Somatostatin Analogs forCancer Treatment and Diagnosis:An Overview
Carmelo Scarpignatoa,b Iva Pelosinia
aDepartment of Internal Medicine, School of Medicine and Dentistry, University of Parma,Italy; bDepartment of Gastroenterology and Hepatology, Faculty of Medicine, University ofNantes, France
Carmelo Scarpignato, MD, DSc, PharmD, FCP, FACGLaboratory of Clinical Pharmacology, Department of Internal MedicineMaggiore University Hospital, I–43100 Parma (Italy)Tel. +39 0521 903863, Fax +39 0521 292499, E-Mail [email protected]
AbstractDue to the limited efficacy and considerabletoxicity of conventional chemotherapy, nov-el cytotoxic agents and innovative noncyto-toxic approaches to cancer treatment are be-ing developed. Amongst the various hor-monal agents, increasing attention is beingdirected to somatostatin analogs. This islargely due to the demonstration of antineo-plastic activity of these compounds in a vari-ety of experimental models in vitro and invivo and to the elucidation of some aspectsof the molecular mechanisms underlyingtheir antineoplastic activity. On the otherhand, clinical experience with somatostatinanalogs in the treatment of conditions like
acromegaly and GEP tumors has shown thatthey are well tolerated compared to otherantineoplastic therapies currently in use. Asa consequence, there is much ongoing clini-cal research to determine whether or notresults from experimental studies will trans-late into clinically useful antineoplastic activi-ty. Besides being used in cancer treatmentand palliation, radiolabelled somatostatinanalogs are employed for the localization ofprimary and metastatic tumors expressingsomatostatin receptors. The so-called ‘soma-tostatin receptor scintigraphy’ is indeed themost important clinical diagnostic investiga-tion for patients with suspected neuroendo-crine tumors. Targeted radiotherapy, whichis being evaluated in clinical trials, repre-sents an obvious extension of somatostatinscintigraphy. Since the short half-life of na-tive somatostatin makes continuous intrave-nous infusion mandatory, several long-act-ing analogs have been synthesized. Amongstthe hundreds of peptides synthesized, oc-treotide (which binds mainly to SSTR-2 and
SSTR-5 receptor subtypes) has been themost extensively investigated. A thoroughanalysis of the pharmacological activitiesand therapeutic efficacy of the native so-matostatin and the synthetic analogs (octreo-tide, lanreotide and vapreotide) reveals thatthe biological actions of these peptides arenot always identical. These differences ap-pear to be related to the different affinities ofthe natural hormone and synthetic deriva-tives for the different receptor subtypes. Forall the three peptides long-lasting formula-tions have been developed to provide pa-tients with the convenience of once or twice amonth administration and to ensure stabledrug serum concentrations between injec-tions. Radiolabelled derivatives of octreotide,lanreotide and vapreotide have been synthe-sized and used as radiopharmaceuticals forsomatostatin receptor scintigraphy and so-matostatin receptor-targeted radiotherapy.The safety profile of synthetic somatostatinanalogs is well established. Most adversereactions to these peptides are merely a con-sequence of their pharmacological activityand consist mainly of gastrointestinal com-plaints, cholelithiasis and effects on glucosemetabolism. They are often of little clinicalrelevance, thus making somatostatin ana-logs safe drugs for long-term use. While im-mediate release preparations are the drugsof choice in the short term, long-acting for-mulations are better indicated, on an outpa-tient basis, for the long-term management ofchronic conditions. New ‘receptor-selective’and ‘universal’ somatostatin analogs are be-ing developed and combinations of currentlyavailable derivatives with other (cytotoxicand/or hormonal) agents are being exploredin the search for an efficacious and well-toler-ated treatment of the various malignancies.Somatostatin receptor-targeted chemothera-py (with conjugates of somatostatin peptideswith cytotoxic drugs) and gene therapy (e.g.
transferring the SSTR-2 gene into neoplasticcells), which have been successfully tested inexperimental studies, should be applied tohuman beings in a not too distant future.
