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Clinical Science (1997) 93 (Suppl.
37),I~-3lp (Printed in Great Britain)
MEDICAL RESEARCH SOCIETY
Communicationsfor the Spring Meeting of the Medical Research Society on IS May 1997 at the Royal College of Physicians, London
MRS Communications
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Communications MI-M58
agents is not established. P2 receptor stimulation has functional
effects in human atrium but P2-mediated effects on human
ventricular myocardium iu vivo have notbeen described. The aim
of this study was to examine the effects of P2-adrenoceptor
stimulation on ventricular repolarisation. 22 patients with coronary
artery disease (CAD: 16 males, mean age 60) were compared to 12
patients with normal coronary arteries (NCA: 9 males, mean age
58). Patients were appropriately stratified for e.g. LV function,
previous myocardial infarction etc. QT dispersion (QTd), defined as
the difference between the maximum and minimum QT interval on
the surface electrocardiogram, was calculated using standard
protocols. Incremental doses of salbutamol (S, 10-30 pg min") or
isoprenaline (I, 1.25-3.75 pg min'l) were infused
through a central vein.
--t IlC*Ol
Heart rate was maintained
constant with atrial pacing.
+S ICADI
Increases in QTd were
0 IINCA)
significant in both CAD
(p<O.OOl; ANOVA) and
130
- - 0 - SINCA)
NCA (p=0.002) patients
with both salbutamol and
isoprenaline but occurred at
lower doses in CAD
patients. In a separate group
of patients intra-coronary
in,jection of salbutamol
resulted in shortening of
right ventricular
monophasic action potential
duration indicating a direct
action on cardiac
10
20
30(S)
repolarisation.
M I ADENOVIRALTRANSFER OF THE MARKER GENE
FOR p GALACTOSIDASE TO THE PIG CORONARY
ARTERY THE EFFECT OF PRE-ESISTING LESIONS.
W ANDREWS, L PACKWOOD, CM DOLLERY, P YIU. A
McCLELLAND, SE HUMPHRIES, JR McEWAN
Department of Medicine (Division of Cardiology), University
College London Hospitals Medical School, London, WClE 6DB.
England and Genetic Therapy Inc, Gaitersbury, MD, USA
The application of local gene transfer to the investigation or therapy
of coronary vascular disease will require high efficiency of gene
transfer in vivo. This is a function of the technique of local drug
delivery, the vector employed and the underlying vascular disease.
We employed an adenoviral vector carrying the gene for p
Galactosidase driven by the rous sarcoma virus promoter (Avl.PGal)
and showed 80% of cultured pig vascular smooth muscle cells
expressing the transgene (MOI 200). 4 large white landrace pigs
(15-20 kg) underwent angioplasty of a single coronary artery, (left
anterior descending (LAD), circumflex (Cx)) with a 3 m m balloon
catheter (balloon to artery ratio 1.3). They were allowed to recover
for 14 - 21 days. Further angioplasty at the same angiographic site
(3mm balloon, balloon to artery ration 1.3) and also of the proximal
segment of the previously uninjured left coronary branch.
Immediately after angioplasty approximately 1.5ml of a suspension
of 4 x 108 pfu A v l . p a l was delivered to the site using a 2.75mm
double skinned microporous balloon, the MIC2 catheter (Cordis).
Three days later the animals were killed and the coronary arteries
retrieved and placed in X-Gal prior to processing for histology.
Previously injured vessels showed neointimal hyperplasia. Four
of 7 vessels examined showed successful gene transfer as evidenced
by prussian blue nuclear staining. Three of these four positive
vessels had sustained a primary injury prior to gene transfer, the
fourth had a pre-existing neointimal lesion. In three of the vessels
medial nuclear staining was sparse and seen in relationship to
angioplasty-induced dissection. In the pre-injured vesssel sparse
neointima cells showed positive staining. In the fourth vessel, a
primary injury with extensive dissection, the adventitial
fibromyoblasts showed evidence of approximately 25% gene
transfer. Vessels without evidence of gene transfer were generally
larger, suggesting poor apposition of the delivery catheter. Distal
myocyte staining (with myositis) implied that intralumenal delivery
had occurred.
-- -
I
ug!min
1.25
2.5
3.75(1)
Increases in QTd with both salbutamol and isoprenaline are
consistent with P2-adrenoceptor stimulation having important
electrophysiological effects in human ventricle.
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MEASUREMENT OF CELL PROLIFERATION IN MAN WITH
STABLE ISOTOPES BY ENDOGENOUS LABELLING OF DNA
DC MACALLAN, CA FULLERTON, RA NEESE and MK HELLERSTEm
Dept of Nutritional Sciences, University of California Berkeley, CA94720
USA &Division of Infectious Diseases, St George's Hospital Medical School,
London SW17 ORE. UK
Current methods for measuring cell proliferation by incorporation of
nucleosides (eg. 'H-thymidine, bromodeoxyuridine) are inapplicable in
man because of toxicity. We have developed a method for quantitation of
cell proliferation in vivo from incorporation of *H-labelled glucose into
deoxyribose of newly synthesised DNA via pentose phosphate and
ribonucleotide reductase pathways. Genomic DNA is isolated, hydrolysed
enzymatically to nucleosides and analysed by gas chromatography mass
spectrometry of the trimethylsilyl derivatives. Labelling of
deoxyadenosine (dA)is detected as enrichment of m/z 469/467. In pilot
M 2 P2-ADRENOCEPTOR STIMULATION INCREASES
DISPERSION OF CARDIAC REPOLARISATION
MD LOWE, PF LUDMAN, E ROWLAND and AA GRACE
Department of Cardiology, Papworth Hospital; Department of
Cardiological Sciences, St. George's Hospital Medical School
P-adrenoceptor blockers reduce risk in some patients with cardiac
disease, but the optimal use of pl-selective versus non-selective
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