Inhibition of murine retrovirus-induced immunodeficiency disease by dideoxycytidine and dideoxycytidine 5'-triphosphate.
The antiretroviral activity of many nucleoside analogues depends not only on their ability to inhibit the virus reverse transcriptase but also on the specific cellular pools of natural deoxynucleosides and on the level of the enzymes responsible for their phosphorylation. In an attempt to overcome these limitations, we have tested the efficacy of the oral administration of 2',3'-dideoxycytidine (DDC) and the administration of its phosphorylated derivative, 2',3'-dideoxycytidine 5'-triphosphate (DDCTP) encapsulated into autologous red blood cells in a murine retrovirus-induced immunodeficiency model of AIDS (MAIDS). The results obtained showed that both single treatments are quite effective in preventing the typical signs of MAIDS. Combined treatment with both oral DDC and encapsulated DDCTP yields an additive response in some, but not all the parameters investigated. Furthermore, animals receiving the simultaneous administration of DDC and DDCTP show a reduction of animal body weight, a persistent high concentration of IgM, and a high titer of anti-LP-BM5 gag immunoglobulins. Thus, the administration of the same drug in different molecular forms and/or with different delivery systems should be carefully evaluated in preclinical animal models because of the unpredictability of the effects of these treatments from the conclusion drawn by studies on single treatment.
Rossi
L
L
Istituto di Chimica Biologica G. Fornaini, University of Urbino, Italy.
Brandi
G
G
Fraternale
A
A
Schiavano
G F
GF
Chiarantini
L
L
Magnani
M
M
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D003845:Deoxycytosine Nucleotides / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D054306:Dideoxynucleotides; D004195:Disease Models, Animal; D004337:Drug Carriers; D004912:Erythrocytes; D005260:Female; D015683:Gene Products, gag / Q000276:immunology / Q000302:isolation & purification; D015151:Immunoblotting; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007150:Immunohistochemistry; D007773:Lactates / Q000097:blood; D008198:Lymph Nodes / Q000187:drug effects; D008214:Lymphocytes / Q000382:microbiology; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016183:Murine Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D012190:Retroviridae / Q000276:immunology / Q000302:isolation & purification; D013154:Spleen / Q000187:drug effects; D016047:Zalcitabine / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity
D000998:Antiviral Agents; D003845:Deoxycytosine Nucleotides; D054306:Dideoxynucleotides; D004337:Drug Carriers; D015683:Gene Products, gag; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007773:Lactates; C037406:2',3'-dideoxycytidine 5'-triphosphate; D016047:Zalcitabine