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The methodology of drug development has been the subject of
extensive dis cussion by a relatively small group of individuals in
industry and government who have been intimately concerned with the
identification and study of new anticancer drugs. The Chemotherapy
Program of the National Cancer In stitute has represented the major
focus of initial efforts in drug development, as summarized in the
historical perspective presented in chapter 1 and its references.
It is no coincidence that the Chemotherapy Program was the origin
of the Division of Cancer Treatment, a government entity that has
had a pivotal role in the growth of clinical oncology. In an
analogous fashion this book presents the methodology employed in
the clinical study of anticancer drugs within the broad context of
cancer treatment. The research orientation promulgated in the study
of new drugs is a central theme in most oncolo gists' approach to
the clinical problem of cancer. Therefore, we hope that this book
will introduce readers to treatment research in clinical oncology.
For the oncologist, the clinical evaluation of antitumor therapy is
both part of the day-to-day management of specific patients and the
critical considera tion of developing therapeutic alternatives. For
physicians in other fields of medicine it is important to acquaint
themselves with the basic tools of the oncologist. For people
without medical training, including patients who might be
interested in treatment research, many of the chapters may be
overly technical.
Concepts, Mechanisms, and New Targets for Chemotherapy describes
new interconnections between rationally designed and empirically
discovered compounds. One route that has not been travelled
previously is that of protein kinase C inhibition. This pathway may
be exploited to give potent inhibitors, such as the bryostatins,
now in clinical trial. A summary is given of the current status of
topoisomerase, focusing on recent clinical advances with
camptothecin analogs based on connecting empiricism with concepts
of drug selectivity. Modification of existing therapies based on
the pursuit of leads arising from mechanistic studies is also being
applied clinically on a wide scale. Greater understanding should
follow from the studies of reversal of the multidrug resistant
phenotype, on the use of hydroxyurea to reverse resistance mediated
by extrachromosomal DNA, and on various aspects of the
fluoropyrimidine pathways. Successful applications of chemotherapy
to the treatment of specific diseases include the growing
applications of systemic therapy using various skin malignancies.
In prostate cancer, estramustine phosphate will likely play an
expanding role. Taxanes are restructuring treatment regimens in
breast cancer, and high-dose strategies are described with
peripheral blood progenitor autografting in the treatment of
ovarian and breast cancers.
The decade of the 1990s will see an increasing emphasis on the
modulation of chemotherapeutic drug selectivity and in the 'lock
and key' approach to new targets to control malignant
proliferation. The contents of this volume appropriately reflect
these scientific undercurrents. An emerging powerful tool of
molecular pharmacology is described by Holcenberg and Wu.
Manipulation of genetic expression by modification of messenger RNA
is now within our reach, and the basic concepts are suc- cinctly
reviewed as a primer on future biochemical engineering of new anti-
cancer molecules. Another concept that appears to be worthy of
further study in both experimental and clinical chemotherapy
concerns obs'ervations on the modulation of activity by the
nucleoside transport inhibitor, dipyri- damole. How potentiation of
several anticancer drugs occurs has practical, as well as
theoretical, ramifications, discussed by Goel and HowelL Finally,
O'Dwyer and La Creta present a fresh look at sensitization of
chemotherapy by the hypoxic radiosensitizer, SR-2731.
F. M. MUGGIA When faced with the inadequacies of current cancer
treatment, we prefer to look at what the future may hold. Quite
often, we take for granted the past, preferring research into
totally new areas. However, the persistent development of fertile
soil may yield surprising rewards for those who choose to build on
the knowledge of the past--hence, this symposium on anthracycline
antibiotics. Although the anthracycline antibiotics represent much
of the present and future of cancer treatment, their actual use c
stretches back barely two decades to the pioneering efforts of
Aurelio Di Marco, who characterized the antitumor properties of
daunomycin and adriamycin. * The clinical application of these two
compounds heralded a decade of excitement among oncologists dealing
with pediatric tumors, breast cancer, leukemias, and lymphomas, and
opened new hope for patients afflicted with sar comas and a variety
of other tumors that had been deemed - sistant to chemotherapy.
