Retinoids in Oncology

117 Pages·1995·7.336 MB·English

by  Laurent Degos, David R. Parkinson (auth.), Professor Laurent Degos, David R. Parkinson M.D. (eds.)

•• •
• •
• • • Monographs
Series Editor: U. Veronesi
The European School of Oncology
gratefully acknowledges sponsorship
for the Task Force received from
Springer
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L. Degas D .R. Parkinson (Eds.)
Retinoids
in Oncology
With 26 Figures and 10 Tables
Springer
Professor Laurent Degos
Institut Universitaire d'Hematologie
H6pital St. Louis
1, Avenue Claude Vellefaux
75010 Paris, France
David R. Parkinson, M.D.
Investigational Drug Branch
Division of Cancer Treatment
National Cancer Institute
6130 Executive Boulevard
Rockville, MD 20892, USA
ISBN-I3: 978-3-642-79708-8 e-ISBN-I3: 978-3-642-79706-4
DOl: 10.1007/978-3-642-79706-4
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Foreword
The European School of Oncology came into existence to respond to a need for
information, education and training in the field of the diagnosis and treatment of
cancer. There are two main reasons why such an initiative was considered necessary.
Firstly, the teaching of oncology requires a rigorously multidisciplinary approach
which is difficult for the Universities to put into practice since their system is mainly
disciplinary orientated. Secondly, the rate of technological development that
impinges on the diagnosis and treatment of cancer has been so rapid that it is not an
easy task for medical faculties to adapt their curricula flexibly.
With its residential courses for organ pathologies and the seminars on new
techniques (laser, monoclonal antibodies, imaging techniques etc.) or on the
principal therapeutic controversies (conservative or mutilating surgery, primary or
adjuvant chemotherapy, radiotherapy alone or integrated), it is the ambition of the
European School of Oncology to fill a cultural and scientific gap and, thereby, create
a bridge between the University and Industry and between these two and daily
medical practice.
One of the more recent initiatives of ESO has been the institution of permanent study
groups, also called task forces, where a limited number of leading experts are invited
to meet once a year with the aim of defining the state of the art and possibly reaching
a consensus on future developments in specific fields of oncology.
The ESO Monograph series was designed with the specific purpose of disseminating
the results of these study group meetings, and providing concise and updated
reviews of the topic discussed.
It was decided to keep the layout relatively simple, in order to restrict the costs and
make the monographs available in the shortest possible time, thus overcoming a
common problem in medical literature: that of the material being outdated even
before publication.
Umberto Veronesi
Chairman Scientific Committee
European School of Oncology
Contents
Introduction
L. Degos and D. R. Parkinson........................................................................................... 1
Molecular Mechanisms of Retinoid Action
A. Zelent.............................................................................................................................. 3
Cellular Biology of the Retinoids
R. Lotan ................. :. ............................................................................................................ 27
Retinoids and Embryos
G. Morriss-Kay ................................................................................................................... 43
Clinical Pharmacology of the Retinoids
U. Pastorino, R. P. Warrell, Jr and F. Formelli.. ............................................................. 55
Clinical Toxicology of the Retinoids
R. P. Warrell, Jr, U. Pastorino and A. Decensi.. .............................................................. 67
Clinical and Molecular Advances in Acute Promyelocytic Leukaemia
H. de The, L. Degos and R. P. Warrell, Jr ........................................................................ 73
Retinoid Therapy of Other Haematological Malignancies
D. R. Parkinson and R. P. Warrell, Jr .............................................................................. 89
Retinoids in the Prevention and Therapy of Solid Tumours
U. Pastorino, D. R. Parkinson and F. Chiesa .................................................................. 93
Retinoids in Oncology: Conclusions and Future Directions
L. Degos and D. R. Parkinson ........................................................................................... 113
