|
|
 Previous Article | Table of Contents | Next Article 
Relationship of p53, bcl-2, and tumor proliferation to clinical drug
resistance in non-Hodgkin's lymphomas
WH Wilson, J Teruya-Feldstein, T Fest, C Harris, SM Steinberg, ES Jaffe and M Raffeld
Medicine Branch and Laboratory of Pathology, National Cancer Institute,
Bethesda, MD 20892, USA.
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.
Volume 89,
Issue 2,
pp. 601-609,
01/15/1997
Copyright © 1997 by The American Society of Hematology
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
K. Dunleavy, S. Pittaluga, M. S. Czuczman, S. S. Dave, G. Wright, N. Grant, M. Shovlin, E. S. Jaffe, J. E. Janik, L. M. Staudt, et al.
Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma
Blood,
June 11, 2009;
113(24):
6069 - 6076.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. E Bosco, J. F Johnson, W. Ni, and Y. Zheng
Rac1 GTPase Targeting Inhibits p53-Deficiency Mediated Lymphomagenesis.
Blood (ASH Annual Meeting Abstracts),
November 16, 2008;
112(11):
1764 - 1764.
[Abstract]
|
|
|
|
|
|
|
K. Fu, D. D. Weisenburger, W. W.L. Choi, K. D. Perry, L. M. Smith, X. Shi, C. P. Hans, T. C. Greiner, P. J. Bierman, R. G. Bociek, et al.
Addition of Rituximab to Standard Chemotherapy Improves the Survival of Both the Germinal Center B-Cell-Like and Non-Germinal Center B-Cell-Like Subtypes of Diffuse Large B-Cell Lymphoma
J. Clin. Oncol.,
October 1, 2008;
26(28):
4587 - 4594.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. H. Wilson, K. Dunleavy, S. Pittaluga, U. Hegde, N. Grant, S. M. Steinberg, M. Raffeld, M. Gutierrez, B. A. Chabner, L. Staudt, et al.
Phase II Study of Dose-Adjusted EPOCH and Rituximab in Untreated Diffuse Large B-Cell Lymphoma With Analysis of Germinal Center and Post-Germinal Center Biomarkers
J. Clin. Oncol.,
June 1, 2008;
26(16):
2717 - 2724.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. G. Harb, B. I. Chyla, and C. S. Huettner
Loss of Bcl-x in Ph+ B-ALL increases cellular proliferation and does not inhibit leukemogenesis
Blood,
April 1, 2008;
111(7):
3760 - 3769.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H Veelken, S Vik Dannheim, J Schulte Moenting, U. Martens, J Finke, and A Schmitt-Graeff
Immunophenotype as prognostic factor for diffuse large B-cell lymphoma in patients undergoing clinical risk-adapted therapy
Ann. Onc.,
May 1, 2007;
18(5):
931 - 939.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Iqbal, V. T. Neppalli, G. Wright, B. J. Dave, D. E. Horsman, A. Rosenwald, J. Lynch, C. P. Hans, D. D. Weisenburger, T. C. Greiner, et al.
BCL2 Expression Is a Prognostic Marker for the Activated B-Cell-Like Type of Diffuse Large B-Cell Lymphoma
J. Clin. Oncol.,
February 20, 2006;
24(6):
961 - 968.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Bauer, D. K. Trask, B. Kumar, G. Los, J. Castro, J. Shin-Jung Lee, J. Chen, S. Wang, C. R. Bradford, and T. E. Carey
Reversal of cisplatin resistance with a BH3 mimetic, (-)-gossypol, in head and neck cancer cells: role of wild-type p53 and Bcl-xL
Mol. Cancer Ther.,
July 1, 2005;
4(7):
1096 - 1104.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Bjorck, S. Ek, O. Landgren, M. Jerkeman, M. Ehinger, M. Bjorkholm, C. A. K. Borrebaeck, A. Porwit-MacDonald, and M. Nordenskjold
High expression of cyclin B1 predicts a favorable outcome in patients with follicular lymphoma
Blood,
April 1, 2005;
105(7):
2908 - 2915.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Katahira, T. Takayama, K. Miyanishi, T. Hayashi, T. Ikeda, Y. Takahashi, R. Takimoto, T. Matsunaga, J. Kato, and Y. Niitsu
Plasma Glutathione S-Transferase P1-1 as a Prognostic Factor in Patients with Advanced Non-Hodgkin's Lymphoma (Stages III and IV)
Clin. Cancer Res.,
December 1, 2004;
10(23):
7934 - 7940.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Grange, T. Petrella, M. Beylot-Barry, P. Joly, M. D'Incan, M. Delaunay, L. Machet, M.-F. Avril, S. Dalac, P. Bernard, et al.
