Combination effects of alkylphosphocholines and gemcitabine in malignant and normal hematopoietic cells.
Cytosine arabinoside (ara-C) and 2',2'-difluorodeoxycytidine (Gem) were compared in leukemia cells, with Gem being more potent than ara-C. Gem was combined with hexadecylphosphocholine (HPC) or erucylphospho-N,N,N-trimethylpropanolamine (ErPC(3)) in resistant CML cells. Supra-additive effects were seen in K-562 cells after concomitant and sequential exposure of Gem followed by HPC. The reverse sequence resulted in antagonism. Both effects were more significant when HPC was exchanged for ErPC(3). Gem or HPC failed to induce DNA laddering in K-562 cells, but apoptotic signals were transferred by the Gem-exposed SKW-3 cytosolic fraction to K-562 nuclei. HPC did not increase the clastogenicity of Gem and counteracted its mitotic inhibition in murine bone marrow. Thus, the combination of Gem and an alkylphosphocholine is advantageous in terms of their complementary mode of action, resulting in increased cytotoxicity and lowered myelotoxicity.
Georgieva
Milka C
MC
Unit of Toxicology and Chemotherapy, German Cancer Research Center, 280 Im Neuenheimer Feld, 69120, Heidelberg, Germany.
Konstantinov
Spiro M
SM
Topashka-Ancheva
Margarita
M
Berger
Martin R
MR
D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D002474:Cell-Free System; D003561:Cytarabine / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018922:HL-60 Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D010767:Phosphorylcholine / Q000633:toxicity*; D012016:Reference Values; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D003841:Deoxycytidine; D010767:Phosphorylcholine; D000093542:Gemcitabine