Table Of ContentPeptides and Non Peptides ofOncologic and
Neuroendocrine Relevance
From Basicto ClinicalResearch
Springer-V erlag Italia Srl.
E.E. MOiler (Ed)
Peptides and Non Peptides
of Oncologic and
Neuroendocrine Relevance
From Basic to Clinical Research
Springer
EUGENIO E. MOLLER
Department of Pharmacology
University of Milan
Milan, Italy
© Springer-Verlag Italia 2003
Originally published by Springer-Verlag Italia, Milano in 2003
Softcover reprint ofthe hardcover Ist edition 2003
ISBN 978-88-470-2170-9
Library of Congress Cataloging-in-Publication Data:
Peptides and non peptides in neuroendocrinology and oncology: from basic to clinic al
research/editor, E.E. Muller.
p.cm.
Includes bibliographical references and index.
ISBN 978-88-470-2170-9 ISBN 978-88-470-2085-6 (eBook)
DOI 10.1007/978-88-470-2085-6
1. Neuroendocrine tumors-Chemotherapy. 2. Hormone antagonists-Therapeutic use. 3.
Peptide hormones. I. Miiller, E.E.
RC280. E55P47 2003
616·99'28-dc22
2003057317
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Preface
Antineoplasticchemotherapyhas been,andstillis,the mostefficientform of
tumor treatment. It has, however, the major drawback that a great many
cytotoxic drugs non selectively alter the function ofhealthy cells as well as
thatofdiseasedcells.Greaterspecificityofthe actionofsubstances endowed
with antineoplastic mechanisms and activity, targeted exclusively at tumor
cells,the oldPaul Ehrlich conceptofthe"magicbullet",provides an antineo
plasticapproach free ofthe constraints ofthe traditional chemotherapy.The
development of monoclonal antibodies directed exclusively against a
tumoral cellclone,sparinghealthycells,brings anewtherapeutic strategyto
counter a metastatic breast cancer, as does the use ofan anti-tumoral DNA
vaccme.
The"old"endocrine-basedtherapyoftumors,too,is puttingoutpromising
signalsfor atargetedantineoplastictherapy.Itiswellknownthattumorsaris
ingfrom hormone-sensitive tissues maintain astate ofhormone dependency
that can be exploited to inhibition of growth. However, major progress in
antineoplastichormone therapyhas been achieved bysubstitutinghormones
produced by peripheral endocrine glands with peptides synthesized in the
brain. These molecules (hypothalamic regulatory hormones, RHs), in most
cases originally identified in the hypothalamus, have been subsequently
found in manyorgans and tissues ofthe body,especiallyin the gastrointesti
nal tract. RHs provide a physiologic stimulus to the pituitarywhen they are
secretedinaphysiologicpulsatilefashion, desensitizingand down-regulating
their pituitaryreceptors when are secreted or,more commonly,administered
either continuously, or in the form of superactive agonists. As an example,
LHRH, the physiologic stimulus for the function of the ovary and the testis
whenissecretedintermittently,inducesastateof"medicalcastration"whenit
is secreted or administered in a way that allows permanent occupancy ofits
pituitary receptors. This mechanism explains the successful use ofLHRH or
its superactive analogues in hormone-sensitive-tumors (breast,ovary,uterus,
prostate). Medical castration functionally inactivates a tumor that has estro
gen or testosterone receptors, blocks cellular proliferation, and, in the most
sensitive forms, induces regression ofmetastases. In addition to this indirect
mechanism, exerted via the pituitary, there also is the possibility ofa direct
action ofthe RH, acting directly on receptor sites embedded in the tumor, a
feature typical,for instance,ofanother RH,somatostatin (SS).
For SS, the ubiquitous location of its receptors lent credence to the idea
that, besides inhibiting GH secretion in acromegalic subjects and inducing
VI Preface
shrinkage of some GH secreting tumors, it may be helpful to counter the
growth of tissues and organs harboring SS receptors, as shown by an anti
tumoral action exerted on neuroendocrine tumors, and, more recently, by
promisingresults oncelllines from solidtumors (breast,prostate,ovary,kid
ney,brain). Development ofsynthetic analogues ofSS more stable in plasma
than the nativepeptideled to thediscoverythat thesensitivityofaparticular
intact or tumoral tissue is based not only on the presence, but also on the
number and the subtype ofSS receptors expressed.Hence,the need to devel
op "universal" SS analogues that, like the native peptide, can act on the full
panoplyofSS tissue receptors.
In the caseofSS,the multiplicityofRH mechanisms ofaction is best testi
fied to bythe additional abilityofthis peptide to exert an indirect,inhibitory
action,i.e.to restrain GH secretion,withensuingreduction ofcirculatingand
tissue titersofIGF-l,apotentmitogenicfactor. Finally,anotherantineoplastic
action of SS is its antiangiogenic action, mediated by peritumoral vascular
receptors, which, when activated, curtail the vascular supply to the tumor. A
similarmultiplicityofmechanismsofactionissharedbyanotherclassofRH
derived peptides,the GHRH antagonists.
