Abstract
Since the recognition of the disease one
hundred years ago, the treatment of leukaemia has
passed through two main phases. During the first
fifty years treatment was by chemical agents. A
,large variety underwent clinical trial and some
were found to temporarily influence the leukaemic
process. Unfortunately many were highly toxic,
and probably on account of this and our ignorance
f their mode of action. they became known as
cytotoxic agents. The discovery of x -rays in the
early part of the Present century led to a new
a_Dproach in treatment, and radiotherapy thereafter
was generally accepted, by most clinicians, as the
treatment of choice for the chronic variety of
leukaemia. During the past decade, however,
interest has been renewed in chemotherapy, and it
seems likely that we are now on the threshold of a
second era of chemotherapy. Since the Second World
sudar a considerable amount of research in this
subject has been carried out in the United Kingdom
and the United States of America and to a lesser
;extent in other parts of the world. As a result
1 number of chemical agents have been discovered
which materially influence not only patients with
chronic leukaemia but also those with the more
rapidly fatal acute disease. Their introduction
has come about in one of three ways: (a) the
observation that a compound being investigated for
other reasons has a depressant effect on
haemopoietic tissues - for example nitrogen mustard
and urethane; (b) the synthesis of compounds
related chemically to substances already known to
be effective, such as in the case of triethylene
melamine, triethylene phosphoramide, and 1:4-
dimethanesulphonyloxybutane (Myeleran); and (c)
the synthesis of analogues of nucleic acid
precursors. Much attention is now being focussed
on the last group of compounds. It is an entirely
new field of research in chemotherapy and is
considered by many investigators to be a more
rational approach to the problem. Not only have
some, e.g. the folic acid analogues and the purine
analogue 6- mercaptopurine, resulted in dramatic
'remissions in patients with acute leukaemia, but
with the aid of modern scientific techniques
information has been obtained relating to their mode
of action In addition their importance as a
stimulus to research into biochemical processes
connected with nucleic acid metabolism in the
normal, leukaemic and neoplastic cell as a whole,
probably outweighs their present therapeutic value.
This thesis contains a study of the advances
in chemotherapy which have taken place during the
past ten years. For descriptive purposes it has
been divided into four main sections. In the first
the history of chemotherapy has been described.
This is followed by a section devoted to a
comprehensive review of modern chemotherapeutic
agents available for the treatment of both acute
and chronic leukaemia. Allied neoplastic disorders
shown to be responsive to these compounds have also
been included in the text. A third section
describes metabolic studies in normal and
leukaemic patients and animals. The metabolism of
the folic acid analogue, amethopterin, with
particular reference to the problem of drug
resistance is principally dealt with. Studies in
the metabolism of folic acid and the citrovorum
factor are also included. The final section deals
with the clinical evaluation, in fifty patients,
of a new compound, 6-mercaptopurine.
