EARLY THERAPY OF FELINE LEUKEMIA-VIRUS INFECTION (FELV-FAIDS) WITH 9-(2-PHOSPHONYLMETHOXYETHYL)ADENINE (PMEA)

被引:19
作者
HOOVER, EA [1 ]
EBNER, JP [1 ]
ZEIDNER, NS [1 ]
MULLINS, JI [1 ]
机构
[1] STANFORD UNIV,MED CTR,DEPT MICROBIOL & IMMUNOL,STANFORD,CA 94305
关键词
D O I
10.1016/0166-3542(91)90060-5
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Cats infected with molecularly cloned FeLV-FAIDS develop an immunodeficiency syndrome characterized by persistent antigenemia, decline in circulating CD4+ T lymphocytes, and impaired T-cell-dependent immune responses and opportunistic infection. We evaluated the capacity of PMEA to inhibit the replication of FeLV-FAIDS in vitro and to inhibit the progression of FeLV-FAIDS infection in vivo. We found that PMEA inhibited replication of FeLV-FAIDS by greater-than-or-equal-to 50% at concentrations of greater-than-or-equal-to 0.5-mu-g/ml (1.63-mu-M) in feline fibroblasts and prevented T lymphocyte killing at concentrations of 3-mu-g/ml. PMEA administered to cats at dosages of greater-than-or-equal-to 6.25 mg/kg/day from 0 to 49 days after FeLV-FAIDS infection prevented the development of persistent antigenemia and the induction of immunodeficiency disease. In contrast to placebo treated controls, cats successfully treated with PMEA contained viral infection, developed neutralizing antibody, and resisted a second virulent virus challenge without further therapy. Manifestations of PMEA toxicity produced by higher dosages (25 or 12.5 mg/kg/day) were anemia, leukopenia, and diarrhea. These results indicate PMEA to be a potent antiretroviral agent effective in aborting fatal progression of FeLV-FAIDS infection when therapy is initiated at the time of virus exposure.
引用
收藏
页码:77 / 92
页数:16
相关论文
共 38 条
[1]  
ANDERSON LJ, 1971, J NATL CANCER I, V47, P807
[2]   MARKED INVIVO ANTIRETROVIRUS ACTIVITY OF 9-(2-PHOSPHONYLMETHOXY-ETHYL)ADENINE, A SELECTIVE ANTI-HUMAN IMMUNODEFICIENCY VIRUS AGENT [J].
BALZARINI, J ;
NAESENS, L ;
HERDEWIJN, P ;
ROSENBERG, I ;
HOLY, A ;
PAUWELS, R ;
BABA, M ;
JOHNS, DG ;
DECLERCQ, E .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (01) :332-336
[3]   ANTIRETROVIRUS ACTIVITY OF 9-(2-PHOSPHONYLMETHOXYETHYL)ADENINE (PMEA) INVIVO INCREASES WHEN IT IS LESS FREQUENTLY ADMINISTERED [J].
BALZARINI, J ;
NAESENS, L ;
DECLERCQ, E .
INTERNATIONAL JOURNAL OF CANCER, 1990, 46 (02) :337-340
[4]   INHIBITORY EFFECTS OF 9-(2-PHOSPHONYLMETHOXYETHYL)ADENINE AND 3'-AZIDO-2',3'-DIDEOXYTHYMIDINE ON TUMOR-DEVELOPMENT IN MICE INOCULATED INTRACEREBRALLY WITH MOLONEY MURINE SARCOMA-VIRUS [J].
BALZARINI, J ;
SOBIS, H ;
NAESENS, L ;
VANDEPUTTE, M ;
DECLERCQ, E .
INTERNATIONAL JOURNAL OF CANCER, 1990, 45 (03) :486-489
[5]  
BALZARINI J, 1990, ANIMAL MODELS AIDS, P131
[6]  
BRONSON JJ, 1989, NUCLEOTIDE ANALOGUES, P72
[7]   LYMPHOCYTE MITOGEN REACTIVITY AND ENUMERATION OF CIRCULATING B-CELLS AND T-CELLS DURING FELINE LEUKEMIA-VIRUS INFECTION IN CAT [J].
COCKERELL, GL ;
HOOVER, EA ;
KRAKOWKA, S ;
OLSEN, RG ;
YOHN, DS .
JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1976, 57 (05) :1095-1099
[8]  
DECLERCQ E, 1987, ANTIVIR RES, V8, P261
[9]   A NOVEL SELECTIVE BROAD-SPECTRUM ANTI-DNA VIRUS AGENT [J].
DECLERCQ, E ;
HOLY, A ;
ROSENBERG, I ;
SAKUMA, T ;
BALZARINI, J ;
MAUDGAL, PC .
NATURE, 1986, 323 (6087) :464-467
[10]   STRONG SEQUENCE CONSERVATION AMONG HORIZONTALLY TRANSMISSIBLE, MINIMALLY PATHOGENIC FELINE LEUKEMIA VIRUSES [J].
DONAHUE, PR ;
HOOVER, EA ;
BELTZ, GA ;
RIEDEL, N ;
HIRSCH, VM ;
OVERBAUGH, J ;
MULLINS, JI .
JOURNAL OF VIROLOGY, 1988, 62 (03) :722-731