These successes were tempered with the realization that the
antitumor effect of anthracyclines could be achieved at times only
at the very high price of risking cardiac decompensation and,
almost invariably, with the occurrence of alopecia and other acute
toxicities. This record of past achievements and problems has
slowly given way to a present increasingly illuminated by our
ability to modify the distressing toxicities of these agents.
Detailed clinical studies supplemented by ingenious laboratory
models have gradually elucidated mechanisms and risk factors im
plicated in the cardiomyopathy."
The Boerhaave Committee for postgraduate Medical Education decided
to organize a course on cancer treatment covering selected solid
tumors, in which they felt important chan ges were emerging in the
basic biologic, diagnostic and therapeutic concepts. Current
management of cancer patients is intimately dependent on precise
morphologic diagnosis, clinical staging and the proper application
of all treat ment modalities. Many prominent investigators and
clinicians of major can cer centers in the United States, Canada,
and Europe con tributed by lecturing and during the panel
discussions. This book is the tangible outcome of the productive ex
changes during the meeting held December 6-8, 1979. In ovarian
cancer the usefulness of histologic grading in determining
prognosis has become clear. The most impor tant advance for the
management of the patient is th- careful staging procedure, based
on new concepts of tumor spread coupled with treatment tailored to
the extent of disease. Survival appears to be directly related to
the extent of the tumor mass. This has resulted in description and
application of optimal cyto-reductive surgery. Radiotherapy and
chemotherapy can both effectively eradi cate small amounts of
tumor."
Where do you begin to look for a recent, authoritative article on
the diagnosis or management of a particular malignancy? The few
general oncology textbooks are generally out of date. Single papers
in specialized journals are informative but seldom comprehensive;
these are more often preliminary reports on a very limited number
of patients. Certain general journals frequently publish good
indepth reviews of cancer topics, and published symposium lectures
are often the best overviews available. Unfor tunately, these
reviews and supplements appear sporadically, and the reader can
never be sure when a topic of special interest will be covered.
Cancer Treatment and Research is a series of authoritative volumes
which aim to meet this need. It is an attempt to establish a
critical mass of oncology literature covering virtually all
oncology topics, revised frequently to keep the coverage up to
date, easily available on a single library shelf or by a single
personal subscription. We have approached the problem in the
following fashion. First, by dividing the oncology literature into
specific subdivisions such as lung can cer, genitourinary cancer,
pediatric oncology, etc. Second, by asking emi nent authorities in
each of these areas to edit a volume on the specific topic on an
annual or biannual basis. Each topic and tumor type is covered in a
volume appearing frequently and predictably, discussing current
diagnosis, staging, markers, all forms of treatment modalities,
basic biology, and more."
Where do you begin to look for a recent, authoritative article on
the diagnosis or management ofa particular malignancy? The few
general onco logy textbooks are generally out of date. Single
papers in specialized journals are informative but seldom
comprehensive; these are more often prelimi nary reports on a very
limited number of patients. Certain general journals frequently
publish good indepth reviews of cancer topics, and published
symposium lectures are often the best overviews available.
Unfortunately, these reviews and supplements appear sporadically,
and the reader can nev er be sure when a topic of special interest
will be covered. Cancer Treatment and Research is a series of
authoritative volumes which aim to meet this need. It is an attempt
to establish a critical mass of oncology literature covering
virtually all oncology topics, revised frequently to keep the
coverage up to date, easily available on a single library shelf or
by a single personal subscription. We have approached the problem
in the following fashion. First, by div iding the oncology
literature into specific subdivisions such as lung cancer,
genitourinary cancer, pediatric oncology, etc. Second, by asking
eminent authorities in each of these areas to edit a volume on the
specific topic on an annual or biannual basis. Each topic and tumor
type is covered in a volume appearing frequently and predictably,
discussing current diagnosis, staging, markers, all forms of
treatment modalities, basic biology, and more."