The "magic bullet" approach of Ehrlich has been strengthened with the
development oftargeted hybrids in which a chemotherapeutic compound is
coupledto an analogue ofan RH.
The presentvolume,structured in17chapters,discussess the manyaspects
and problems ofthis new antineoplastic approach. Excellent preclinical and
clinicalresearchersofthefield,first amongthemAndrewV.Schally,oneofthe
discoverers of RHs, extensively and critically review and update our knowl
edge ofthe diagnostic and therapeutic use ofendocrine-derived compounds
not only hypothalamic or pituitary (LHRH agonists and antagonists, GHRH
antagonists,suppressors ofGH secretion,such as somatostatin,corticostatin,
orGH receptorsantagonists),butalso selectiveestrogenreceptormodulators,
antiandrogens,andenzyme inhibitors aimed at exerting antineoplastic activ
ity or potentiating the activity of traditional chemotherapy on neuroen
docrineand/orsolidtumors.Inaddition,four chaptersofthebookaredevot
ed to the physiologic functions ofa new class ofpotent GH releasers,ghrelin
and ghrelin mimetics, their receptors, and to the important endocrine and
non endocrine actions ofthese compounds.
Given the importance and novelty ofthe matter and the excellence ofthe
authors, it is hoped that this book may be of appealing interest not only to
basicandclinicaloncologists,endocrinologists,gynecologists,andurologists,
but also to students ofcellbiologyworldwide.
Grateful thanks are due to Ardana Biosciences, Astra Zeneca, Consiglio
Nazionaledelle Ricerche,Keryos,NovartisFarma,Pharmacia-Upjohn,Sanofi
Synthelabo,Zentarisfor the generousfinancial support,which made possible
the publication ofthis book.
Milan,July2003 E.E. Milller
Table ofContents
LHRH/SOMATOSTATIN
CHAPTER 1
Twenty-fiveYearsofEndocrineOncologywithAnalogsofHypothalamic
Peptides:anOverview
A.V.SCHALLY ..•........................... 3
CHAPTER2
AnalogsofLuteinizingHormone-releasing Hormone inBenignProstatic
Hyperplasia andAdvancedRenalCellCarcinoma
A.M.COMARU-SCHALLY . . . . . . . . . . . . . . . . . . . . . . . . . 21
CHAPTER3
LuteinizingHormone-releasing Hormone AntagonistsinGynecology
J.B.ENGELAND K.DIEDRICH ....................• 29
CHAPTER4
PhysiologyandPharmacologyofSomatostatinandItsReceptors
J.EPELBAUM ..............•............. 39
CHAPTER5
InvestigationofLHRH ReceptorInvolvementinMelanomaGrowthandProgression
M.MONTAGNANI MARELLI,R.M.MORETTIAND P.LIMONTA 47
SOMATOSTATIN/GHRHIGH
CHAPTER6
Cortistatin:NotSimplyaNaturalSomatostatinAnalogue
R.DEGHENGHI,F.BROGLIO,F.PRODAM,C.GOTTERO,M.PAPOTTI,
G.MUCCIOLIAND E.GHIGO . 57
CHAPTER 7
AntineoplasticandAntiangiogenicActionsofSomatostatinAnalogs
L.BUSCAIL . 65
CHAPTER8
SomatostatininClinicalEndocrinology
WWDEHERDERAND S.WJ.LAMBERTS 73
VIII TableofContents
CHAPTER9
AntagonistsofGrowthHormone-releasing Hormone inOncology
A.V.SCHALLY .•..•......•.•.••......•... 83
CHAPTER 10
GH ReceptorAntagonists:BasicKnowledgeandClinicalPerspectives
A.I.VAN DERLELY .•.•..•....•......••.•....• 99
GHRELIN ANDGHRELIN MIMETICS(GHS)
CHAPTER 11
Hypothalamic CircuitsResponsivetoGhrelin:RegulationbyLeptinandInsulin
S.L.DICKSON,L.Y.C.TUNGANDA.K.HEWSON ...••••.•••••.••• 109
CHAPTER 12
PhysiologicalFunctionofGrowthHormone SecretagogueReceptorsinthe
CardiovascularSystem
H.ONG,D.LAMONTAGNE,A.DEMERSANDS.MARLEAU • • . . . • • . . . • •• 117
CHAPTER 13
EndocrineandExtraendocrineActivityofGhrelinandtheGHS: BasicResearch
E.BRESCIANI,A.TORSELLO,R.AVALLONE,1.BULGARELLI,C.NETTI,
V.SIBILIA,G.RINDI,E.E.MOLLERANDV.loCATELLI •..••.••.....• 129
CHAPTER 14
EndocrineandNonendocrineActionsofGhrelinandGHS: StateoftheArt
inClinicalResearch
A.BENSO,F.BROGLIO,C.GOTTERO,F.PRODAM,S.DESTEFANIS,M.VOLANTE,
