Oncogene
-
The clinical application of rituximab (chimeric mouse anti-human CD20 mAb, Rituxan, IDEC-C2B8), alone and/or combined with chemotherapy, has significantly ameliorated the treatment outcome of patients with relapsed and refractory low-grade or follicular non-Hodgkin's lymphoma (NHL). The exact in vivo mechanisms of action of rituximab are not fully understood, although antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis have been suggested. We have proposed that modifications of the cellular signaling pathways by rituximab may be crucial for its clinical response. ⋯ Resistant clones display different phenotypic, genetic and functional properties compared to wild-type cells. This review summarizes the data highlighting a novel role of rituximab as a signal-inducing antibody and as a chemosensitizing agent through negative regulation of major survival pathways. Studies presented herein also reveal several intracellular targets modified by rituximab, which can be exploited for therapeutic and prognostic purposes in the treatment of patients with rituximab- and drug-refractory NHL.
-
Large prospective studies show a significant association with obesity for several cancers, and the International Agency for Research on Cancer has classified the evidence of a causal link as 'sufficient' for cancers of the colon, female breast (postmenopausal), endometrium, kidney (renal cell), and esophagus (adenocarcinoma). These data, and the rising worldwide trend in obesity, suggest that overeating may be the largest avoidable cause of cancer in nonsmokers. Few obese people are successful in long-term weight reduction, and thus there is little direct evidence regarding the impact of weight reduction on cancer risk. If the correlation between obesity and cancer mortality is entirely causal, we estimate that overweight and obesity now account for one in seven of cancer deaths in men and one in five in women in the US.
-
There has been steady progress in antisense technology over the past 14 years. We now have a far better appreciation of the attributes and limitations of the technology. Antisense oligonucleotides have been used to selectively inhibit thousands of genes in mammalian cells, hundreds, if not thousands, of genes in rodents and other species and multiple genes in humans. ⋯ Like any other class of drugs in development, there will continue to be successes and failures in the clinic. Despite some disappointments with the technology, it appears to be a valid platform for both drug discovery and as an experimental tool for functionalizing genes. Advances in the medicinal chemistry and formulation of antisense oligonucleotides will further enhance their therapeutic and commercial potential.
-
Rituximab, a chimeric monoclonal antibody targeted against the pan-B-cell marker CD20, was the first monoclonal antibody to be approved for therapeutic use. Treatment with rituximab at standard weekly dosing is effective in more than 50% of patients with relapsed or refractory CD20-positive follicular non-Hodgkin's lymphoma, but is not curative. It is less effective in other subtypes of CD20-positive lymphoma and for retreatment, even with CD20 still expressed. ⋯ Thus, the role of various resistance pathways, some documented in experimental systems and others still hypothetical, remains uncertain. Resistance could potentially be mediated by alterations in CD20 expression or signaling, elevated apoptotic threshold, modulation of complement activity or diminished cellular cytotoxicity. As the first of an expanding class of anticancer agents, lessons learned regarding the mechanism of rituximab action and resistance will be of increasing importance.