Experimental chemotherapy continues to be at the forefront of
cancer thera- peutics. Topics covered in the preceding volume on
cancer chemotherapy in this series such as study of drugs by
alkaline elution, the development of the antimetabolite tiazofurin,
and the treatment of germ cell tumors have become informative
references to current experimentalists and practitioners. In even
earlier volumes, reviews of the platinum compounds, anthracyclines,
and osteosarcoma represent topics associated with such rapid
progress requiring a look back to provide the appropriate
perspective. Similarly, we venture to predict that the topics in
this volume will become useful landmarks for future drug
development and disease strategies. In the area of drug
development, what is being learned about old, estab- lished
antineoplastics is raising renewed expectations that it will be
translated into improved applications and patient benefit. For
example, we now have the ability to modulate the action of
alkylating agents and fluorinated pyri- midines to achieve greater
sensitivity. A new compound for an old target, trimetrexate, an
antifolate that does not polyglutaminate, will have a role not only
in treatment of neoplastic diseases, but also protozoal infection.
As in CANCER CHEMOTHERAPY 1, this volume brings to the reader
highlights in three different areas of cancer therapeutics: new
concepts and models; drug classes; and clinical settings. Topics
were chosen because of their timeliness or probable current impact
in cancer treatment. Authors were selected on the basis of their
ability to provide a critical overview of specific subjects and
their involvement in original work. I shall review the aims of this
second volume, and then elaborate on the scope of its con tents.
The principal aim of the volumes on cancer chemotherapy in the'
Cancer Treatment and Research' series, as stated in the preface to
the first volume, is to assemble in a concentrated form selected
ingredients of chemothera peutic progress. These ingredients are to
include concepts in therapeutic strategy, pre-clinical studies,
development of major classes of compounds, identificatlon of new
directions and of landmarks of clinical progress. Thus we do not
foresee overlap with series which provide an yearly update of
chemotherapy in an encyclopedic manner, or reviews of cancer
chemother apy. Unlike those publications, our volumes are not
intended to seek a place in shelves as a reference manual. It is
this Editor's hope that persons repre senting various biomedical
disciplines will seek the' Cancer Treatment and Research'
chemotherapy volumes to survey advances in the field at regular
intervals."
Concepts, Mechanisms, and New Targets for Chemotherapy describes
new interconnections between rationally designed and empirically
discovered compounds. One route that has not been travelled
previously is that of protein kinase C inhibition. This pathway may
be exploited to give potent inhibitors, such as the bryostatins,
now in clinical trial. A summary is given of the current status of
topoisomerase, focusing on recent clinical advances with
camptothecin analogs based on connecting empiricism with concepts
of drug selectivity. Modification of existing therapies based on
the pursuit of leads arising from mechanistic studies is also being
applied clinically on a wide scale. Greater understanding should
follow from the studies of reversal of the multidrug resistant
phenotype, on the use of hydroxyurea to reverse resistance mediated
by extrachromosomal DNA, and on various aspects of the
fluoropyrimidine pathways. Successful applications of chemotherapy
to the treatment of specific diseases include the growing
applications of systemic therapy using various skin malignancies.
In prostate cancer, estramustine phosphate will likely play an
expanding role. Taxanes are restructuring treatment regimens in
breast cancer, and high-dose strategies are described with
peripheral blood progenitor autografting in the treatment of
ovarian and breast cancers.
The decade of the 1990s will see an increasing emphasis on the
modulation of chemotherapeutic drug selectivity and in the 'lock
and key' approach to new targets to control malignant
proliferation. The contents of this volume appropriately reflect
these scientific undercurrents. An emerging powerful tool of
molecular pharmacology is described by Holcenberg and Wu.
Manipulation of genetic expression by modification of messenger RNA
is now within our reach, and the basic concepts are suc- cinctly
reviewed as a primer on future biochemical engineering of new anti-
cancer molecules. Another concept that appears to be worthy of
further study in both experimental and clinical chemotherapy
concerns obs'ervations on the modulation of activity by the
nucleoside transport inhibitor, dipyri- damole. How potentiation of
several anticancer drugs occurs has practical, as well as
theoretical, ramifications, discussed by Goel and HowelL Finally,
O'Dwyer and La Creta present a fresh look at sensitization of
chemotherapy by the hypoxic radiosensitizer, SR-2731.
