THE IMPACT OF SELECTED CELL SURVIVAL REGULATORS (OF AKT-2,
BCL-2, CD29, PKC-DELTA AND SURVIVIN) ON PREDICTION OF CLINICAL
OUTCOME IN DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL)

J 2007

THE IMPACT OF SELECTED CELL SURVIVAL REGULATORS (OF AKT-2, BCL-2, CD29, PKC-DELTA AND SURVIVIN) ON PREDICTION OF CLINICAL OUTCOME IN DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL)

SVOBODA, Marek, Pavel FABIAN, Ingrid VÁŠOVÁ, Lenka RADOVÁ, Jitka BERKOVCOVÁ et. al.

Basic information

Original name

THE IMPACT OF SELECTED CELL SURVIVAL REGULATORS (OF AKT-2, BCL-2, CD29, PKC-DELTA AND SURVIVIN) ON PREDICTION OF CLINICAL OUTCOME IN DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL)

Name in Czech

Význam vybraných regulátorů buněčného přežívání (Akt-2, Bcl-2, CD29, PKC-delta, survivin) v predikci klinického vývoje difúzního velkobuněčného B-lymfomu.

Authors

SVOBODA, Marek (203 Czech Republic, guarantor), Pavel FABIAN (203 Czech Republic), Ingrid VÁŠOVÁ (203 Czech Republic), Lenka RADOVÁ (203 Czech Republic), Jitka BERKOVCOVÁ (203 Czech Republic), Martin KLABUSAY (203 Czech Republic), Rudolf NENUTIL (203 Czech Republic) and Aleš REJTHAR (203 Czech Republic)

Edition

Haematologica/the hematology journal, Pavia, Italy, European Hematology Association, 2007, 0390-6078

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30200 3.2 Clinical medicine

Country of publisher

Italy

Confidentiality degree

není předmětem státního či obchodního tajemství

Impact factor

Impact factor: 5.516

RIV identification code

RIV/00216224:14110/07:00019098

Organization unit

Faculty of Medicine

UT WoS

000247176900704

Keywords in English

Akt; DLBCL; Prognostic factor; Survivin

Abstract

ORIG CZ

V originále

Background: Apoptosis plays an important role in normal and malignant lymphopoiesis. Therefore signaling pathways participating in this process are intensively investigated to find their crucial molecules suitable for development and application of new antineoplastic agents. Aims: Based on results of our previous studies and literature search, we selected 9 molecules which play an important role in survival of malignant cells to validate their impact for prediction of outcome in DLBCL. Methods and materials: We studied 46 patients with primary DLBCL.The group consisted of 29 men and 27 women with a median age of 59 years (range, 24-79). Advanced stage (III/IV) was observed in 24 cases (52%) and the distribution according to the IPI was as follows: low risk, 20 cases (44%); low/intermediate risk, 12 (26%); high/intermediate risk 9 (19%); and high risk, 5 (11%). All patients were treated with curative intent and, except for one case, an initial treatment started with a CHOP chemotherapy regimen with a median of 6 administrated cycles. Overall response rate was 69% with a complete response (CR) in 31 patients (67%). For subsequent analyses patients were divided into two subgroups: 1. with cured disease (31 cases, 54%; median follow-up 4,3 years), and 2. with fatal course of disease (21 cases, 46%; median follow-up 9 months). Only patients, who died of disease progression were included. Imunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue sections with monoclonal antibodies against: Akt-1, Akt-2, phospho-Akt-Ser-473 and phospho-Akt-Thr-307, Bcl-2, integrin-betaI (CD29), protein kinase C beta I and II (PKC-betaI, PKC-betaII), gama (PKC-gamma), delta (PKC-delta), and Survivin. The expression was considered positive if 5% or more of the tumor cells were stained with the antibody, except for the cases of CD29, Survivin and Bcl-2, where the limits were: 10%, 20% and 40%, respectively. In addition, the expression of PKC isoforms was analyzed by Real-Time-PCR and obtained Ct-values were compared. P-value was based on Gehan-Wilcoxon test or chi-square test and P-values <0,05 were considered significant. The Kaplan-Meier method was used to estimate overall (OS) and progression-free survival (PFS). Results: Tumor cells expression of phospho-Akt-2-Ser-473, Bcl-2, CD29 and Survivin correlated with an inferior OS and PFS and predicted an adverse outcome in patients with DLBCL. Thus, patients with positive expression of phospho-Akt-2-Ser-473 had a median of OS and PFS lower compared to those with negative expression (OS: 45vs11 months, p<0,008; PFS: 37vs10 months, p<0,004). Similar data were obtained for: Survivin (OS: 40vs29 months, p=0,1; PFS: 40vs15 months, p<0,035), Bcl-2 (OS: 45vs12 months, p<0,015; PFS: 30vs6 months, p<0,02), CD29 (OS: 45vs20 months, p<0,04; PFS: 40vs10 months, p<0,025). In the case of PKC-delta higher mRNA expression correlated with unfavourable outcomes (OS: 45vs10 months, p<0,015; PFS: 35vs9 months, p<0,075). The other results were not statistically significant. Conclusions: Our results have shown that expression of Akt-2, Bcl-2, CD29 and Survivin was significantly associated with a poorer clinical outcome in DLBCL patients. Those molecules could be potential targets for therapeutic interventions in DLBCL. Acknowledgment: This project was supported by Internal Grant Agency, Ministry of Health, Czech Republic. No.:NR/8335-3. E-mail:msvoboda@mou.cz