Introduction
Laurent Degos 1 and David R. Parkinson 2
1 Institut Universitaire d'Hematologie, Hopital St. Louis, 1, Avenue Claude Vellefaux, 75010 Paris, France
2 Investigational Drug Branch, Division of Cancer Treatment, National Cancer Institute, Bethesda, MD 20892, U.S.A.
The retinoids consist of a family of compounds structurally and functionally related to all
trans-retinoic acid, the physiologically active metabolite of vitamin A. While the biology of
this class of agents has long been of interest to developmental biologists and to those
interested in the physiology of vision, it is much more recently that investigators con
cerned with the prevention and treatment of malignancy have focussed on this class of
agents. This recent attention has been fuelled by the rapid increases in our understand
ing of the normal biology of the retinoids, the appreciation of their powerful influences on
gene expression, and the demonstration of their ability in some preclinical settings to in
terfere with the malignant process.
In this monograph we have attempted to integrate the latest findings from both basic lab
oratory and clinical research regarding the retinoids. Our purpose has been to sum
marise under one cover and in a timely manner the spectrum of findings regarding
retinoid biology, activity in preclinical model systems, and results from initial therapeutic
applications in humans. We have been joined in this project by a knowledgeable and
experienced group of individuals who have worked together to produce a summary of
this extensive amount of information. The role of natural retinoids in growth and devel
opment and the latest information concerning both the structure and function of nuclear
retinoid receptors and the mechanisms through which the retinoids influence gene ex
pression are summarised by Zelent. The cell biological consequences of retinoid action
on normal, premalignant, and malignant cells are then described by Lotan. The role of
retinoids and their receptors in embryogenesis is explained by Morriss-Kay. These three
initial chapters represent comprehensive summaries of a huge body of information, and
form a basis for understanding the rationales and strategies for the use of retinoids in
clinical applications in individuals at risk for malignancy, and in patients with established
cancer. The pharmacology of the retinoids, emphasising the differences which have
been found among the retinoids used clinically to date, is then summarised by Pastorino,
Warrell and Formelli. The need for detailed pharmacological study of each new retinoid
is emphasised by the surprising findings with respect to all-trans retinoic acid, which dif
fers so remarkably in this respect from its stereoisomer, 13-cis retinoic acid. Warrell,
Pastorino and Decensi then summarise the acute and chronic toxicities of the retinoids,
emphasising the "retinoic acid syndrome" which has been encountered only with the use
of all-trans retinoic acid in therapy of acute promyelocytic leukaemia (APL), and the ocu
lar toxicities encountered with the use of fenretinide in chemoprevention studies. The
effects of all-trans RA in APL are then described in a chapter by de The, Degos and
Warrell which attempts to integrate the clinical effects with progress in the understanding
of the molecular and cellular biology of this malignancy. The clinical finding of this thera-
2 L. Dagos and D.R. Parkinson
peutic effect, first described by Professor Huang and his colleagues in China, must rank
with some of the most remarkable therapeutic findings in cancer treatment. Beyond its
relevance to the treatment of this particular malignancy, the appreciation that the mech
anism of the antitumour effects is through induction of differentiation has represented a
profound stimulus for studies into differentiation and apoptosis induction as therapeutic
strategies in malignancy. The more limited, and less dramatic, therapeutic experiences
in other haematological malignancies and premalignant states are then summarised by
Parkinson and Warrell. Finally, Pastorino, Parkinson and Chiesa have integrated into
one chapter the latest information concerning the use of retinoids in the prevention and
therapy of solid tumours. Traditionally these subjects, prevention and therapy, have been
separated, both with respect to organisation of meetings and organisation of manu
scripts. It increasingly has become clear that both groups of investigators have much to
learn from each other, and furthermore, that the conduct of secondary chemoprevention
trials is in fact the conduct of adjuvant therapy trials. While clinical and laboratory end
points for prevention and treatment may differ, and the number of patients in a trial nec
essary to answer the prevention question be larger than those necessary for the thera
peutic goals, the trial design issues, and the populations of patients under therapy are
identical. The most efficient path to solving important cancer management questions
therefore may lie with increased cooperation between prevention- and treatment-di-
rected clinical researchers. .