Although cytotoxic chemotherapy is veryeffective in the management of certain neo-plasms such as testicular cancer, the efficacyof this therapeutic modality in the treatmentof many common neoplasms such as those ofthe lung, breast, prostate, bowel, pancreas andkidney is limited. Cure of macroscopic meta-static disease is exceedingly rare, and pallia-tion of symptoms of metastatic neoplasms bychemotherapy can be problematic since thetoxicity of the treatment often outweighs anyimprovement in quality of life resulting fromthe temporary decrease in tumor burden [1–4]. Moreover, postsurgical adjuvant chemo-therapy is frequently without beneficial effect(as in the case of renal cancer), or is associat-ed with only small improvements in disease-free survival (as in the case of colon can-cer, for instance). This situation has not onlymotivated attempts to develop novel cyto-toxic agents, but also has stimulated the re-search regarding innovative noncytotoxic ap-proaches to cancer treatment [1–4].
Amongst the various hormonal agents, in-creasing attention is being directed to so-matostatin analogs [5–12]. This is largely dueto the demonstration of antineoplastic activi-ty of these compounds in a variety of experi-mental models in vitro and in vivo [5, 7] andto the elucidation of some aspects of the mo-lecular mechanisms underlying their antineo-plastic activity [13–16]. On the other hand,clinical experience with somatostatin analogsin the treatment of conditions like acromegalyand GEP tumors has shown that they are well
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tolerated compared to other antineoplastictherapies currently in use [16, 17]. As a conse-quence, there is much ongoing clinical re-search to determine whether or not resultsfrom experimental studies will translate intoclinically useful antineoplastic activity.
Besides being used in cancer treatment andpalliation, radiolabelled somatostatin analogsare employed for the localization of prima-ry and metastatic tumors expressing somato-statin receptors [18–21]. The so-called ‘so-matostatin receptor scintigraphy’ is indeedthe most important clinical diagnostic investi-gation for patients with suspected neuroendo-crine tumors [19]. Targeted radiotherapy,which is being evaluated in clinical trials [22,23], represents an obvious extension of so-matostatin scintigraphy. This paper will re-view the chemistry and pharmacokinetics ofcurrently used synthetic peptides and summa-rize the rationale for their use in cancer treat-ment and diagnosis.
Somatostatin Analogs:Chemistry and Pharmacokinetics
Due to its central role in the regulation ofgrowth hormone secretion, somatostatin is of-ten referred to as somatotropin release-inhib-iting factor (SRIF) or growth hormone (GH)release-inhibiting factor [24]. This peptidedisplays a wide range of biological actions thatcan make it an appropriate drug for the treat-ment of a variety of human diseases.
Shortly after the isolation of somatostatin,protein chemists began to synthesize peptideanalogs with a similar spectrum of action butwith much longer biological half-life [25]. Theshort half-life of the native peptide [26] makesindeed continuous intravenous infusion man-datory.
To design a more stable peptide derivativeone needs to strengthen the metabolic resis-
Fig. 1. Sites of enzymatic degradation of natural so-matostatin.
tance of the cleavage sequences of the nativepeptide. In the case of somatostatin, at least 5sites of enzymatic degradation are known(fig. 1) [27]. The most dangerous cleavage canoccur after Trp8 because such a rupture leads tocompletely inactive fragments. Aminopepti-dase attack at the N-terminal is less importantsince sequences which are 1 or 2 amino acidsshorter are as potent as the native peptide.
The usual trick to prevent or slow downenzymatic degradation of a peptide is thereplacement of an L-amino acid by its D-iso-mer. Fortunately, the systematic replacementof L- by D-amino acids demonstrated that thisexchange at position 8 is not only well tolerat-ed but also leads to an enhanced GH-inhibito-ry potency [28].
Further important information on the ac-tive site can be deduced by systematic re-placement of all amino acids in SRIF by aneutral amino acid such as Ala. The totalinactivity of analogs with Ala in positions 6, 7,8 or 9 indicates that these residues are essen-tial for its biological activity. Similarly, yetmore information can be gained by systemati-cally deleting single amino acids from the nat-ural sequence. Such studies showed that thefirst two amino acids, Ala-Gly, are not neces-sary for full biological activity [28].