Bcl-2 protein expression is the strongest independent prognostic factor of survival in primary cutaneous large B-cell lymphomas
Blood,
May 15, 2004;
103(10):
3662 - 3668.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. F. Little, S. Pittaluga, N. Grant, S. M. Steinberg, M. F. Kavlick, H. Mitsuya, G. Franchini, M. Gutierrez, M. Raffeld, E. S. Jaffe, et al.
Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology
Blood,
June 15, 2003;
101(12):
4653 - 4659.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Mounier, J. Briere, C. Gisselbrecht, J.-F. Emile, P. Lederlin, C. Sebban, F. Berger, A. Bosly, P. Morel, H. Tilly, et al.
Rituximab plus CHOP (R-CHOP) overcomes bcl-2--associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL)
Blood,
June 1, 2003;
101(11):
4279 - 4284.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Sanchez-Beato, A. Sanchez-Aguilera, and M. A. Piris
Cell cycle deregulation in B-cell lymphomas
Blood,
February 15, 2003;
101(4):
1220 - 1235.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. M. Braziel, M. A. Shipp, A. L. Feldman, V. Espina, M. Winters, E. S. Jaffe, E. F. Petricoin III, and L. A. Liotta
Molecular Diagnostics
Hematology,
January 1, 2003;
2003(1):
279 - 293.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. K. Erban and Z. Tang
Case 38-2002 - A 54-Year-Old Man with Hypercalcemia, Renal Dysfunction, and an Enlarged Liver
N. Engl. J. Med.,
December 12, 2002;
347(24):
1952 - 1960.
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Leroy, C. Haioun, E. Lepage, N. Le Metayer, F. Berger, E. Labouyrie, V. Meignin, B. Petit, C. Bastard, G. Salles, et al.
p53 gene mutations are associated with poor survival in low and low-intermediate risk diffuse large B-cell lymphomas
Ann. Onc.,
July 1, 2002;
13(7):
1108 - 1115.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. H. Wilson, M. L. Grossbard, S. Pittaluga, D. Cole, D. Pearson, N. Drbohlav, S. M. Steinberg, R. F. Little, J. Janik, M. Gutierrez, et al.
Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy
Blood,
April 15, 2002;
99(8):
2685 - 2693.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. L. Barrans, I. Carter, R. G. Owen, F. E. Davies, R. D. Patmore, A. P. Haynes, G. J. Morgan, and A. S. Jack
Germinal center phenotype and bcl-2 expression combined with the International Prognostic Index improves patient risk stratification in diffuse large B-cell lymphoma
Blood,
February 15, 2002;
99(4):
1136 - 1143.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Gruszka-Westwood, R. A. Hamoudi, E. Matutes, E. Tuset, and D. Catovsky
p53 abnormalities in splenic lymphoma with villous lymphocytes
Blood,
June 1, 2001;
97(11):
3552 - 3558.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Gutierrez, B. A. Chabner, D. Pearson, S. M. Steinberg, E. S. Jaffe, B. D. Cheson, A. Fojo, and W. H. Wilson
Role of a Doxorubicin-Containing Regimen in Relapsed and Resistant Lymphomas: An 8-Year Follow-Up Study of EPOCH
J. Clin. Oncol.,
November 1, 2000;
18(21):
3633 - 3642.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Poelman, M. O. Adeyanju, M.-A. Robertson, W. M. Recant, T. Karrison, G. F. Fleming, O. I. Olopade, and S. D. Conzen
Human Breast Cancer Susceptibility to Paclitaxel Therapy Is Independent of Bcl-2 Expression
Clin. Cancer Res.,
October 1, 2000;
6(10):
4043 - 4048.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
M. Filipits, U. Jaeger, I. Simonitsch, C. Chizzali-Bonfadin, H. Heinzl, and R. Pirker
Clinical Relevance of the Lung Resistance Protein in Diffuse Large B-Cell Lymphomas
Clin. Cancer Res.,
September 1, 2000;
6(9):
3417 - 3423.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
S. Renner, J. Weisz, S. Krajewski, M. Krajewska, J. C. Reed, and A. Lichtenstein
Expression of BAX in Plasma Cell Dyscrasias
Clin. Cancer Res.,
June 1, 2000;
6(6):
2371 - 2380.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
W. H. Wilson, L. Sorbara, W. D. Figg, E. K. Mont, E. Sausville, K. E. Warren, F. M. Balis, K. Bauer, M. Raffeld, A. M. Senderowicz, et al.
