2′-Fluoro-2′,3′-dideoxyarabinosyladenine (F-ddA), an anti-human immunodeficiency virus (HIV) drug currently in clinical trial, was compared with zidovudine (AZT), ddl and ddC for anti-HIV activity and potency in HIV-1 strains both sensitive and resistant to zidovudine, ddl and non-nucleoside reverse transcriptase inhibitors. A variety of host cell systems [MT-2, MT-4, phytohaemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC)] was used. F-ddA was effective against each of the drug-resistant isolates, including the strain resistant to ddl, the other purine dideoxynucleoside evaluated in this study. The anti-HIV-1 activities of F-ddA and zidovudine were also determined against clades A-E in PHA-PBMCs. Although activities were similar, zidovudine was significantly more potent than F-ddA in the PHA-PBMC system.
BoyleMJFlaniganMEFordHBaselerMAdelsbergerJDaveyRT & LaneHC (1995) The Hu-HIV/PBL-SCID mouse: a modified Hu-PBL-SCID model for the study of HIV pathogenesis and therapy. Journal of Immunology154: 6212–6223.
2.
D'AquilaRT (1994) HIV-1 drug resistance. Clinics in Laboratory Medicine14: 393–422.
3.
De ClercqE (1992) HIV inhibitors targeted at the reverse transcriptase. AIDS Research and Human Retroviruses8: 119–133.
4.
De ClercqE (1994) HIV resistance to reverse transcriptase inhibitors. Biochemical Pharmacology47: 155–169.
5.
De ClercqE (1995) Antiviral therapy for human immunodeficiency virus infections. Clinical Microbiology Reviews8: 200–239.
6.
DriscollJSSiddiquiMAFordHKelleyJARothJSMitsuyaHTanakaM & MarquezVE (1996) Lipophilic, acidstable, adenosine deaminase-activated anti-HIV prodrugs for central nervous system delivery. 3. 6-Amino prodrugs of 2′-β-fluoro-2′,3′-dideoxyinosine. Journal of Medicinal Chemistry39: 1619–1625.
7.
EriceA & BalfourHH (1994) Resistance of human immunodeficiency virus type 1 to antiretroviral agents: a review. Clinical Infectious Diseases18: 149–156.
8.
GaoW-YShirasakaTJohnsDGBroderS & MitsuyaH (1993) Differential phosphorylation of azidothymidine, dideoxycytidine, and dideoxyinosine in resting and activated peripheral blood mononuclear cells. Journal of Clinical Investigation91: 2326–2333.
9.
GaoW-YAgbariaRDriscollJS & MitsuyaH (1994) Divergent anti-human immunodeficiency virus activity and anabolic phosphorylation of 2′,3′-dideoxynucleoside analogs in resting and activated human cells. Journal of Biological Chemistry269: 12633–12638.
10.
HallidaySHLackman-SmithCDeckerWDBaderJPRiceWClantonDJ & BuckheitRW (1996) Inhibition of HIV replication by the sulfonated dye, resobene. Antiviral Research (in press).
11.
HitchcockMJMWoodsKDe BoeckK & HoH-T (1990) Biochemical pharmacology of 2′-fluoro-2′,3′-dideoxyarabinosyladenine, an inhibitor of HIV with improved metabolic and chemical stability over 2′,3′-dideoxyadenosine. Antiviral Chemistry and Chemotherapy1: 319–327.
12.
JapourAJMayersDLJohnsonVAKuritzkesDRBeckettLAArduinoJ-MLaneJBlackRAReichelderferPFD'AquilaRT & CrumpackerCS (1993) Standardized peripheral blood mononuclear cell culture assay for determination of drug susceptibilities of clinical human immunodeficiency virus type 1 isolates. Antimicrobial Agents and Chemotherapy37: 1095–1101.
13.
KilbyJM & SaagMS (1994) Is there a role for non-nucleoside reverse transcriptase inhibitors in the treatment of HIV infection?Infectious Agents and Disease3: 313–323.