Experimental chemotherapy continues to be at the forefront of
cancer thera- peutics. Topics covered in the preceding volume on
cancer chemotherapy in this series such as study of drugs by
alkaline elution, the development of the antimetabolite tiazofurin,
and the treatment of germ cell tumors have become informative
references to current experimentalists and practitioners. In even
earlier volumes, reviews of the platinum compounds, anthracyclines,
and osteosarcoma represent topics associated with such rapid
progress requiring a look back to provide the appropriate
perspective. Similarly, we venture to predict that the topics in
this volume will become useful landmarks for future drug
development and disease strategies. In the area of drug
development, what is being learned about old, estab- lished
antineoplastics is raising renewed expectations that it will be
translated into improved applications and patient benefit. For
example, we now have the ability to modulate the action of
alkylating agents and fluorinated pyri- midines to achieve greater
sensitivity. A new compound for an old target, trimetrexate, an
antifolate that does not polyglutaminate, will have a role not only
in treatment of neoplastic diseases, but also protozoal infection.
Where do you begin to look for a recent, authoritative article on
the diagnosis or management of a particular malignancy? The few
general oncology textbooks are generally out of date. Single papers
in specialized journals are informative but seldom comprehensive;
these are more often preliminary reports on a very limited number
of patients. Certain general journals frequently publish good
indepth reviews of cancer topics, and published symposium lectures
are often the best overviews available. Unfor tunately, these
reviews and supplements appear sporadically, and the reader can
never be sure when a topic of special interest will be covered.
Cancer Treatment and Research is a series of authoritative volumes
which aim to meet this need. It is an attempt to establish a
critical mass of oncology literature covering virtually all
oncology topics, revised frequently to keep the coverage up to
date, easily available on a single library shelf or by a single
personal subscription. We have approached the problem in the
following fashion. First, by dividing the oncology literature into
specific subdivisions such as lung can cer, genitourinary cancer,
pediatric oncology, etc. Second, by asking emi nent authorities in
each of these areas to edit a volume on the specific topic on an
annual or biannual basis. Each topic and tumor type is covered in a
volume appearing frequently and predictably, discussing current
diagnosis, staging, markers, all forms of treatment modalities,
basic biology, and more."
The methodology of drug development has been the subject of
extensive dis cussion by a relatively small group of individuals in
industry and government who have been intimately concerned with the
identification and study of new anticancer drugs. The Chemotherapy
Program of the National Cancer In stitute has represented the major
focus of initial efforts in drug development, as summarized in the
historical perspective presented in chapter 1 and its references.
It is no coincidence that the Chemotherapy Program was the origin
of the Division of Cancer Treatment, a government entity that has
had a pivotal role in the growth of clinical oncology. In an
analogous fashion this book presents the methodology employed in
the clinical study of anticancer drugs within the broad context of
cancer treatment. The research orientation promulgated in the study
of new drugs is a central theme in most oncolo gists' approach to
the clinical problem of cancer. Therefore, we hope that this book
will introduce readers to treatment research in clinical oncology.
For the oncologist, the clinical evaluation of antitumor therapy is
both part of the day-to-day management of specific patients and the
critical considera tion of developing therapeutic alternatives. For
physicians in other fields of medicine it is important to acquaint
themselves with the basic tools of the oncologist. For people
without medical training, including patients who might be
interested in treatment research, many of the chapters may be
overly technical."
Neoplastic disease confined to the liver is an important worldwide
problem. In the industrialized nations, metastatic disease of the
most common cancers involves the liver in upwards of 50% of cases.
