hodgkin lymphoma (B-NHL). However, a substantial fraction of patients with aggressive B-NHL fails first-line therapy, and most patients with relapsing indolent B-NHL eventually acquire Rituximab resistance. Molecular understanding of the underlying mechanisms facilitates the development of pharmacologic strategies to overcome resistance. Rituximab exerts its activity on CD20-expressing B-cells by indirect and direct effector mechanisms. Indirect mechanisms are complement-dependent cytotoxicity (CDC), and antibody-dependent cell-mediated cytotoxicity (ADCC). Direct activities, such as growth inhibition, induction of apoptosis and... (More)
The introduction of Rituximab has greatly improved therapeutic options for patients with B-cell non-Hodgkin lymphoma (B-NHL). However, a substantial fraction of patients with aggressive B-NHL fails first-line therapy, and most patients with relapsing indolent B-NHL eventually acquire Rituximab resistance. Molecular understanding of the underlying mechanisms facilitates the development of pharmacologic strategies to overcome resistance. Rituximab exerts its activity on CD20-expressing B-cells by indirect and direct effector mechanisms. Indirect mechanisms are complement-dependent cytotoxicity (CDC), and antibody-dependent cell-mediated cytotoxicity (ADCC). Direct activities, such as growth inhibition, induction of apoptosis and chemosensitisation, have been reported, but are less defined. Moreover, the relative contribution of CDC, ADCC and direct mechanisms to the activity of Rituximab in vivo is unclear. Down-regulation of CD20 and expression of complement inhibitors have been described as escape mechanisms in B-NHL. Recent reports suggest that deregulated phosphoinositide-3-kinase (PI3K)/Akt, mitogen-activated kinases (MAPK) and nuclear-factor kappaB (NF-kappaB), as well as up-regulation of anti-apoptotic proteins may determine the efficacy of Rituximab to kill B-NHL cells in vitro and in vivo. The latter signalling pathways are attractive targets for pharmacologic modulation of resistance to Rituximab. With the advent of new inhibitors and antibodies, rationally designed clinical trials addressing Rituximab resistance are feasible. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Leukemia & lymphoma
volume
50
pages
873 - 885
publisher
Taylor & Francis
external identifiers
  • WOS:000266810900006
  • PMID:19373595
  • Scopus:68449093749
ISSN
1029-2403
DOI
10.1080/10428190902878471
language
English
LU publication?
yes
id
e066bd22-bc03-437e-bdb9-7ad2fd8f03ea (old id 1392033)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19373595?dopt=Abstract
date added to LUP
2009-05-06 12:58:24
date last changed
2016-11-20 04:20:56
@misc{e066bd22-bc03-437e-bdb9-7ad2fd8f03ea,
  abstract     = {The introduction of Rituximab has greatly improved therapeutic options for patients with B-cell non-Hodgkin lymphoma (B-NHL). However, a substantial fraction of patients with aggressive B-NHL fails first-line therapy, and most patients with relapsing indolent B-NHL eventually acquire Rituximab resistance. Molecular understanding of the underlying mechanisms facilitates the development of pharmacologic strategies to overcome resistance. Rituximab exerts its activity on CD20-expressing B-cells by indirect and direct effector mechanisms. Indirect mechanisms are complement-dependent cytotoxicity (CDC), and antibody-dependent cell-mediated cytotoxicity (ADCC). Direct activities, such as growth inhibition, induction of apoptosis and chemosensitisation, have been reported, but are less defined. Moreover, the relative contribution of CDC, ADCC and direct mechanisms to the activity of Rituximab in vivo is unclear. Down-regulation of CD20 and expression of complement inhibitors have been described as escape mechanisms in B-NHL. Recent reports suggest that deregulated phosphoinositide-3-kinase (PI3K)/Akt, mitogen-activated kinases (MAPK) and nuclear-factor kappaB (NF-kappaB), as well as up-regulation of anti-apoptotic proteins may determine the efficacy of Rituximab to kill B-NHL cells in vitro and in vivo. The latter signalling pathways are attractive targets for pharmacologic modulation of resistance to Rituximab. With the advent of new inhibitors and antibodies, rationally designed clinical trials addressing Rituximab resistance are feasible.},
  author       = {Stolz, Claudia and Schuler, Martin},
  issn         = {1029-2403},
  language     = {eng},
  pages        = {873--885},
  publisher    = {ARRAY(0x944f6f0)},
  series       = {Leukemia & lymphoma},
  title        = {Molecular mechanisms of resistance to Rituximab and pharmacologic strategies for its circumvention.},
  url          = {http://dx.doi.org/10.1080/10428190902878471},
  volume       = {50},
  year         = {2009},
}