Against this background, hundreds of so-matostatin analogs have been synthesized inmany research centers all over the world.Amongst the different peptides (table 1), theoctapeptide SMS 201-995, called octreotide,has been the most extensively investigated[for reviews, see 29–32]. More recently, two
additional peptides [33], namely lanreotide(BIM 23014) [34] and vapreotide (RC-160)[35], have become available for clinical use. Itis worthwhile to emphasize that all the threepeptides share a common feature, namelythe tetrapeptide X7-Trp8-Lys9-Y10 (where Xcould be either Phe or Tyr and Y either Thr or
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Fig. 3. Stability of octreotide (SMS201-995) and SIRF against degra-dation by rat kidney homogenates[from 25].Fig. 4. Plasma levels of unchangedpeptides in the rat: intravenousapplication of [3H-Phe6]SRIF (o)and [4C-D-Trp4]octreotide ()).SRIF was injected at 1.6 mg/kg(12–16 mCi/mmol), octreotide at1 mg/kg (35 ÌCi/mg). Unchangedpeptides were recovered after high-pressure liquid chromatographypurification of plasma samples.Data are taken from Peters [42] forSRIF and from Lemaire et al. [38]for octreotide. Only the most rele-vant alpha phases of eliminationare indicated.
Val, fig. 2), thus suggesting that this aminoacid sequence is essential for receptor binding[36]. And indeed conformational analysis ofthe bioactive analogs of somatostatin thathave conformational constraints revealed thatthe peptide backbone is not directly involvedin binding, but serves mainly as a scaffoldallowing the side chains to adopt the neces-sary pharmacophore spatial arrangement nec-essary for receptor binding [37].
Compared with native somatostatin, thesynthetic derivatives show a remarkable stabil-ity. Indeed, introduction of a D-amino acid (D-Phe or D-ßnal) at the N-terminus protectsagainst exopeptidases, as does the amino-alco-hol Thr(ol) at the C-terminus of octreotide and
lanreotide. The disulfide bridge itself offerssome protection, and the D-Trp protects a posi-tion which would otherwise be cleaved by aspecific endopeptidase. For instance, when in-cubated with kidney homogenate, a systemknown to degrade natural peptides within a fewminutes, more than 90% of the biological activ-ity of octreotide was still present after 20 h,whereas the natural peptide was almost com-pletely destroyed in less than 1 h (fig. 3) [25].
The pharmacokinetics of octreotide wasinvestigated in rats after administration ofunlabelled and labelled (3H- and 14C-) pep-tides [38], and data were compared with thosefrom a study with 3H-labelled SRIF [39](fig. 4). The marked stability of octreotide
Fig. 5. Tissue levels of octreotideafter subcutaneous administrationof 1 mg/kg in the rat. Tissue lev-els were measured by means ofa specific radioimmunoassay af-ter extraction into a mixture ofmethanol-trifluoroacetic acid (80–0.1%) and subsequent lyophiliza-tion and reconstitution in buffer.For each organ the columns repre-sent (from left to right) concentra-tions measured 0.5, 4, 7 and 24 hafter administration [from 39].
against proteolytic degradation together witha reduced hepatic clearance is responsible forthe dramatically improved elimination half-life in rats [39, 40]. In both rats and monkeys,the peptide is well absorbed after subcuta-neous administration, the elimination rate(based on plasma levels) being slower in thelatter species [41]. Significant levels of octreo-tide can also be detected in the rat after oraladministration of the peptide [41].
While extensive degradation into smallfragments and amino acids is evident in alltissues within the first minutes after intrave-nous injection of 3H-SRIF in rats [42], octreo-tide proved to be quite stable in all the tissuesexamined [38]. Concentrations measured byquantitative whole body autoradiography,which determines total radioactivity, and byspecific radioimmunoassay were quite com-parable. Thirty minutes after intravenous ad-ministration the highest concentrations weredetected in the kidney, skin and liver. By fol-lowing the time course of organ distributionof total radioactivity and of unchanged oc-treotide (fig. 5) it became apparent that elimi-nation from presumed target organs such aspituitary and pancreas was much slower whencompared with nontarget tissues such as mus-cle, lung and heart. This indicates high-affini-
ty binding to target receptors characterized byslow off-kinetics.
