Sensitivity of CFU-GM from normal human bone marrow and leukaemic clonogenic cells (CFU-L) from blood of patients with myelogenous leukaemia to 3?-deoxy-3?-fluorothymidine in comparison to 3?-azido-3?-deoxythymidine

Abstract

3'-Deoxy-3'-fluorothymidine (FT), a thymidine analogue highly effective against HIV 1 in vitro was investigated as to its in vitro effect on normal human bone marrow CFU-GM (agar colony assay) and on human peripheral myeloid leukaemic clonogenic cells (CFU-L, colony assay in methylcellulose). For comparison, 3'-azido-3'-deoxythymidine (AZT), structurally related and used in AIDS treatment, was included in the study. Both compounds inhibit the formation of clusters and colonies from bone marrow stem cells with an [IC]50 between 10(-6) and 10(-5)M. In concentrations only 5-10 times lower than the [IC]50, FT begins to stimulate cluster and colony formation. AZT and FT also inhibit the formation of clusters and colonies from CFU-L. Compared to CFU-GM, CFU-L were more sensitive to FT, and a stimulation was not seen. It is concluded that similar side effects on bone marrow could be expected for possible use of FT against AIDS as have been found for AZT and that both compounds are potential candidates for anti-leukaemic drugs.

Anti-human immunodeficiency virus synergism by zidovudine (3'-azidothymidine) and didanosine (dideoxyinosine) contrasts with their additive inhibition of normal human marrow progenitor cells

“…Although the molecular mechanism responsible for the synergistic inhibition of HIV by the combination of AZT and ddl is not clear, the data indicate that the occurrence of synergy is independent of cell type. Also, synergy appears not to be the result of increased groups (1,5,7,10,19,28,29,34,42,43) for both HIV infection and antiviral drugs. The effects of combined AZT and ddI on dose-limiting toxicities have not been previously reported.…”

“…These adverse effects are most frequently noted at higher doses and in those patients with more-advanced disease (12, 14, 18, 32, 35, 45-47, 52, 57). AZT inhibits hemopoietic progenitor cells in vitro from both normal and HIV-infected marrow donors (7,10,19,28,29,42). The mechanism of AZT marrow toxicity has yet to be elucidated and is the subject of current investigation (1,5,34,43,55).…”

[ 18 F] 3-deoxy-3′-fluorothymidine positron emission tomography: alternative or diagnostic adjunct to 2-[ 18 f]-fluoro-2-deoxy- d -glucose positron emission tomography in the workup of suspicious central focal lesions?

“…FLT was first evaluated as a chemotherapeutic agent for the treatment of leukemia. 26 Researchers soon discovered its exceptional anti-HIV activity. 27 Toxicity observed during phase II clinical trials with FLT deterred investigation of the drug administered at pharmacologic doses.…”

In vitro effects of perifosine, bortezomib and lenalidomide against hematopoietic progenitor cells from healthy donors

“…Colony-forming unit assays CFU assays were performed as previously reported [25,26]. Briefly, HPC were adjusted to a concentration of 1×10 5 /mL (without previous CD34 + selection) or 1×10 3 /mL cells (after CD34 + selection) using a commercially available cell medium (MethoCult®, Stem Cell Technologies Inc.; previously Terry Fox, Vancouver, BC, Canada).…”