PMID- 15188002
OWN - NLM
STAT- MEDLINE
DCOM- 20040806
LR  - 20220309
IS  - 0007-0920 (Print)
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Linking)
VI  - 91
IP  - 1
DP  - 2004 Jul 5
TI  - Activation of protein kinase A (PKA) by 8-Cl-cAMP as a novel approach for 
      antileukaemic therapy.
PG  - 186-92
AB  - Activation of PKA by cAMP agonists, such as 8-Cl-cAMP activation, selectively 
      causes rapid apoptosis in v-abl transformed fibroblasts by inhibiting the Raf-1 
      kinase. Here we investigated whether 8-Cl-cAMP is useful for the treatment of 
      chronic myelogenous leukaemia (CML), which is hallmarked by the expression of the 
      p210(bcr/abl) oncogene. Autologous bone marrow transplantation is a feasible 
      alternative for patients with no suitable donor, but hampered by the risk of 
      relapse due to the persistence of leukaemia cells in the transplant. To study the 
      effects of 8-Cl-cAMP on primary leukaemic cells, bone marrow cells (BMCs) from 
      eight CML patients (one at diagnosis, three in chronic and four in accelerated 
      phase) were treated. Ex vivo treatment of BMCs obtained in chronic phase of CML 
      with 100 microM 8-Cl-cAMP for 24-48 h led to the selective purging of 
      Philadelphia Chromosome (Ph1 chromosome) without toxic side effects on BMCs from 
      healthy donors as measured by colony-forming unit (CFU) assays. BMCs from 
      patients in accelerated phase showed selective, but incomplete elimination of Ph1 
      chromosome positive colony forming cells. The mechanism of 8-Cl-cAMP was 
      investigated in FDCP-mix cells transformed by p210(bcr/abl), a cell culture model 
      for CML. The results showed that 8-Cl-cAMP reduced DNA synthesis and viability 
      independent of Raf inhibition as Raf inhibitors had no effect. MEK inhibitors 
      interfered with DNA synthesis, but not with viability. In summary, our results 
      indicate that 8-Cl-cAMP could be useful to purge malignant cells from the bone 
      marrow of patients with CML and certain other forms of leukaemias.
FAU - Weissinger, E M
AU  - Weissinger EM
AD  - Medizinische Hochschule Hannover (MHH), Department of Hematology and Oncology, 
      Hannover, Germany.
FAU - Oettrich, K
AU  - Oettrich K
FAU - Evans, C
AU  - Evans C
FAU - Genieser, H-G
AU  - Genieser HG
FAU - Schwede, F
AU  - Schwede F
FAU - Dangers, M
AU  - Dangers M
FAU - Dammann, E
AU  - Dammann E
FAU - Kolb, H-J
AU  - Kolb HJ
FAU - Mischak, H
AU  - Mischak H
FAU - Ganser, A
AU  - Ganser A
FAU - Kolch, W
AU  - Kolch W
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - 0 (Antineoplastic Agents)
RN  - 23583-48-4 (8-Bromo Cyclic Adenosine Monophosphate)
RN  - 9007-49-2 (DNA)
RN  - BQ94Z7E5OR (8-chloro-cyclic adenosine monophosphate)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
SB  - IM
MH  - 8-Bromo Cyclic Adenosine Monophosphate/*analogs & derivatives/*pharmacology
MH  - Antineoplastic Agents/*pharmacology
MH  - Bone Marrow Cells/*physiology
MH  - Bone Marrow Purging/*methods
MH  - *Bone Marrow Transplantation
MH  - Cyclic AMP-Dependent Protein Kinases/*pharmacology
MH  - DNA/biosynthesis
MH  - Humans
MH  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug therapy/pathology
MH  - Transplantation, Autologous
MH  - Tumor Cells, Cultured
MH  - Tumor Stem Cell Assay
PMC - PMC2364761
EDAT- 2004/06/10 05:00
MHDA- 2004/08/07 05:00
PMCR- 2005/06/08
CRDT- 2004/06/10 05:00
PHST- 2004/06/10 05:00 [pubmed]
PHST- 2004/08/07 05:00 [medline]
PHST- 2004/06/10 05:00 [entrez]
PHST- 2005/06/08 00:00 [pmc-release]
AID - 6601909 [pii]
AID - 10.1038/sj.bjc.6601909 [doi]
PST - ppublish
SO  - Br J Cancer. 2004 Jul 5;91(1):186-92. doi: 10.1038/sj.bjc.6601909.