title: Non-Hodgkin's B-cell lymphoma: advances in molecular strategies targeting drug resistance.
abstract: Non-Hodgkin's lymphoma (NHL) is a heterogeneous class of cancers displaying a diverse range of biological phenotypes, clinical behaviours and prognoses. Standard treatments for B-cell NHL are anthracycline-based combinatorial chemotherapy regimens composed of cyclophosphamide, doxorubicin, vincristine and prednisolone. Even though complete response rates of 40-50% with chemotherapy can be attained, a substantial proportion of patients relapse, resulting in 3-year overall survival rates of about 30%. Relapsed lymphomas are refractory to subsequent treatments with the initial chemotherapy regimen and can exhibit cross-resistance to a wide variety of anticancer drugs. The emergence of acquired chemoresistance thus poses a challenge in the clinic preventing the successful treatment and cure of disseminated B-cell lymphomas. Gene-expression analyses have increased our understanding of the molecular basis of chemotherapy resistance and identified rational targets for drug interventions to prevent and treat relapsed/refractory diffuse large B-cell lymphoma. Acquisition of drug resistance in lymphoma is in part driven by the inherent genetic heterogeneity and instability of the tumour cells. Due to the genetic heterogeneity of B-cell NHL, many different pathways leading to drug resistance have been identified. Successful treatment of chemoresistant NHL will thus require the rational design of combinatorial drugs targeting multiple pathways specific to different subtypes of B-cell NHL as well as the development of personalized approaches to address patient-to-patient genetic heterogeneity. This review highlights the new insights into the molecular basis of chemorefractory B-cell NHL that are facilitating the rational design of novel strategies to overcome drug resistance.
authors.affiliation: Texas A&M Health Science Center, College Station, TX 77843-1114, USA.
authors.forename: Steve A
authors.initials: SA
authors.lastname: Maxwell
authors.forename: Seyed
authors.initials: S
authors.lastname: Mousavi-Fard
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004359:Drug Therapy, Combination; D020869:Gene Expression Profiling; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents
keywords: Akt; B-cell lymphoma; Drug resistance; MAP kinases; NFκB; NHL; TGFβ; apoptosis; cluster differentiation antigens; drug metabolism; epigenetics; geranylation; mechanisms of drug resistance; microRNAs; microsatellite instability; multidrug resistance; oxidative stress; p53; positive regulatory domain I protein; proteasome; retinaldehyde dehydrogenase; sphingosine kinase; stroma; stromal influences; tyrosine kinases; zinc transporter