title: Relationship of p53, bcl-2, and tumor proliferation to clinical drug resistance in non-Hodgkin's lymphomas.
abstract: Although the cause(s) of clinical drug resistance in non-Hodgkin's lymphomas (NHL) is unknown, in vitro studies suggest that abnormalities of the p53 gene, bcl-2 overexpression, and low tumor proliferation rates may increase chemotherapy resistance. We analyzed tumor tissue from 75 patients with relapsed/refractory NHL (Working Formulation A through H) for p53 mutation/overexpression (abnormality), bcl-2 expression, and tumor proliferation and correlated them with multiple clinical characteristics, response to therapy, disease-free survival, and overall survival (OS). All tumor biopsy specimens were obtained within 6 weeks of treatment with EPOCH (infusional etoposide, vincristine, and doxorubicin and bolus prednisone and cyclophosphamide) chemotherapy. Overall, 16 (21%) tumors had a p53 abnormality. Of 13 tumors with overexpression, mutations were confirmed by sequence analysis in 11, and, in 44 tumors without overexpression, 3 showed mutations. A multivariate analysis showed that tumors with a p53 abnormality were more likely to be drug resistant than tumors with normal p53 (56% v 17%; P2 = .008) and to have a shorter median progression-free survival (PFS; 2.1 v 8.2 months; P2 = .008) and OS (11.7 v 21.5 months; P2 = .038), respectively. The presence of a p53 abnormality did not correlate with any clinical characteristic, bcl-2 expression, or tumor proliferation. A significant correlation was found between low tumor proliferation and drug resistance in a univariate (P2 < .006) but not multivariate analysis. Patients with tumor proliferation of less than 80% were significantly more likely to have no response to therapy (31% v 6%) or to fail to achieve a complete response (16% v 44%) and tended to have shorter PFS and OS than did patients with higher proliferation. No significant association was found between bcl-2 expression and drug resistance, PFS or OS, although patients with intermediate-grade histologies and high bcl-2 expression tended to be drug resistant as compared with low level expressors (P2 < .065). Of interest was the finding of a significant association between high bcl-2 and low tumor proliferation (P2 = .0045). In studies that have found an association between high bcl-2 expression and short PFS, bcl-2 may have been a surrogate for low tumor proliferation. Further studies are warranted to examine this question. These results suggest that p53 mutation and low tumor proliferation, but not bcl-2, may be important causes of clinical drug resistance in NHL.
authors.affiliation: Medicine Branch and Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: W H
authors.initials: WH
authors.lastname: Wilson
authors.forename: J
authors.initials: J
authors.lastname: Teruya-Feldstein
authors.forename: T
authors.initials: T
authors.lastname: Fest
authors.forename: C
authors.initials: C
authors.lastname: Harris
authors.forename: S M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: E S
authors.initials: ES
authors.lastname: Jaffe
authors.forename: M
authors.initials: M
authors.lastname: Raffeld
mesh_terms: D002455:Cell Division / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D009154:Mutation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53