On behalf of the entire group of authors we would like to express our personal apprecia
tion to the staff of the European School of Oncology for their assistance in this project.
We have produced this monograph under an accelerated schedule in order to make
available to the reader the latest information concerning retinoids and malignancy. It is
our sincere hope that these efforts will prove useful to all those interested in the devel
opment and application of new therapies or preventive strategies for cancer.
Molecular Mechanisms of Retinoid Action
Arthur Zelent
Leukaemia Research Fund Centre at the Institute of Cancer Research, Chester Beatty Laboratories, Fulham Road,
London SW3 6JB, United Kingdom
Shortly after the discovery of vitamin A (retinol) transcription initiation by DNA polymerase II, is
in 1913 [1], scientists began to realise the ex of extreme importance. Nuclear receptors, such
treme importance of this simple fat-soluble as steroid receptors or RARs, are soluble pro
molecule in a large number of complex and di teins which can bind as dimers to specific
verse physiological processes such as vision, DNA-regulatory elements (hormone response
reproduction, as well as the development and elements) and act as cell-type and promoter
homeostasis of vertebrates (see ref. [2-9] for specific transcription factors. In contrast to
reviews). Over the years considerable effort other transcription factors, however, their ac
has been devoted to study the cellular tivities can be modulated through binding of the
metabolism of vitamin A and to characterise its corresponding hydrophobic ligands such as
biologically active derivatives (see ref. [10] for steroid hormones or retinoids. The aim of this
review). The term retinoids has been used to chapter is to provide the reader with a compre
encompass a continuously growing family of hensive summary of what has been learned
synthetiC and natural compounds which are about the molecular components of the retinoid
both structurally and functionally related to vi signalling pathway and the mechanisms of
tamin A and its physiologically active metabo their action in physiological processes other
lites, such as all-trans-retinoic acid (RA). By than visual perception.
the end of the 1960s the role of retinoids in the
visual cycle was well understood [11], how
ever, the molecular mechanism of retinoid action Natural Retinoids and Development
in processes other than vision remained elu
sive for the next 2 decades. The discovery of
a nuclear retinoic acid receptor (RAR) [12,13], Early work on the effects of vitamin A defi
which was shown to be a member of the su ciency in a number of mammalian species im
perfamily of steroid/thyroid hormone nuclear re plicated it in the control of normal differentiation
ceptors [14-16] functioning as ligand-inducible and proliferation of epithelial cells [3]. This loss
transcription factors, was a breakthrough in of control in a vitamin A deficient animal was re
understanding how retinoids exert their pleio flected in structural and functional abnormalities
tropic effects. of various organs and tissues such as the
Regulation of gene expression at the transcrip skin, thymus and prostate, as well as the tra
tional level is an essential component of impor cheobronchial, urogenital and gastro-intestinal
tant cellular and developmental processes epithelia [3,17]. For example, in the absence of
such as growth, differentiation and lineage dietary retinol, the secretory and stratified
commitment. In this respect, the concerted ac squamous epithelia undergo keratinization
tion of cell-type specific transcription factors, (squamous metaplasia) and hyperkeratiniza
which bind to the DNA elements (response el tion, respectively. Hypervitaminosis A also
ements) located in the regulatory regions (such was found to have deleterious effects on epi
as promoters and/or enhancers) of specific dermal differentiation causing decreased kera
genes and either inhibit or stimulate the rate of tinization and hair loss (see [18] and references
4 A. Zelent
therein). It is perhaps not surprising that these limb morphogenesis (see [33, 34] and refer
early observations led scientists to consider ences therein). In 1968 Saunders and
the use of retinoids in cancer therapy (see [19] Gasseling [35] described a region of mes
for review) and treatment of cutaneus disorders enchymal cells in the posterior margin of the
of keratinization (for review see [20] and refer developing chicken limb bud, named zone of
