Modulating apoptosis pathways in low-grade B-cell malignancies using biological response modifiers

Collectively, low-grade B-cell malignancies constitute the fifth most common form of potentially lethal cancer in North America and Europe, with chronic lymphocytic leukemia (CLL) and follicular non-Hodgkin's lymphoma (FL) representing the most prevalent of these disorders. Chronic lymphocytic leukemia and FL represent quintessential examples of human malignancies that are caused primarily by defects in programmed cell death (apoptosis). During the early stages of disease, the mature B lymphocytes that comprise most CLLs and FLs are largely quiescent G(0) phase cells, which accumulate not because they are dividing more rapidly than normal but because they survive longer than their normal counterparts because of defects in the normal pathways for apoptosis. Defects in apoptosis pathways contribute to chemoresistance, rendering tumor cells less sensitive to the cytotoxic actions of currently available anticancer drugs, and can also promote resistance to cellular immune responses. Several biological agents or their synthetic derivatives show promise as apoptosis modulators, having the potential to place neoplastic cells into a more susceptible state or activating latent programs for cell suicide. These biological response modifiers include monoclonal antibodies such as rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA) that alter signal transduction pathways, cytokines such as TRAIL (Apo2 ligand), ligands for retinoid/steroid family nuclear receptors, and small-molecule compounds that bind and inhibit protein kinases. Knowledge about the mechanisms by which these agents influence apoptosis pathways in neoplastic diseases may suggest strategies for more effective and less toxic therapies for patients suffering from CLL, FL, and other malignancies.