Pharmacokinetic investigations have alsobeen performed in healthy subjects and pa-tients with pituitary tumors and the review byChanson et al. [40], to which the reader isreferred, thoroughly summarizes all the avail-able data. Studies in healthy volunteers [43]demonstrated that octreotide plasma levelsare proportional to the dose administeredboth after intravenous and subcutaneous ad-ministration. Plasma peak concentration val-ues, which were reached after 30 min, wereapproximately half those obtained after intra-venous injection of the same dose. Systemicbioavailability after subcutaneous octreotidewas reported to be almost complete [44].Plotting the areas under concentration-timecurves (AUCs) against the dose administered,gives a linear relationship and this suggeststhat the pharmacokinetic of octreotide is li-near – at least in the dose range studied – irre-spective of the route of administration [43].The disposition half-life ranged from 80 to100 min for both routes of administration,depending on the dose, that is more than 30times the half-life of the natural peptide.
In blood, octreotide is mainly distributedin the plasma, 65% of the drug being bound to
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lipoprotein and, to a lesser extent, albumin,while negligible amounts are taken up by redcells [38]. No conclusive data are availableconcerning the tissue distribution of octreo-tide in humans [45], although it has beenshown that the drug concentrates in many tis-sues in the rat [38].
Pharmacokinetic data on the metabolismand elimination of octreotide are similar inacromegalic and healthy individuals [46, 47].When compared with healthy volunteers, to-tal body clearance of octreotide was reducedto 75 ml/min (4.5 liters/h) in patients withchronic renal failure [48]. Although biliaryexcretion and proteolysis are also importantelimination pathways in the rat and the dog,they have not been thoroughly studied in hu-mans.
The pharmacokinetics of lanreotide inhealthy volunteers [49, 50] has shown a pat-tern similar to that observed with octreotide,i.e. a Tmax of about 30 min and an eliminationhalf-life of 90 min after single subcutaneousinjection of the peptide. The pharmacokinet-ics of lanreotide proved to be linear eitherafter subcutaneous or intravenous route. Thesignificant negative correlation between plas-ma GH and peptide concentrations observedin the study does suggest a dose-dependentbiological effect [49]. Conversely from octreo-tide, lanreotide in blood is mainly bound toalbumin [51].
Given the very short half-life of SRIF, dis-tribution and elimination studies become al-most obsolete, and application is restricted tocontinuous infusion to maintain therapeuti-cally relevant plasma concentrations. Withoctreotide and lanreotide, however, the highlyimproved metabolic stability, small volumeof distribution and low clearance result in along duration of exposure; consequently, long-lasting biological activity after a single subcu-taneous injection of the analogs is obtained.
Receptor Selectivity of SomatostatinAnalogs
The action of somatostatin is mediatedthrough specific receptors that are functional-ly coupled to inhibition of adenylyl cyclase viapertussis toxin-sensitive GTP binding pro-teins [for reviews, see 15, 52–54]. Up to fivecell-surface somatostatin receptors have beencharacterized. They have been termed SSTR-1 through SSTR-5 according to the chronolo-gy of their discovery and because they all dis-play the structural hallmark of the seven-transmembrane-domain receptor (SSTR is in-deed the acronym for somatostatin seven-transmembrane-domain receptor). Their tis-sue distribution is depicted in figure 6. Hu-man SSTRs (hSSTRs) are encoded by a fami-ly of 5 genes which map to separate chromo-somes and which, with one exception, areintronless. SSTR-2 gives rise to spliced vari-ants, SSTR-2A and 2B. hSSTR-1 to hSSTR-4display weak selectivity for SST-14 bindingwhereas hSSTR-5 is SST-28-selective. Basedon structural similarity and reactivity for oc-tapeptide and hexapeptide SST analogs (ta-ble 2), hSSTR-2, 3 and 5 belong to a similarSSTR subclass. hSSTR-1 and 4 react poorlywith these analogs and belong to a separatesubclass [55, 56].
