Donald C. DeLong

BIOCHEMISTRY AND BIOLOGICAL EFFECTS OF THE PYRAZOFURINS* (PYRAZOMYCINS): INITIAL CLINICAL TRIAL

Pyrazofurin* (PF)’*2 is one of three biologically active C-nucleosides isolated from the broth filtrates of a strain of Streptomyces candidus. Along with PF, this culture produces lesser amounts of its C1,-a-anomer, Pyrazofurin B (PFB),3*4 and a third factor, tentatively identified as OxazinomycinS (Minimycin).6 Among these and the four other naturally occurring C-nucleosides, PF alone enjoys the distinction of possessing pharmacological activity that warrants its consideration as a clinical candidate.

Relation of arginine-lysine antagonism to herpes simplex growth in tissue culture.

In the studies conducted, arginine deficiency suppressed herpes simplex virus replication in tissue culture. Lysine, an analog of arginine, as an antimetabolite, antagonized the viral growth-promoting action of arginine. The in vitro data may be the basis for the observation that patients prone to herpetic lesions and other related viral infections, particularly during periods of stress, should abstain from arginine excess and may also require supplemental lysine in their diet.

Identification of functional subpopulations of murine natural killer cells based on their cell surface asialo GM1 phenotype

HSV-1 infection renders a mouse fibroblast cell line (MCN) sensitive to murine splenic NK killing which is independent of interferon (IFN) induction during the assay. This NK (HSV-1) activity is distinctive from conventional NK (YAC-1) in that they cannot be aborted by anti-asialo GM1 (anti-ASGM1) antibody plus complement treatment as NK (YAC-1) does. Further characterization of these two subpopulations was carried out by fluorescence-activated cell sorting (FACS) technique based on their cell surface asialo GM1 (ASGM1) phenotype. While almost all NK (YAC-1) activity resides within FACS-positive population, both ASGM1 positive and negative cell populations can kill the virally infected MCN equally well. One interesting observation is that only the ASGM1 positive cells respond significantly to IL-2 NK boosting. Five different mouse strains (CD-1, C57BL/6J, C57BL/6J-BG, SM/J, and SJL) were compared on their FACS profile with anti-ASGM1 antibody as well as their NK function. The differences observed are discussed.

Murine Thymocytes Mediate a Natural Killer‐Like Activity against Herpes Virus‐Infected Target Cells but Not YAC‐1 Target Cells

In this report, we demonstrated a natural killer (NK)‐like activity against HSV‐1 infected ceils mediated by CD‐1 mouse thymocytes. This cytolytic activity is specific for HSV‐1‐infected MCN cells, since both uninfected MCN and Y AC‐1 target cells are not susceptible to thymocyte lysis. Antibody plus complement depletion experiments indicate that a portion of the activity is associated with the Lyt 2 /L3T4− thymocyte subpopulation. This NK‐like activity cannot be enhanced by addition of interleukin 2 in vitro.

PRECLINICAL STUDIES WITH 5-(3,4-DICHLOROPHENYL)-5-ETHYL-HEXAHYDROPYRIMIDINE-2,4,6-TRIONE

Investigations in our laboratory have indicated that 5 ( 3 , k dichloropheny1)5ethylhexahydropyrimidine-2,4, 6-trione (DEHT) is a potent inhibitor of Coxsackie A21 virus multiplication in mice. The activity was found during an invest’igation o f a wide variety of compounds. In this report we would like to describe laboratory studies of the nature and degree of DEHT’s ability to inhibit Coxsackie A21 virus multiplication.