In Czech

Publikace dostupná pouze v anglickém jazyce.

Links

NR8335, research and development project

Name: Predikce chemosenzitivity / chemorezistence na cílenou protinádorovou terapii u pacientek s karcinomem prsu s prokázanou HER-2 pozitivitou, na podkladě analýzy Akt signální dráhy a sérové hladiny HER-2 receptoru

Citovat

SVOBODA, Marek, Pavel FABIAN, Ingrid VÁŠOVÁ, Lenka RADOVÁ, Jitka BERKOVCOVÁ, Martin KLABUSAY, Rudolf NENUTIL and Aleš REJTHAR. THE IMPACT OF SELECTED CELL SURVIVAL REGULATORS (OF AKT-2, BCL-2, CD29, PKC-DELTA AND SURVIVIN) ON PREDICTION OF CLINICAL OUTCOME IN DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL). Haematologica/the hematology journal. Pavia, Italy: European Hematology Association, 2007, vol. 2007, S1, p. 261-262. ISSN 0390-6078.

@article{726210,
   author = {Svoboda, Marek and Fabian, Pavel and Vášová, Ingrid and Radová, Lenka and Berkovcová, Jitka and Klabusay, Martin and Nenutil, Rudolf and Rejthar, Aleš},
   article_location = {Pavia, Italy},
   article_number = {S1},
   keywords = {Akt; DLBCL; Prognostic factor; Survivin},
   language = {eng},
   issn = {0390-6078},
   journal = {Haematologica/the hematology journal},
   title = {THE IMPACT OF SELECTED CELL SURVIVAL REGULATORS (OF AKT-2, BCL-2, CD29, PKC-DELTA AND SURVIVIN) ON PREDICTION OF CLINICAL OUTCOME IN DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL)},
   volume = {2007},
   year = {2007}
}