Somatostatin receptors have also been de-tected in a number of tumors such as pituitaryadenomas, neuroendocrine and nonendo-crine tumors [57–60]. Pituitary and islet tu-mors express several SSTR genes suggestingthat multiple SSTR subtypes are coexpressedin the same cell [56]. However, there is vari-ability in both the number and the distribu-tion of somatostatin receptors between tu-mors and from site to site in a given tumor[61, 62]. Since a variable suppression of GHplasma levels following administration of so-matostatin or octreotide has been demon-strated in an acromegalic patient, it has been
Derived from data in table 2 by using a cut-off value for agonist selectivity (Ki) of 6 nM.
hypothesized that the heterogeneity of boththe number and distribution of somatostatinreceptors might in part explain the individualvariable sensitivity to treatment with soma-tostatin or its analogs [61, 62].
Although the actions of synthetic analogsare similar to those of native somatostatin,some differences have emerged that probablyrelate to the different ligand affinities forSSTR subtypes (table 3). This may have sev-
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eral clinical consequences and the spectrumof the therapeutic efficacy of octreotide andits derivatives (i.e. lanreotide and vapreotide)may not be the same as somatostatin. Indeed,cells expressing SSTR-1 or SSTR-4 will re-spond poorly or not at all to somatostatin ana-logs.
Somatostatin Analogs: Mechanismsof the Antineoplastic Action
Besides having an important role in thesymptomatic treatment of endocrine tumorsthrough peptide suppression, somatostatinmay also exert an antiproliferative effect,which is not limited to endocrine tumors.Nonendocrine tumors may also be affected,although some somatostatin influence may inpart be hormonally mediated. Some authorshave actually reported – after treatment withsomatostatin and synthetic analogs – tumorregression either in patients or animals withexperimentally induced neoplasms.
More recent research has provided infor-mation regarding mechanisms underlying theantiproliferative and apoptosis-inducing ac-tions of somatostatin analogs. These includeboth direct mechanisms that are sequelae ofbinding of somatostatin analogs to somato-statin receptors present on neoplastic cells[57–60] and indirect mechanisms related toeffects of somatostatin analogs on the host[for reviews, see 7, 14, 15].
The indirect mechanism would operatethrough a suppression of the GH release fromthe pituitary and the resulting inhibition ofthe hepatic production of insulin-like growthfactor-1 (IGF-1) [14, 15]. The fall in IGF-1could inhibit the growth of various tumorssince IGF-1 and IGF-2 as well as other growthfactors, including EGF, appear to be involvedin the proliferation of neoplastic cells. Thepotential importance of these mechanisms of
action is emphasized by the in vivo antineo-plastic activity of these compounds againstsomatostatin receptor-negative neoplasms.
Another potential mechanism throughwhich somatostatin may exert an antitumoreffect is through its inhibition of tumor angio-genesis, which is essential for implantationand growth [63–65]. Several experimentalpieces of evidence suggest that SSTR-2 prefer-ring agonists such as octreotide do inhibitangiogenesis in vitro and in vivo [11]. Sinceperitumoral vessels express somatostatin re-ceptors [66] and neovascularization is en-hanced by IGF-1 [67], inhibition of angiogen-esis itself might involve direct and/or indirectactions of somatostatin analogs on the non-transformed cells comprising the microvascu-lature of neoplastic tissue.
Studies performed over the past 5 yearshave demonstrated that induction of apop-tosis represents one of the mechanisms bywhich cytotoxic drugs exert their antineoplas-tic action [68]. Several lines of evidence sug-gest that somatostatin analogs can also induceapoptosis via interaction with SSTR-3 [14]. Inthis connection it is worth mentioning thatIGF-1 is recognized as a potent antiapoptoticfactor [69]. Thus, the inhibitory effects ofsomatostatin analogs on IGF-1 gene expres-sion may enhance their direct apoptosis-in-ducing action and contribute to the apoptoticeffect of these compounds. A recent investiga-tion [70], performed in patients with gut neu-roendocrine tumors, did show that treatmentwith high-dose somatostatin analogs inducesapoptosis in tumor cells, which correlatedwith the biochemical response (i.e. decrease intumor markers), while low-dose somatostatinanalogs do not modify the apoptotic index.