ences therein). The action of vitamin A in con polarising activity (ZPA), that, when trans
trolling cellular proliferation and differentiation planted to the anterior margin, would induce
was not, however, restricted to epithelial cells mirror image digit duplication. These results led
(see [21,22] for reviews). Avitaminosis A was to the suggestion that ZPA was the source of a
also associated with a reduction in the number diffusable morphogen whose concentration
of haemopoietic cells in the bone marrow [3] gradient across the antero-posterior axis of the
and anaemia [23]. An important role for retinoids limb bud would specify positional values re
in haemopoiesis was corroborated by studies quired for proper digit patterning [36]. Possibly
demonstrating that all-trans RA can stimulate influenced by the earlier observations of Niazi
the proliferation and maturation of erythroid and and Saxena on the adverse effects of the ex
myeloid precursor cells in vitro [24], and exert cess of vitamin A on amphibian tail [37] and
beneficial effects on the function of the human limb [38] regeneration, and/or by the nature of
immune system (see [25] and references all-trans RA-induced limb malformations in
therein). Indeed, recent experimental results mammals [29], Tickle and co-workers [39] im
[26] have shown that 9-cis retinoic acid (9-cis planted in the anterior region of the limb bud an
RA), a stereoisomer of all-trans RA, may play anion exchange bead soaked in all-trans RA.
a role in T-cell selection. They discovered that the released all-trans RA
Given the observations that avitaminosis or induced the same pattern of digit duplication as
hypervitaminosis A adversely affects most, if transplanted ZPA, and suggested that all-trans
not all, cells in adult vertebrate organisms, it RA may indeed be the putative ZPA mor
was considered very likely that vitamin A and phogen. Further support for this hypothesis
its derivatives would also play an important came in 1987 from Eichele and Thaller [40] who
role during embryogenesis. Early indirect evi showed that all-trans RA can be isolated from
dence for such a role came from observations chicken limb buds and that its concentration is
of the teratogenic effects of both retinoid defi approximately 2.5-fold higher in the posterior
ciency and excess on embryonic development (ZPA-containing) than in the anterior region.
[4,5,27]. Interestingly, the spectrum of malfor Since this time, endogenous retinoids such as
mations produced by these two different con all-trans-3,4-didehydroretinoic acid and 9-cis
ditions were very similar and included primarily RA have also been shown to be potent in
skeletal and eye defects, as well as limb, ducers of digit duplication [41,42]. Neverthe
craniofacial, cardiovascular, central nervous less, despite the initial excitement [43] the role
system (eNS) and urogenital malformations. of retinoids as morphogens during chicken limb
The nature of these observed embryonic de development remains very controversial ([44],
fects was highly dependent on the stages of see also [34] for review and references
maternal exposure [28,29], indicating specific therein). In fact, recent results [45,46] suggest
intervals of retinoid sensitivity during the de that retinoids act not as morphogens but as
velopment of various anatomical structures and ZPA inducers, i.e., they simply convert the
organ systems. These periods of sensitivity cells that they come into contact with to ZPA
probably reflect developmental windows dur cells and subsequently are not required for
ing which activities of endogenous retinoid are polarising activity. This was illustrated by an
required for proper functioning of normal phys experiment which showed that when a wedge
iological processes such as programmed cell of tissue next to the all-trans RA-releasing
death (apoptosis) and/or migration of neural bead is cleared from all-trans RA and implanted
crest cells. Indeed, non-physiological levels of in the anterior margin of another limb bud, it still
retinoid(s) have been associated with abnor causes digit duplication. The most recent re
mal migration of neural crest cells [30] and ex sults have shown that all-trans RA can induce
cessive apoptosis [31,32]. expression of a gene called Sonic hedgehog,
More direct evidence for the role of retinoids in whose product is strongly associated with the
embryogenesis came from studies on avian polarising activity in the chicken limb bud [47].