Pharmacogenetic influences on treatment response to nucleoside analogues
- Efforts in the individualization of therapy in hematological malignancies | Application
Pharmacogenetic influences on treatment response to nucleoside analogues
- Efforts in the individualization of therapy in hematological malignancies

Registration number: LIO-4910
ALF-forskartjänst
Application started by: Kourosh Lotfi, 2005-05-31
Professional title at the time of application: MD, PhD
Work place at the time of application: Hematologiklin
Last updated / corrected by: Agneta Linghag, 2008-01-30
Application received by: Region Östergötland
Granted and completedGranted and completed
Applicant: Kourosh Lotfi
Överläkare/Docent, Centrum för Kirurgi, Ortopedi och Cancervård

Välj den originalansökan du söker fortsatt anslag för

  1. LIO-4910 : Pharmacogenetic influences on treatment response to nucleoside analogues - Efforts in the individualization of therapy in hematological malignancies, ALF-forskartjänst
    Granted and completed Granted and completed
    application started: 2005-05-31 , Applicant: Kourosh Lotfi, Hematologiklin
  2. LIO-10490 : Pharmacogenetic influences on treatment response to nucleoside analogues - Efforts in the individualization of therapy in hematological malignancies, Fortsättningsanslag - ALF forskartjänst (föregående ansökan elektronisk)
    Granted and completed Granted and completed
    application started: 2007-05-22 , Applicant: Kourosh Lotfi, Hematologiklin

Övergripande projektinformation

Klinik

Hematologiska kliniken

Institutionsavdelning

Klinisk farmakologi

Sammanfattning av forskningsprogram (max 2000 tecken)

Motstånd mot cytostatika är troligen huvudorsaken till sviktande kemoterapi vid behandling av patienter med leukemi. Denna resistens kan visa sig redan vid inledande terapi eller utvecklas under behandlingens gång. Många leukemipatienter behandlas framgångsrikt med rådande behandling men vissa patienter utvecklar resistenta celler och svarar därför inte på behandlingen. Det är mycket viktigt att utveckla en effektiv behandling även för denna grupp. Vi har under många år undersökt vilken roll resistensmekanismer identifierade på cellinjenivå spelar för klinisk cytostatikaresistens hos akuta och kroniska leukemier vid behandling med nucleosidanaloger. Syftet med den här ansökan är att introducera 5´-nukleotidashämmare i kombination med vissa nukleosidanaloger såsom kladribin, fludarabine, clofarabine och nelarabin vid cancer behandlingen. 5´-nukleotidaser, vilka de finns flera olika i olika celler, motverkar aktiveringen av nukleosidanaloger genom att avlägsna en fosfatgrupp som behövs för att få en cytostatisk effekt. Om nukleotidaserna kan hämmas bör en väsentligt högre intracellulär halt av aktiva nukleotidanaloger kunna erhållas, vilket möjliggör bättre terapi och kanske vidgat användningsområde för dessa cytostatika. Vi har producerat flera av de viktigaste 5´-nukleotidaserna i rekombinant och ren form och har ett unikt bibliotek av speciella hämmare genom samarbete med tjeckiska organkemister. För att kombinera nukleosidanalogerna med dessa 5´-nukleotidas hämmare krävs noggrann kartläggning av enzymer involverade i nukleosidanalog metabolism och deras farmakodynamik och farmakokinetik i leukemiceller. Att kombinera dessa analoger med 5´-nukleotidaser för klinisk resistens mot dessa nukleosidanaloger ger möjlighet att i framtiden optimera och eventuellt bredda behandling med nukleosidanaloger.