Finally, somatostatin analogs stimulate theactivity of the reticuloendothelial and lym-phopoietic systems in the rat [6]. Changes innatural killer cell activity were reported inman [6]. It is, therefore, possible that modula-
Table 4. Possible mechanisms of the antineoplasticaction of somatostatin analogs
1 Direct antimitotic effects via somatostatinreceptors on tumor cells
2 Suppression of the release of trophic hormones(e.g. GH, insulin, prolactin and gut peptides)
3 Direct or indirect inhibition of growth factors(e.g. IGF-1, EGF, PDGF)
4 Inhibition of angiogenesis5 Induction of apoptosis6 Modulation of the immune response
tion of immune defense mechanisms mightcontribute to the tumor growth inhibitory ef-fects of these compounds.
In summary, somatostatin and its analogsmay have tumoricidal or antiproliferative ef-fects mediated by suppressing promotor hor-mones, by inhibiting mitogens (directly sup-pressing cell division, protein synthesis, ortranslation), by inhibiting angiogenesis andinducing apoptosis or by stimulating the im-mune system (table 4). Although the clinicalrelevance of some experimental models is atpresent unknown, the prospects of such in-vestigations are worthy of serious considera-tion. Octreotide and its derivatives may thusevolve towards an adjunctive, albeit limitedrole, in a direct chemotherapeutic manage-ment of endocrine and nonendocrine tumors.The key to this problem appears to be in theheterogeneity of somatostatin receptor sub-type. There is no doubt that not all of thereceptor subtypes are responsible for growthinhibition [58, 59]. Indeed, there is evidencethat some may even promote cell growth. Thefuture of somatostatin as a clinically usefulanticancer drug thus lies in the characteriza-tion of the specific receptors that mediategrowth inhibition and the synthesis of analogsthat bind selectively to them.
Long-Lasting Formulations ofSomatostatin Analogs
Several studies [71–75] showed that San-dostatin® administered by continuous subcu-taneous pump infusion produced better sup-pression of GH and IGF-1 serum concen-trations, rapid clinical improvement, andshrinkage of GH-secreting adenomas in com-parison to intermittent subcutaneous injec-tions. Data on the very good efficacy of San-dostatin administered by pump infusion stim-ulated research to develop a new galenical for-mulation that could ensure long-lasting, sus-tained and consistent drug delivery. Nasal ad-ministration provides a satisfactory control ofGH hypersecretion, but because of poor localtolerability, its chronic use is not feasible atpresent [76]. An extended-release formulationmimicking the continuous subcutaneous infu-sion of octreotide to be injected monthlywould be an obvious improvement in thetreatment of acromegalic patients requiringlong-term Sandostatin therapy by twice dailyor 3 times daily dosing. Sandostatin LAR®,obtained by incorporating octreotide into mi-crospheres of a biodegradable polymer, po-ly(DL-lactide-co-glycolide glucose), was de-veloped to provide patients with the conve-nience of a once-a-month administration andto ensure a stable serum octreotide concentra-tion between injections, sustained GH andIGF-1 suppression, good clinical control ofsymptoms and signs of acromegaly, and im-proved acceptability and compliance for long-term treatment with Sandostatin [for a re-view, see 77].