14.
LarderBADarbyG & RichmanDD (1989) HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science243: 1731–1734.
15.
LarderBAChesebroB & RichmanDD (1990) Susceptibilities of zidovudine-susceptible and -resistant human immunodeficiency virus isolates to antiviral agents determined by using a quantitative plaque reduction assay. Antimicrobial Agents and Chemotherapy34: 436–441.
16.
MarquezVETsengCK-HKelleyJAMitsuyaHBroderSRothJS & DriscollJS (1987) 2′,3′-Dideoxy-2′-fluoro-ara-A. An acidstable purine nucleoside active against human immunodeficiency virus (HIV). Biochemical Pharmacology36: 2719–2722.
17.
MarquezVETsengCK-HMitsuyaHAokiSKelleyJAFordHRothJSBroderSJohnsDG & DriscollJS (1990) Acidstable 2′-fluoro purine dideoxynucleosides as active agents against HIV. Journal of Medicinal Chemistry33: 978–985.
18.
MasoodRAhluwaliaGSCooneyDAFridlandAMarquezVEDriscollJSHaoZMitsuyaHPernoC-FBroderS & JohnsDG (1990) 2′-Fluoro-2′,3′-dideoxyarabinosyladenine: a metabolically stable analogue of the antiretroviral agent 2′,3′-dideoxyadenosine. Molecular Pharmacology37: 590–596.
19.
MayersDL (1996) Resistance and cross-resistance to nucleoside reverse transcriptase inhibitors. HIV: Advances in Research and Therapy6: 15–21.
20.
MayersDLJapourAJArduinoJ-MHammerSMRcichmanRWagnerKFChungRLaneJRobertsCRWinslowDBurkeD & the RV43 Study Group (1994) Dideoxynucleoside resistance emerges with prolonged zidovudine monotherapy. Antimicrobial Agents and Chemotherapy38: 307–314.
21.
MellorsJWLarderBA & SchinaziRR (1995) Mutations in HIV-1 reverse transcriptase and protease associated with drug resistance. International Antiviral News3: 8–13.
22.
MooreJPCaoYLeuJQinLKorberB & HoDD (1996) Interand intraclade neutralization of human immunodeficiency virus type 1: genetic clades do not correspond to neutralization serotypes but partially correspond to gp 120 antigenic serotypes. Journal of Virology70: 427–444.
23.
OttoMJGarberSWinslowDLReidCDAldrichPJadhavPKPattersonCEHodgeCN & ChengY-SE (1993) In vitro isolation and identification of human immunodeficiency virus (HIV) variants with reduced sensitivity to C-2 symmetrical inhibitors of HIV type 1 protease. Proceedings of the National Academy of Sciences, USA90: 7543–7547.
24.
RichmanDD (1993) Resistance of clinical isolates of human immunodeficiency virus to antiretroviral agents. Antimicrobial Agents and Chemotherapy37: 1207–1213.
25.
RichmanDD (1994) Resistance, drug failure, and disease progression. AIDS Research and Human Retroviruses10: 901–905.
26.
RuxrungthamKBooneEFordHDriscollJSDaveyRT & LaneHC (1996) Potent activity of 2′-β-fluoro-2′,3′-dideoxyadenosine against human immunodeficiency virus type 1 infection in hu-PBL-SCID mice. Antimicrobial Agents and Chemotherapy40: 2369–2374.
27.
SmithMSalomonH & WainbergMA (1994) Development and significance of nucleoside drug resistance in infection caused by the human immunodeficiency virus type 1. Clinical and Investigative Medicine17: 226–243.
28.
WeislowOSKiserRFineDLBaderJShoemakerRH & BoydMR (1990) New soluble-formazan assay for HIV-1 cytopathic effects: application to high-flux screening of synthetic and natural products for AIDS-antiviral activity. Journal of the National Cancer Institute81: 577–586.