Rapport vid projektets avslutande

Rapport

Doktorand/student handledning
-Clara Rick, D-uppsats 2006 LiU
Methylation studies of the deoxycytidine kinase gene promoter.
-Alan Kambiz Fotoohi, Disputation 2007 KI
Pharmacological and molecular investigations on the mechanisms underlying resistance of human leukaemia cells to the antimetabolites methotrexate, 6-mercaptopurine and 6-thioguanine.
-Anna Fyrberg, Halvtid 4 juni, 2007 LiU
Pharmacogenetic Approaches to Nucleoside Analogue Therapy; Focus on metabolism and resistance mechanisms,
-Jonny Kumlin, D-uppsats 2007 LiU
Nucleoside ananlogues in solid tumors.
Abstracts
-Real-time quantitative PCR assay together with activity measurements for enzymes involved in purine analogues metabolism in previously untreated symptomatic B-cell chronic lymphocytic leukemia
K. Lotfi, A. Nilsson, K. Karlsson, G. Juliusson, C. Peterson, S. Eriksson, and F. Albertioni
American Association for Cancer research, 95th Annual Meeting, 2004, Orlando, Florida U.S.A.
-The expression of mRNA and enzyme activity of deoxycytidine- and deoxyguanosine kinases in cell from patients with untreated B-cell chronic lymphocytic leukemia
Kourosh Lotfi, Karin Karlsson, Gunnar Juliusson, Curt Peterson, Staffan Eriksson, and Freidoun Albertioni
The American Society of Hematology, 46th Annual Meeting, 2004,
San Diego, California, U.S.A.
-Enhanced platelet adhesion in essential thrombocythemia assessed by a novel platelet function assay
Andreas C. Eriksson, Kourosh Lotfi, Per A. Whiss
10th Congress of the European Hematology Association, Stockholm, Sweden, June 2-5, 2005.
-Evidence of cell cycle-dependent regulation of Deoxycytidine kinase and Cytosolic 5´ nucloetidase-I activity
Anna Fyrberg, Freidoun Albertioni, and Kourosh Lotfi,
European Society for the Study of Purine and Pyrimidine Metabolism in Man, Prag 8-11 June 2005.
-Influence of CYP3A4 Activity on Imatinib Response in Patients with Chronic Myeloid Leukemia.Oral presentation
Henrik Gréen, Karin Skoglund, Franz Rommel, Leif Bertilsson, and Kourosh Lotfi
11th Congress of the European Hematology Association, June 15-18, 2006, Amsterdam, The Netherlands.
-RNA interference technique in studying nucleoside analogue activity
Anna Fyrberg, Freidoun Albertioni, and Kourosh Lotfi,
American Association for Cancer research, 97th Annual Meeting, 2006, Washington, U.S.A.
-Relationship of 5´-nuclotidase and deoxynucleoside kinase activity to the clinical activity of cladribine and fludarabine
Freidoun Albertioni, Karin Karlsson, Gunnar Juliusson, and Kourosh Lotfi
American Association for Cancer research, 98th Annual Meeting, 2007, Los Angeles, U.S.A.
-RNAi silencing of deoxycytidine and deoxyguanosine kinases as a tool to study nucleoside analogue activity and resistance mechanisms in human leukemic CEM cell line. Oral presentation
Anna Fyrberg, Freidoun Albertioni, and Kourosh Lotfi,
European Society for the Study of Purine and Pyrimidine Metabolism in Man, Chicago, USA, 24-28 June 2007.

Publikationer (publicerade, in press, accepterade, manuskript)

Publicerade

Mechanisms of cross-resistance between nucleoside analogues and vincristine or daunorubicin in leukemic cells
Biochem Biophys Res Commun. 2004 Jul 30;320(3):825-32.
Lofgren C, Hjortsberg L, Blennow M, Lotfi K, Paul C, Eriksson S, Albertioni F.

Monitoring oral cyclosporine therapy. Bone Marrow Transplant. 2005 Aug;36(4):367.
Lotfi K, Peterson C, Juliusson G.

The pattern of deoxycytidine- and deoxyguanosine kinase activity in relation to messenger RNA expression in blood cells from untreated patients with B-cell chronic lymphocytic leukemia
Biochem Pharmacol. 2006 Mar 14;71(6):882-90. Epub 2006 Jan 24.
Kourosh Lotfi, Karin Karlsson, Anna Fyrberg, Gunnar Juliusson, Viggo Jonsson, Curt Peterson, Staffan Eriksson, Freidoun Albertioni.

Cell cycle dependent regulation of deoxycytidine kinase, deoxyguanosine kinase, and cytosolic 5'-nucleotidase I activity in MOLT-4 cells.
Nucleosides Nucleotides Nucleic Acids. 2006;25(9-11):1201-4.
Fyrberg A, Mirzaee S, Lotfi K.

Cell cycle effect on the activity of deoxynucleoside analogue metabolising enzymes
Biochem Biophys Res Commun 357 (2007) 847–853
Anna Fyrberg, Freidoun Albertioni, and Kourosh Lotfi

Accepterade

RNAi depletion of deoxycytidine and deoxyguanosine kinase in human leukemic CEM cells
Nucleosides Nucleotides Nucleic Acids (2007)
Anna Fyrberg, Freidoun Albertioni , Kourosh Lotfi

Submitterade
Influence of CYP3A4 Activity on Imatinib Response in Patients with Chronic Myeloid Leukemia, Blood
Henrik Gréen, Karin Skoglund, Franz Rommel, Leif Bertilsson, and Kourosh Lotfi

Manuskript
Platelet density variation in Essential thrombocytemia
M. Milovanovic, K. Lotfi, T.L Lindahl, C. Hallert and P. Järemo

Platelet activation in patients with essential thrombocythemia and polycythemia vera
Andreas C. Eriksson, Per A. Whiss, and Kourosh Lotfi

Methylation studies of the deoxycytidine kinase gene promoter
Clara Rick, Anna Fyrberg, and Kourosh Lotfi

Nucleoside ananlogues in solid tumors
Anna Fyrberg, Jonny Kumlin, and Kourosh Lotfi

Decision

Decision date: 2005-12-21

Brief description of each costApplied sumDecision SEKDecision comment
Lönekostnad
31800x1.54x6x2587 664587 664 
sum587 664587 664 

Pharmacogenetic influences on treatment response to nucleoside analogues
- Efforts in the individualization of therapy in hematological malignancies | Application, from Region Östergötland
http://researchweb.org/is/en/lio/ansokan/4910