Primary hepatic tumors are virtually epidemic in most third world
countries and certainly constitute one of the ten most common
causes of cancer deaths on a worldwide scale. Amazingly, little
specific attention has been devoted to therapeutic approaches of
liver and biliary tumors until recently. We attribute this apparent
lack of interest to the uniformly poor progno sis of patients so
afflicted, and attribute the renewed interest to the exciting new
developments in diagnostic and therapeutic technology as well as in
tumor biology. The purpose of this book is to collect in one volume
an integrated selection of articles that would provide the
therapist with a comprehensive, yet practical, overview of liver
cancer. We believe the contributors to the book are superbly
qualified experts on the various subjects and provide in-depth
information on respective fields. The edit ing process for us was
not only educational but thrilling as the high quality and
complementary nature of the chapters became evident as we received
them. Be cause many areas in the field of liver cancer are
controversial, the reader will notice that contradictory opinions
are presented by some of the authors."
As in CANCER CHEMOTHERAPY 1, this volume brings to the reader
highlights in three different areas of cancer therapeutics: new
concepts and models; drug classes; and clinical settings. Topics
were chosen because of their timeliness or probable current impact
in cancer treatment. Authors were selected on the basis of their
ability to provide a critical overview of specific subjects and
their involvement in original work. I shall review the aims of this
second volume, and then elaborate on the scope of its con tents.
The principal aim of the volumes on cancer chemotherapy in the'
Cancer Treatment and Research' series, as stated in the preface to
the first volume, is to assemble in a concentrated form selected
ingredients of chemothera peutic progress. These ingredients are to
include concepts in therapeutic strategy, pre-clinical studies,
development of major classes of compounds, identificatlon of new
directions and of landmarks of clinical progress. Thus we do not
foresee overlap with series which provide an yearly update of
chemotherapy in an encyclopedic manner, or reviews of cancer
chemother apy. Unlike those publications, our volumes are not
intended to seek a place in shelves as a reference manual. It is
this Editor's hope that persons repre senting various biomedical
disciplines will seek the' Cancer Treatment and Research'
chemotherapy volumes to survey advances in the field at regular
intervals.
Where do you begin to look for a recent, authoritative article on
the diagnosis or management ofa particular malignancy? The few
general onco logy textbooks are generally out of date. Single
papers in specialized journals are informative but seldom
comprehensive; these are more often prelimi nary reports on a very
limited number of patients. Certain general journals frequently
publish good indepth reviews of cancer topics, and published
symposium lectures are often the best overviews available.
Unfortunately, these reviews and supplements appear sporadically,
and the reader can nev er be sure when a topic of special interest
will be covered. Cancer Treatment and Research is a series of
authoritative volumes which aim to meet this need. It is an attempt
to establish a critical mass of oncology literature covering
virtually all oncology topics, revised frequently to keep the
coverage up to date, easily available on a single library shelf or
by a single personal subscription. We have approached the problem
in the following fashion. First, by div iding the oncology
literature into specific subdivisions such as lung cancer,
genitourinary cancer, pediatric oncology, etc. Second, by asking
eminent authorities in each of these areas to edit a volume on the
specific topic on an annual or biannual basis. Each topic and tumor
type is covered in a volume appearing frequently and predictably,
discussing current diagnosis, staging, markers, all forms of
treatment modalities, basic biology, and more."
Neoplastic disease confined to the liver is an important worldwide
problem. In the industrialized nations, metastatic disease of the
most common cancers involves the liver in upwards of 50% of cases.
Primary hepatic tumors are virtually epidemic in most third world
countries and certainly constitute one of the ten most common
causes of cancer deaths on a worldwide scale. Amazingly, little
specific attention has been devoted to therapeutic approaches of
liver and biliary tumors until recently. We attribute this apparent
lack of interest to the uniformly poor progno sis of patients so
afflicted, and attribute the renewed interest to the exciting new
developments in diagnostic and therapeutic technology as well as in
tumor biology. The purpose of this book is to collect in one volume
an integrated selection of articles that would provide the
therapist with a comprehensive, yet practical, overview of liver
cancer. We believe the contributors to the book are superbly
qualified experts on the various subjects and provide in-depth
information on respective fields. The edit ing process for us was
not only educational but thrilling as the high quality and
complementary nature of the chapters became evident as we received
them. Be cause many areas in the field of liver cancer are
controversial, the reader will notice that contradictory opinions
are presented by some of the authors."
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