didanosine and Lymphoma--Large-B-Cell--Diffuse

Topics: Acquired Immunodeficiency Syndrome; Adult; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Bleomycin; CD4 Lymphocyte Count; Cyclophosphamide; Didanosine; Doxorubicin; Etoposide; Humans; Lymphoma, AIDS-Related; Lymphoma, Large B-Cell, Diffuse; Prednisone; Prognosis; Reverse Transcriptase Inhibitors; T-Lymphocyte Subsets; Treatment Outcome; Vincristine

The dideoxynucleoside analogue 2',3'-dideoxyinosine (ddI) has been used in the clinic as an alternative drug to zidovudine (AZT) in the treatment of patients with the acquired immunodeficiency syndrome (AIDS). However, it shows significant and variable toxicity in patients. It is known that various dideoxynucleoside analogues can cause the termination of the DNA chain following incorporation of the corresponding triphosphate metabolite by the polymerases. In the case of ddI, the presumed active metabolite is 2',3'-dideoxyadenosine 5'-triphosphate (ddATP). In order to understand the molecular basis for the toxicity of ddI, we evaluated the relationship between the intracellular formation of ddATP, its incorporation into cellular DNA and the effects on the growth of U937 cells, a human monocytoid cell line. Dideoxyinosine was not significantly toxic to U937 cells at concentrations as high as 500 microM in a 72 hrs. growth inhibition assay. The results of the uptake of 3HddI in this cell line showed a proportional increase in total metabolites with increasing concentrations of the drug (1-20 microM) after a 24 hrs. exposure. Incubation with 10 microM 3HddI resulted in the formation of low levels of ddATP within a period of 2 hrs. A significant amount of ddI-derived radioactivity was found in both DNA and RNA after exposure to 10 microM 3HddI for 24 to 72 hrs. However, no evidence of incorporation of ddATP into the cellular DNA fraction was obtained in these experimental conditions. Therefore, the lack of significant toxicity of ddI to U937 cells can be explained, at least in part, by its inability to incorporate ddATP into its cellular DNA at the doses studied.

Topics: Biological Transport; Biotransformation; Cell Division; Deoxyadenine Nucleotides; Didanosine; Dideoxynucleotides; DNA Damage; DNA Replication; DNA, Neoplasm; Humans; Lymphoma, Large B-Cell, Diffuse; Monocytes; RNA, Neoplasm; Tumor Cells, Cultured; Zidovudine

To evaluate the effect of liposome encapsulation on the in vitro antiviral efficacy, intracellular uptake and in vivo pharmacokinetics of 2',3'-dideoxyinosine (ddl).. The accumulation of free and liposome-encapsulated ddl was determined in murine monocyte-macrophage RAW 264.7 cells and human premonocytoid U937 cells. The antiviral efficacy was evaluated in U937 cells infected with HIVIIIB. Tissue distribution and pharmacokinetics of free and liposomal ddl were determined in female Sprague-Dawley rats following the administration of a single intravenous bolus dose (3 mg ddl/kg).. The entrapment of ddl in liposomes results in a lower drug accumulation in both U937 and RAW 264.7 cells. A lower antiviral efficacy against HIVIIIB replication in U937 cells was observed on encapsulation of ddl in liposomes. Improved pharmacokinetics were observed on entrapment of ddl in liposomes. Higher drug levels were found in plasma for the liposomal formulation. The systemic clearance of the liposomal drug was 120 times lower than that of free drug. Liposome encapsulation of ddl greatly enhanced the drug accumulation in organs of the reticuloendothelial system.. The encapsulation of ddl in liposomes modified the tissue distribution and plasma pharmacokinetics of the antiviral agent resulting in a marked improvement of drug biodisponibility. The antiviral efficacy of liposomal ddl was lower than that of free drug in HIVIIIB-infected U937 cells.

Topics: 1,2-Dipalmitoylphosphatidylcholine; Analysis of Variance; Animals; Biological Transport; Cell Line; Cell Survival; Didanosine; Drug Carriers; Enzyme-Linked Immunosorbent Assay; Female; HIV; HIV Core Protein p24; Humans; Kinetics; Liposomes; Lymphoma, Large B-Cell, Diffuse; Macrophages; Male; Mice; Monocytes; Phosphatidylcholines; Phosphatidylglycerols; Rats; Rats, Sprague-Dawley; Time Factors