Modulation of Clinical Drug Resistance in a B Cell Lymphoma Patient by the Protein Kinase Inhibitor 7-Hydroxystaurosporine: Presentation of a Novel Therapeutic Paradigm
Clin. Cancer Res.,
February 1, 2000;
6(2):
415 - 421.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
C.A. SCHMITT, R.R. WALLACE-BRODEUR, C.T. ROSENTHAL, M.E. MCCURRACH, and S.W. LOWE
DNA Damage Responses and Chemosensitivity in the E{micro}-myc Mouse Lymphoma Model
Cold Spring Harb Symp Quant Biol,
January 1, 2000;
65(0):
499 - 510.
[Abstract]
[PDF]
|
|
|
|
|
|
|
C. A. Schmitt, M. E. McCurrach, E. de Stanchina, R. R. Wallace-Brodeur, and S. W. Lowe
INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53
Genes & Dev.,
October 15, 1999;
13(20):
2670 - 2677.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
S. Indraccolo, S. Minuzzo, L. Nicoletti, E. Cretella, M. Simon, G. Papakonstantinou, R. Hehlmann, M. Mion, R. Bertorelle, J. Roganovic, et al.
Mutator Phenotype in Human Hematopoietic Neoplasms and Its Association With Deletions Disabling DNA Repair Genes and bcl-2 Rearrangements
Blood,
October 1, 1999;
94(7):
2424 - 2432.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Montesinos-Rongen, A. Roers, R. Kuppers, K. Rajewsky, and M.-L. Hansmann
Mutation of the p53 Gene Is Not a Typical Feature of Hodgkin and Reed-Sternberg Cells in Hodgkin's Disease
Blood,
September 1, 1999;
94(5):
1755 - 1760.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. B. Moller, A.-M. Gerdes, K. Skjodt, L. S. Mortensen, and N. T. Pedersen
Disrupted p53 Function as Predictor of Treatment Failure and Poor Prognosis in B- and T-Cell Non-Hodgkin's Lymphoma
Clin. Cancer Res.,
May 1, 1999;
5(5):
1085 - 1091.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Klampfer, J. Cammenga, H.-G. Wisniewski, and S. D. Nimer
Sodium Salicylate Activates Caspases and Induces Apoptosis of Myeloid Leukemia Cell Lines
Blood,
April 1, 1999;
93(7):
2386 - 2394.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Quintanilla-Martinez, C. Thieblemont, F. Fend, S. Kumar, M. Pinyol, E. Campo, E. S. Jaffe, and M. Raffeld
Mantle Cell Lymphomas Lack Expression of p27kip1, a Cyclin-Dependent Kinase Inhibitor
Am. J. Pathol.,
July 1, 1998;
153(1):
175 - 182.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Dogan, M.-Q. Du, A. Aiello, T. C. Diss, H.-T. Ye, L.-X. Pan, and P. G. Isaacson
Follicular Lymphomas Contain a Clonally Linked But Phenotypically Distinct Neoplastic B-Cell Population in the Interfollicular Zone
Blood,
June 15, 1998;
91(12):
4708 - 4714.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Cordone, S. Masi, F. R. Mauro, S. Soddu, O. Morsilli, T. Valentini, M. L. Vegna, C. Guglielmi, F. Mancini, S. Giuliacci, et al.
p53 Expression in B-Cell Chronic Lymphocytic Leukemia: A Marker of Disease Progression and Poor Prognosis
Blood,
June 1, 1998;
91(11):
4342 - 4349.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. N. Winter, J. Andersen, J. C. Reed, S. Krajewski, D. Variakojis, K. D. Bauer, R. I. Fisher, L. I. Gordon, M. M. Oken, S. Jiang, et al.
BCL-2 Expression Correlates With Lower Proliferative Activity in the Intermediate- and High-Grade Non-Hodgkin's Lymphomas: An Eastern Cooperative Oncology Group and Southwest Oncology Group Cooperative Laboratory Study
Blood,
February 15, 1998;
91(4):
1391 - 1398.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. R.K. Koduru, K. Raju, V. Vadmal, G. Menezes, S. Shah, M. Susin, J. Kolitz, and J. D. Broome
Correlation Between Mutation in P53, p53 Expression, Cytogenetics, Histologic Type, and Survival in Patients With B-Cell Non-Hodgkin's Lymphoma
Blood,
November 15, 1997;
90(10):
4078 - 4091.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Ichikawa, T. Kinoshita, T. Watanabe, H. Kato, H. Nagai, K. Tsushita, H. Saito, and T. Hotta
Mutations of the p53 Gene as a Prognostic Factor in Aggressive B-Cell Lymphoma
N. Engl. J. Med.,
August 21, 1997;
337(8):
529 - 534.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
