Chemotherapeutic Strategy: Proceedings of the Symposium held on June 2–4 1982 at the World Trade Centre, London UK

233 Pages·1983·19.808 MB·English

by  D I Edwards, D R Hiscock (eds.)

Chemotherapeutic Strategy
Chemotherapeutic Strategy
Proceedingsofthe Symposiumheld onJune2-41982
at the World TradeCentre,London UK
Editedby
DIEDWARDS
and
DRHISCOCK
ChemotherapyResearch Unit
DepartmentofParamedical Sciences
North East London Polytechnic
London E154LZ
M
©The Contributors
All rightsreserved.Nopartofthispublicationmaybe reproduced
or transmitted, inanyform or byanymeans, without permission.
Softcoverreprint ofthe hardcover 1st edition 1983
First published 1983by
Scientificand MedicalDivision
THEMACMILLAN PRESS LTD.
London and Basingstoke
Companies and representatives throughout the world
ISBN 978-1-349-06542-4 ISBN 978-1-349-06540-0 (eBook)
DOI 10.1007/978-1-349-06540-0
TheorganisersoftheSymposiumand editorsofthebookare
indebtedtothefollowing whoprovided
sponsorshipforthemeetingon
ChemotherapeuticStrategy
BeechamPharmaceuticalsLtd
Janssen PharmaceuticalsLtd
The MacmillanPress
Mayand BakerLtd
Roche ProductsLtd
Roussel LaboratoriesLtd
Squibb & SonsLtd
UpjohnLtd
Contents
Contributors viii
ChemotherapeuticStrategy- AnOverview.D.I.EdwardsandD.R.Hiscock
AntibioticsaffectingDNAfunction.S.Neidle 5
Antimicrobialagents affectingmembranefunction.S.Hammond 25
Antibioticsaffectingmicrobialcellwalls- progressafter 112years.S.Selwyn 47
Antibioticsasprobesofribosomalstructureandfunction.E.Cundliffe 65
Mechanismsofdrugresistance.J.T.Smith 79
Newstrategiesinthesearchforantiprotozoa!drugs.B.A.Newton 85
Anthelminticchemotherapy.R.E.Howells 103
Majorproblemsincancerchemotherapy.K.Hellmann 131
Chemotherapyofanaerobicbacteria.A.T.Willis 141
The strategyofdrug developmentinhypoxic cellradiosensitization
andchemosensitization.I.Stratford 155
Quantitativestructure-activityrelationships(QSARs):
principleandpractice.P.Wardman 173
Three-dimensionalaspectsofmoleculesindrugdesign.J.Tollenaere 193
Targetingofdrugs withliposomes. G.Gregoriadis 211
Index 221
The Contributors
E Cundliffe D R Hiscock
Department of Biochemistry Department of Paramedical
University of Leicester Sciences
Adrian Building North East London Polytechnic
University Road Romford Road
Leicester LEI 7RH, UK London E15 4L2, UK
D I Edwards R E Howells
Chemotherapy Research Unit Department of Parasitology
Department of Paramedical Liverpool School of Tropical
Sciences Medicine
North East London Polytechnic Pembroke Place
Romford Road Liverpool L3 SQA, UK
London E15 4L2, UK
S Neidle
G Gregoriadis Cancer Research Campaign
Division of Clinical Sciences Biomolecular Structure
Clinical Research Centre Research Group
Watford Road Department of Biophysics
Harrow King's College
Middlesex HAl 3UJ, UK 26-29 Drury Lane
London WC2B 5RL, UK
S MHammond
Department of Microbiology B A Newton
University of Leeds Medical Research Council Unit
Leeds LS2 9JT, UK for Biochemical Parasitology
The Molteno Institute
K Hellmann Downing Street
Cancer Chemotherapy Department Cambridge CB2 3EE, UK
Imperial Cancer Research Fund
POBox 123
Lincoln's Inn Fields
London WC2A 3PX, UK
viii
S Selwyn J P Tollenaere
Department of Medical Department of Theoretical
Microbiology Medicinal Chemistry
Westminster Medical School Janssen Pharmaceutica
Horseferry Road B-2340 Beerse, Belgium
London SW1P 2AR, UK
P Wardman
J T Smith Cancer Research Campaign
The Microbiology Section Gray Laboratory
Department of Pharmaceutics Mount Vernon Hospital
The School of Pharmacy Northwood
University of London Middlesex HA6 2RN, UK
Brunswick Square
London WC1N lAX, UK A T Willis
Public Health Laboratory
I J Stratford Luton and Dunstable Hospital
Radiobiology Group Lewsey Road
Department of Physics Luton LU4 ODZ, UK
Institute of Cancer Research
Clifton Avenue
Sutton
Surrey SM2 SPX, UK
ix
Chemotherapeutic Strategy - An Overview
D I Edwards and D R Hiscock
DepartmentofParamedicalSciences
North EastLondon Polytechnic
Romford Road, London E15 4LZ,UK
This volume reports the proceedings of a symposium on Chemo
therapeutic Strategy held at the World Trade Centre, London in June
1982 and which was organised by the Chemotherapy Research Unit of
North East London Polytechnic. During the Symposium three major
aspects of chemotherapeutic strategy were discussed; the targets
within the susceptible cell (including resistance), problems of the
chemotherapy of infection (including cancer), and lastly, new