P.CASSONI,F.CATAPANO,E.TANABRA,L.FILTRI,R.DEGHENGHI,E.ARVAT,
M.PAPOTTI,G.MUCCIOLIAND E.GHIGO .•....•••..•• •• 147
HORMONAL TREATMENTSFORENDOCRINE-DEPENDENTTUMORS
CHAPTER 15
Hormonal TreatmentsofEndocrine-DependentTumors:
PreclinicalAspects
P.MAGNIANDM.MOTTA ..•....••.....•.••.•..•..•.• 161
CHAPTER 16
Hormonal TreatmentofEndocrine-DependentTumors:
ClinicalConsiderations
F.BOCCARDO,E.VERRI AND P.GUGLIELMINI ....••.•.•. . • • . . .. 169
CHAPTER 17
LetrozoleintheTreatmentofAdvancedBreastCancer
P.PRONZATOANDA.TOGNONI 183
SubjectIndex 193
List ofContributors
E.ARVAT I.BULGARELLI
DivisionofEndocrinologyand DepartmentofExperimental
Metabolism,DepartmentofInternal andEnvironmental
Medicine,UniversityofTurin, Medicineand Biotechnology,
Turin,Italy UniversityofMilano- Bicocca,
Monza,Italy
R.AvALLONE
DepartmentofExperimentaland L.BUSCAIL
EnvironmentalMedicine and INSERM Unit531 and Department
Biotechnology,UniversityofMilano ofGastroenterology,CHURangueil,
Bicocca,Monza,Italy Toulouse,France
A.BENSO P.CASSONI
DivisionofEndocrinology DepartmentofBiomedical
andMetabolism,Departmentof Sciencesand Oncology,
InternalMedicine, DepartmentofInternalMedicine,
UniversityofTurin, UniversityofTurin,
Turin,Italy Turin,Italy
F.BOCCARDO F.CATAPANO
AcademicDepartmentofMedical DepartmentofAnatomy,
Oncology(MedicalOncologyB), Pharmacology,andForensicMedicine,
UniversityandNationalCancer UniversityofTurin,
Research Institute, Turin,Italy
Genoa,Italy
A.-M.COMARU-SCHALLY
E.BRESCIANI Endocrine,PolypeptideandCancer
DepartmentofExperimentaland Institute,VAMedicalCenter,and
EnvironmentalMedicine and SectionofExperimentalMedicine,
Biotechnology,UniversityofMilano TulaneUniversitySchoolofMedicine,
Bicocca,Monza,Italy NewOrleans,LA,USA
F.BROGLIO R.DEGHENGHI
Division ofEndocrinologyand Division ofEndocrinologyand
Metabolism,DepartmentofInternal Metabolism,DepartmentofInternal
Medicine,UniversityofTurin, Medicine,UniversityofTurin,
Turin,Italy Turin,Italy
x
ListofContributors
A.DEMERS C.GOTTERO
FacultyofPharmacy, Division ofEndocrinologyand
UniversityofMontreal, Metabolism,DepartmentofInternal
Montreal,Quebec,Canada Medicine,UniversityofTurin,
Turin,Italy
W.W.DEHERDER
DepartmentofInternalMedicine, P.GUGLIELMINI
SectionofEndocrinology, AcademicDepartmentofMedical
ErasmusMC,Rotterdam, Oncology(MedicalOncologyB),
The Netherlands UniversityandNationalCancer
Research Institute,
S.DESTEFANIS Genoa,Italy
DivisionofEndocrinologyand
Metabolism,DepartmentofInternal A.K.HEWSON
Medicine,UniversityofTurin, DepartmentofPhysiology,
Turin,Italy UniversityofCambridge,
Cambridge,UK
S.L.DICKSON
DepartmentofPhysiology, S.w.J.LAMBERTS
UniversityofCambridge, DepartmentofInternalMedicine,
Cambridge,UK SectionofEndocrinology,ErasmusMC,
Rotterdam,The Netherlands
K.DIEDRICH
DepartmentofGynecologyand D.LAMONTAGNE
Obstetrics,UniversityClinic, FacultyofPharmacy,
Lubeck,Germany UniversityofMontreal,
Montreal,Quebec,Canada
J.B.ENGEL
DepartmentofGynecologyand P.LIMONTA
Obstetrics,UniversityClinic, InstituteofEndocrinology,
Lubeck,Germany CenterforEndocrinologicalOncology,
UniversityofMilan,
J.EPELBAUM Milan,Italy
U.549 INSERM,
IFR77Broca-SainteAnne, V.LOCATELLI
Paris,France DepartmentofExperimentaland
EnvironmentalMedicine and
L.FILTRI Biotechnology,UniversityofMilano
DivisionofEndocrinologyand Bicocca,Monza,Italy
Metabolism,DepartmentofInternal
Medicine,UniversityofTurin, P.MAGNI
Turin,Italy Institute ofEndocrinology,
UniversityofMilan,
E.GHIGO Milan,Italy
DivisionofEndocrinologyand
Metabolism,DepartmentofInternal S.MARLEAU
Medicine,UniversityofTurin, FacultyofPharmacy,
Turin,Italy UniversityofMontreal,
Montreal,Quebec,Canada
