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Intracellular activation and cytotoxicity of three different combinations of 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine. 1995

S Palmer, and S Cox
Virology Department, Swedish Institute for Infectious Disease Control, Karolinska Institute, Stockholm, Sweden.

We measured the intracellular activation and cytotoxicity of 3'-azido-3'-deoxythymidine (zidovudine, ZDV) and 2',3'-dideoxyinosine (ddI) when combined at three different clinically relevant combinations of 1:1, 1:10, and 10:1 (ZDV:ddI). The activation of ddI to ddA-TP was increased in all three combinations with ZDV, compared to ddI alone. A maximum twofold increase in ddA-TP was observed, which could not be further increased by raising the concentration of ZDV in the combination. On the other hand, the concentration of ZDV in the combination could be reduced to one-tenth while retaining increased activation of ddI. We also examined the cytotoxicity of these combinations in CEM cells, phytohemagglutinin (PHA)-stimulated and resting human peripheral blood mononuclear cells (PBMCs). CEM cells were the least sensitive overall to the drugs. ZDV showed greater cytotoxicity in stimulated PBMCs than resting PBMCs, whereas the reverse was true for ddI. This could be explained by the different activation pathways of these two drugs. The 1:1 and 10:1 ZDV:ddI combinations showed reduced toxicity compared to the separate drugs. These results indicate that ZDV and ddI need not necessarily be combined together at a ratio of ZDV:ddI of 1:1, but that some alteration in the dosages of ZDV or ddI in patients could be possible without loss of the benefits of combined ZDV:ddI therapy.

UI MeSH Term Description Entries
D002455 Cell Division The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION. M Phase,Cell Division Phase,Cell Divisions,Division Phase, Cell,Division, Cell,Divisions, Cell,M Phases,Phase, Cell Division,Phase, M,Phases, M
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D004347 Drug Interactions The action of a drug that may affect the activity, metabolism, or toxicity of another drug. Drug Interaction,Interaction, Drug,Interactions, Drug
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000998 Antiviral Agents Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. Antiviral,Antiviral Agent,Antiviral Drug,Antivirals,Antiviral Drugs,Agent, Antiviral,Agents, Antiviral,Drug, Antiviral,Drugs, Antiviral
D013942 Thymine Nucleotides Phosphate esters of THYMIDINE in N-glycosidic linkage with ribose or deoxyribose, as occurs in nucleic acids. (From Dorland, 28th ed, p1154) Thymidine Phosphates,Nucleotides, Thymine,Phosphates, Thymidine
D015215 Zidovudine A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by an azido group. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA during reverse transcription. It improves immunologic function, partially reverses the HIV-induced neurological dysfunction, and improves certain other clinical abnormalities associated with AIDS. Its principal toxic effect is dose-dependent suppression of bone marrow, resulting in anemia and leukopenia. AZT (Antiviral),Azidothymidine,3'-Azido-2',3'-Dideoxythymidine,3'-Azido-3'-deoxythymidine,AZT Antiviral,AZT, Antiviral,BW A509U,BWA-509U,Retrovir,3' Azido 2',3' Dideoxythymidine,3' Azido 3' deoxythymidine,Antiviral AZT,BWA 509U,BWA509U
D016049 Didanosine A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by a hydrogen. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. Didanosine is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA by binding to reverse transcriptase; ddI is then metabolized to dideoxyadenosine triphosphate, its putative active metabolite. 2',3'-Dideoxyinosine,Dideoxyinosine,ddI (Antiviral),NSC-612049,Videx,2',3' Dideoxyinosine,NSC 612049,NSC612049
D054306 Dideoxynucleotides The phosphate esters of DIDEOXYNUCLEOSIDES. Dideoxynucleotide Triphosphates,ddNTPs,Triphosphates, Dideoxynucleotide
D018894 Reverse Transcriptase Inhibitors Inhibitors of reverse transcriptase (RNA-DIRECTED DNA POLYMERASE), an enzyme that synthesizes DNA on an RNA template. Reverse Transcriptase Inhibitor,Inhibitors, Reverse Transcriptase,Inhibitor, Reverse Transcriptase,Transcriptase Inhibitor, Reverse

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