approaches to chemotherapeutic strategy which are of current
interest and which may prove of greater value in the future.
The scope of the Symposium was intended to encompass as broad
an area as possible so as to afford the opportunity to stimulate
common ideas and approaches. The use of liposomes in drug targeting
for example may not ultimately prove to be of use in cancer but the
idea has been adopted for other drug delivery systems including
antiprotozoal chemotherapy. Similarly, a knowledge of free radicals
is essential in understanding the action and selective toxicity of
nitroimidazole drugs in anaerobic protozoal and bacterial chemo
therapy as well as their enormous potential as radiosensitizers for
the treatment of hypoxic tumours in man. It was thus a synthesis
of different approaches within the separate disciplines which
compose the wider field of chemotherapy that the Symposium was
concerned.
Those involved in developing new drugs are aware that the
strategy of chemotherapy, all too often, is one of random screening
of potential new compounds, the cost of which has increased alarm
ingly over recent years. With the knowledge of molecular targets
within the cell and the powerful technique of QSAR analysis screen
ing methods are, however, changing. In this respect a glimpse of
the future was given to us by Dr Tollenaere who demonstrated the
value of knowing the three-dimensional structure of drugs - an
approach which has led to the successful marketing of at least one
drug which was based ab initio upon X-ray crystallographic data
analysis of congeners.
A more commonly used approach is that of Hansch or QSAR analy
sis which, although extremely useful, requires careful choice of
the correct physico-chemical and biological parameters. Dr Wardman
ably showed that this approach is readily available to all who have
access to computing facilities.
Nevertheless, if a new drug is developed and marketed and its
mechanism of action known there is every chance that, eventually,
resistance will develop - whether to an infecting bacterium or
cancer cell and the mechanisms of such resistance in bacteria were
reviewed by Professor Smith.
It is only relatively recently that the importance of estab
lishing the mode of action of drugs at the molecular level has been
fully realised and this knowledge is paramount in appreciating the
selective toxicity of drugs. Even where useful chemotherapeutic
agents are not particularly selectively toxic - witness the ma
jority of anticancer drugs as Professor Hellman showed - they may
be of potential value elsewhere, as antiprotozoal drugs, or their
activity enhanced by an increase in their selectivity of delivery
by liposome encapsulation as Dr Gregoriadis illustrated.
Although present anticancer chemotherapy is probably at the
level of bacterial chemotherapy at the turn of the century when
arsenical drugs were the therapy of choice, new and exciting ap
proaches are bound to make an impact and Dr Stratford convincingly
demonstrated the future potential of radiosensitisers in his
lecture. However, even when chemotherapy appears to be highly
successful, and Dr Willis showed this to be true of anaerobic
bacterial infection, there are some areas where effective drugs are
noticeably lacking. In antiprotozoal chemotherapy Professor Newton
showed that the UNDP/World Bank/WHO special programme for Research
and Training in Tropical Diseases has been developed in an attempt
to rectify the situation. A similar state of affairs seems to
exist in the field of anthelmintic chemotherapy. As Dr Howells
pointed out, although novel strategies for helminth control are
being actively pursued, the problems of host-parasite relationships
are immense and what is needed are new drugs with different targets
of action.
In this respect the four major targets of chemotherapeutic
action were discussed. ~r Neidle showed that current knowledge of
anticancer drugs which bind to DNA can serve as a useful starting
point for the rational design of new agents with enhanced activity
and/or selective toxicity. Dr Hammond showed that although the
membrane can be a selectively toxic target, particularly as regards
antifungal agents, the field is hampered by a lack of knowledge of
the nature of the target itself. Where DNA is the best charac
terised target the membrane is the least. The situation, however,
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