TY  - JOUR
ID  - 726210
AU  - Svoboda, Marek - Fabian, Pavel - Vášová, Ingrid - Radová, Lenka - Berkovcová, Jitka - Klabusay, Martin - Nenutil, Rudolf - Rejthar, Aleš
PY  - 2007
TI  - THE IMPACT OF SELECTED CELL SURVIVAL REGULATORS (OF AKT-2, BCL-2, CD29, PKC-DELTA AND SURVIVIN) ON PREDICTION OF CLINICAL OUTCOME IN DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL)
JF  - Haematologica/the hematology journal
VL  - 2007
IS  - S1
SP  - 261-262
EP  - 261-262
PB  - European Hematology Association
SN  - 03906078
KW  - Akt
KW  - DLBCL
KW  - Prognostic factor
KW  - Survivin
N2  - Background: Apoptosis plays an important role in normal and malignant lymphopoiesis. Therefore signaling pathways participating in this process are intensively investigated to find their crucial molecules suitable for development and application of new antineoplastic agents. Aims: Based on results of our previous studies and literature search, we selected 9 molecules which play an important role in survival of malignant cells to validate their impact for prediction of outcome in DLBCL. Methods and materials: We studied 46 patients with primary DLBCL.The group consisted of 29 men and 27 women with a median age of 59 years (range, 24-79). Advanced stage (III/IV) was observed in 24 cases (52%) and the distribution according to the IPI was as follows: low risk, 20 cases (44%); low/intermediate risk, 12 (26%); high/intermediate risk 9 (19%); and high risk, 5 (11%). All patients were treated with curative intent and, except for one case, an initial treatment started with a CHOP chemotherapy regimen with a median of 6 administrated cycles. Overall response rate was 69% with a complete response (CR) in 31 patients (67%). For subsequent analyses patients were divided into two subgroups: 1. with cured disease (31 cases, 54%; median follow-up 4,3 years), and 2. with fatal course of disease (21 cases, 46%; median follow-up 9 months). Only patients, who died of disease progression were included. Imunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue sections with monoclonal antibodies against: Akt-1, Akt-2, phospho-Akt-Ser-473 and phospho-Akt-Thr-307, Bcl-2, integrin-betaI (CD29), protein kinase C beta I and II (PKC-betaI, PKC-betaII), gama (PKC-gamma), delta (PKC-delta), and Survivin. The expression was considered positive if 5% or more of the tumor cells were stained with the antibody, except for the cases of CD29, Survivin and Bcl-2, where the limits were: 10%, 20% and 40%, respectively. In addition, the expression of PKC isoforms was analyzed by Real-Time-PCR and obtained Ct-values were compared. P-value was based on Gehan-Wilcoxon test or chi-square test and P-values <0,05 were considered significant. The Kaplan-Meier method was used to estimate overall (OS) and progression-free survival (PFS). Results: Tumor cells expression of phospho-Akt-2-Ser-473, Bcl-2, CD29 and Survivin correlated with an inferior OS and PFS and predicted an adverse outcome in patients with DLBCL. Thus, patients with positive expression of phospho-Akt-2-Ser-473 had a median of OS and PFS lower compared to those with negative expression (OS: 45vs11 months, p<0,008; PFS: 37vs10 months, p<0,004). Similar data were obtained for: Survivin (OS: 40vs29 months, p=0,1; PFS: 40vs15 months, p<0,035), Bcl-2 (OS: 45vs12 months, p<0,015; PFS: 30vs6 months, p<0,02), CD29 (OS: 45vs20 months, p<0,04; PFS: 40vs10 months, p<0,025). In the case of PKC-delta higher mRNA expression correlated with unfavourable outcomes (OS: 45vs10 months, p<0,015; PFS: 35vs9 months, p<0,075). The other results were not statistically significant. Conclusions: Our results have shown that expression of Akt-2, Bcl-2, CD29 and Survivin was significantly associated with a poorer clinical outcome in DLBCL patients. Those molecules could be potential targets for therapeutic interventions in DLBCL. Acknowledgment: This project was supported by Internal Grant Agency, Ministry of Health, Czech Republic. No.:NR/8335-3. E-mail:msvoboda@mou.cz
ER  -

SVOBODA, Marek, Pavel FABIAN, Ingrid VÁŠOVÁ, Lenka RADOVÁ, Jitka BERKOVCOVÁ, Martin KLABUSAY, Rudolf NENUTIL and Aleš REJTHAR. THE IMPACT OF SELECTED CELL SURVIVAL REGULATORS (OF AKT-2, BCL-2, CD29, PKC-DELTA AND SURVIVIN) ON PREDICTION OF CLINICAL OUTCOME IN DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL). \textit{Haematologica/the hematology journal}. Pavia, Italy: European Hematology Association, 2007, vol.~2007, S1, p.~261-262. ISSN~0390-6078.

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