title: Activation of protein kinase A (PKA) by 8-Cl-cAMP as a novel approach for antileukaemic therapy.
abstract: 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.
authors.affiliation: Medizinische Hochschule Hannover (MHH), Department of Hematology and Oncology, Hannover, Germany.
authors.forename: E M
authors.initials: EM
authors.lastname: Weissinger
authors.forename: K
authors.initials: K
authors.lastname: Oettrich
authors.forename: C
authors.initials: C
authors.lastname: Evans
authors.forename: H-G
authors.initials: HG
authors.lastname: Genieser
authors.forename: F
authors.initials: F
authors.lastname: Schwede
authors.forename: M
authors.initials: M
authors.lastname: Dangers
authors.forename: E
authors.initials: E
authors.lastname: Dammann
authors.forename: H-J
authors.initials: HJ
authors.lastname: Kolb
authors.forename: H
authors.initials: H
authors.lastname: Mischak
authors.forename: A
authors.initials: A
authors.lastname: Ganser
authors.forename: W
authors.initials: W
authors.lastname: Kolch
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000502:physiology*; D016465:Bone Marrow Purging / Q000379:methods*; D016026:Bone Marrow Transplantation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D014182:Transplantation, Autologous; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
chemical_list: D000970:Antineoplastic Agents; D015124:8-Bromo Cyclic Adenosine Monophosphate; D004247:DNA; C044258:8-chloro-cyclic adenosine monophosphate; D017868:Cyclic AMP-Dependent Protein Kinases