Motecular and Cellular Radiobiology
Project Title: Storage and Transfer of the Genetic Message
15.
Relationship ro Other Projects:
(Cont‘'d.)
RX-03-02-(d)
Merigan, Colby at University of Connecticut, and Carter at Johns Hopkins
University are working on interferon stimulation and factors affecting
interferon.
Braun at Rutgers University, and Johnson at University of
Michigan are working on the adjuvant action. of polynucleotides on humoral
and cell-mediated immunity, Morrell at Upjohn Company, Kalamazoo and Talal
at NIH, are studying the effects of polynucleotides on macrophages and on
immunity and tolerance.
Although some of these investigators work on closely
related biological effects, the studies done here and at collaborating laboratories differ importantly in:
(1) physical characterization of the
polynucleotide complexes; (2) uniqueness of viruses studied, e.g. FMDV only
at Plum Island; (3) uniqueness of experimental tumors tested at SloanKettering; (4) comprehensiveness of pharmacology and toxicological studies
at Sloan-Kettering; (5) broadness of spectrum of biological effect$ studied
with same complexes,
16,
Technical Progress in FY 1973:
During the past 12 months there has been an increase in thinking and
experiment on the interaction of various molecules with nucleic acids and
synthetic polynucleotides in collaboration with Drs. Fuller, M. Davies and
Pigram, King's College,
This has arisen as a reverse spin-off from efforts
to decrease the biodegradability of synthetic polynucleotides in vivo by
complexing them with other molecules and also because of increased interest
in how environmental pollutants, e.g. polynuclear hydrocarbons, may damage
by complexing with nucleic acids,
Since intercalation--an interaction
whereby the planar portion of a molecule slips in between adjacent base-pairs™
in double-helical DNA--is widely assumed to be an important mechnaism of the
action of many basic drugs, e.g. acriflavin, ethidium, etc,, but rigorous
proof has been lacking hitherto and models have been ambiguous,
action of daunomycin with DNA was reviewed further,
the inter-
Daunomycin--a glycosidic anthracycline antibiotic widely used for the
palliation of acute leukemia and solid tumors in man--is a molecule of
considerable biological interest,
Its biological activity seems to be due
to complex formation with DNA,
Evidence for the first time from both x-ray
diffraction and molecular model-building studies have provided data on the
stereochemistry of intercalation into DNA of daunomycin.
These are the
first gtudies to present detailed x-ray evidence that intercalation of a
chemi
into DNA is occuring and to give accurately the degree of untwisting
of t
molecule--an inevitable consequence of intercalation--per
moleew¥@ of bound intercalated chemical.
There are many references in the
literature, particularly on circular DNA, to the paper by Fuller and Waring
(Bunsengesellschaft flr Physiklische Chemie, 68, 805, 1963), where a value
for this important parameter--i,e, the untwisting of DNA--was proposed.
(See Continuation Sheet)
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RX- 253