PMID- 7647961
OWN - NLM
STAT- MEDLINE
DCOM- 19950928
LR  - 20191031
IS  - 1067-5582 (Print)
IS  - 1067-5582 (Linking)
VI  - 17
IP  - 2
DP  - 1995 Feb
TI  - Enhancement of immunostimulatory activity by dual substitution of C8-substituted 
      guanine ribonucleosides: correlation with increased cytokine secretion.
PG  - 98-108
AB  - Guanine ribonucleosides with single substitutions at the C8 position 
      (monosubstituted) or with dual substitutions at the C8 and N7 positions 
      (disubstituted) up-regulate a spectrum of immunologic responses, including 
      cytolytic responses to tumor cells. The current studies were undertaken to 
      determine the effects of dual substitution on a number of nucleoside-inducible 
      immunological parameters. To do so, two monosubstituted analogues, 
      8-bromoguanosine and 8-mercaptoguanosine, were directly compared with two 
      disubstituted analogues, 7-methyl-8-oxoguanosine and 7-allyl-8-oxoguanosine 
      (loxoribine). All of the compounds enhance natural killer (NK) activity, 
      lymphocyte proliferation, and antibody production in dose-dependent fashion. 
      However, the potency and maximal activity of the disubstituted analogues are 
      considerably greater than those of the monosubstituted analogues. Spleen cells 
      stimulated for 48 h with the disubstituted compounds produce immunoreactive 
      interleukin (IL) 1 alpha, IL-6, tumor necrosis factor-alpha (TNF alpha), and 
      interferon-gamma (IFN gamma). Monosubstituted analogues induce lower quantities 
      of IL-6, TNF alpha, and IFN gamma and fail to induce detectable levels of IL-1 
      alpha. Total IFN activity, assessed by viral inhibition assay, is also lower for 
      the monosubstituted analogues. Augmentation of antibody secretion by B cells is 
      diminished for neither mono- nor disubstituted compounds upon incubation with 
      anti-cytokine antibodies. In contrast, anti-IFN alpha beta markedly reduces the 
      effects of monosubstituted analogues on NK activity but has less marked effects 
      on NK induction by the disubstituted compounds. A similar pattern of differences 
      is seen for lymphocyte proliferation. Thus, although the analogues induce 
      synthesis of several cytokines, to date only IFN alpha beta appears directly 
      involved in enhancement of NK activity and lymphocyte proliferation. The present 
      data do not, however, exclude the existence of an autocrine stimulatory mechanism 
      not susceptible to inhibition by anti-cytokine antibodies.
FAU - Pope, B L
AU  - Pope BL
AD  - R. W. Johnson Pharmaceutical Research Institute, Don Mills, Ontario, Canada.
FAU - Chourmouzis, E
AU  - Chourmouzis E
FAU - Lee, S
AU  - Lee S
FAU - Goodman, M G
AU  - Goodman MG
LA  - eng
GR  - AI15284/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Immunother Emphasis Tumor Immunol
JT  - Journal of immunotherapy with emphasis on tumor immunology : official journal of 
      the Society for Biological Therapy
JID - 9418950
RN  - 0 (Adjuvants, Immunologic)
RN  - 0 (Cytokines)
RN  - 0 (Immunoglobulins)
RN  - 0 (Interferon Type I)
RN  - 12133JR80S (Guanosine)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Adjuvants, Immunologic/physiology
MH  - Animals
MH  - Cytokines/*biosynthesis
MH  - Cytotoxicity Tests, Immunologic/methods
MH  - Enzyme-Linked Immunosorbent Assay/methods
MH  - Guanosine/*analogs & derivatives/*immunology
MH  - Immunity, Cellular/physiology
MH  - Immunoglobulins/biosynthesis
MH  - Immunologic Techniques/standards
MH  - Interferon Type I/biosynthesis
MH  - Interferon-gamma/analysis
MH  - Killer Cells, Natural/immunology
MH  - Lymphocyte Activation/immunology
MH  - Male
MH  - Mice
MH  - Mice, Inbred CBA
MH  - Neutralization Tests/methods
MH  - Tumor Cells, Cultured
MH  - Vesicular stomatitis Indiana virus/immunology
EDAT- 1995/02/01 00:00
MHDA- 1995/02/01 00:01
CRDT- 1995/02/01 00:00
PHST- 1995/02/01 00:00 [pubmed]
PHST- 1995/02/01 00:01 [medline]
PHST- 1995/02/01 00:00 [entrez]
AID - 10.1097/00002371-199502000-00004 [doi]
PST - ppublish
SO  - J Immunother Emphasis Tumor Immunol. 1995 Feb;17(2):98-108. doi: 
      10.1097/00002371-199502000-00004.