The release characteristics and toxicologyof Sandostatin LAR were studied in rats andrabbits [32, 78]. Single intramuscular injec-tions of Sandostatin LAR resulted in an initialpeak, attributed to drug adsorbed to the sur-face of microspheres, followed by low concen-trations over 1–2 weeks and thereafter by sus-
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Fig. 7. Time course of serum oc-treotide concentrations after ad-ministration of single doses of10 mg (P, n = 16), 20 mg (d, n =39) or 30 mg ($, n = 37) of Sandos-tatin LAR to acromegalic patients.Each point is the mean of 12-hourmean concentrations per patient.Vertical bars are standard errors[from 78].
tained octreotide plasma levels over a periodof 4–6 weeks. After repeated injections at 4-week intervals, consistent and stable plasmaconcentrations of octreotide were recorded.Toxicological studies performed in rabbitsand rats revealed only a very limited, revers-ible granulomatous myositis at the injectionsite. The biodegradation of the microspheresis completed within 10–12 weeks, and toxico-logical studies showed that Sandostatin LARhas low toxicity and good local tolerability[32, 78].
Three different preparations (i.e. 10, 20 or30 mg) are available for clinical use. Theirpharmacokinetics has been studied in acro-megalic patients [78]. A consistent pattern ofoctreotide release from the polymer matrix of
Sandostatin LAR was documented in all stud-ies and for all dose levels investigated. A rapidincrease in octreotide serum concentrationswas noted after intramuscular injection ofSandostatin LAR, with a peak occurring with-in 1 h after the injection followed by a pro-gressive decrease to low octreotide levelswithin 12 h. On days 2 through 7, after singledoses of Sandostatin LAR, octreotide serumconcentrations were at lowest levels. Thereaf-ter, an increase in serum octreotide concen-trations occurred, and dose-dependent pla-teau concentrations were observed betweendays 14 and 42 followed by a progressivedecrease from day 42 on (fig. 7). In the plateauphase (days 14–42), the daily average plasmaconcentrations remained very stable over the
tmax = Time to maximum concentration; Cmax = maximum concentration; Cmax/D = maxi-mum concentration normalized on dose; AUC0–60 days = area under the curve from day 0 today 60; AUC0–60 days/D = AUC normalized on dose. Plateau duration is the duration duringwhich the concentrations were above 80% of Cmax.1 Relative bioavailability with respect to subcutaneous 3 times daily treatment; values arethe geometric mean.
12-hour observation period, similar to thoseseen after subcutaneous continuous infusion.The height of the octreotide peak on day 1 forall doses tested was lower than the plateauconcentrations, and the area under the peakon the day of injection of Sandostatin LARwas not larger than 0.5% of the total AUC(0–60 days).
A dose-dependent increase of the maxi-mum concentration and AUC of octreotidewas recorded in the dose range between 10and 30 mg. The computed key pharmacoki-netic parameters are summarized in table 5.
In agreement with animal data, humanstudies also showed good systemic and localtolerability as well as a lack of dose dumping(i.e. immediate release of significant quanti-ties of drug). Preliminary results from studiesperformed in acromegalic subjects, respon-sive to subcutaneous octreotide, have shownthat one single injection of 30 mg SandostatinLAR is followed by 4- to 6-week GH suppres-sion in 80% of patients [78–80]. It is likely,
therefore, that this long-lasting formulationcan replace 3 times daily subcutaneous injec-tions by an intramuscular injection at 4-weekintervals to improve the acceptability of long-term therapy in acromegalics. In addition, byreleasing consistent concentrations of serumoctreotide and by producing a consistent sup-pression of GH secretion, Sandostatin LARappears to be as effective as subcutaneousinfusions of Sandostatin and more effectivethan intermittent subcutaneous administra-tion. Indeed, in the patients switched fromsubcutaneous treatment to Sandostatin LAR,suppression of GH secretion and serumIGF-1 concentrations and the clinical im-provement have been either as good as or bet-ter than with Sandostatin administered sub-cutaneously [78]. Indeed, a larger number ofpatients showed a normalization of serumIGF-1 concentrations and a clinical improve-ment. Beyond the improvement/disappear-ance of symptoms/signs of acromegaly, somepatients actually become asymptomatic. The
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Fig. 8. Pharmacokinetics of lan-reotide and GH pattern in 21 pa-tients at the first intramuscular in-jection of the drug (Somatuline SR,30 mg) [from 89].
usefulness of this octreotide formulation inthe management of malignant carcinoid syn-drome has been recently shown [81].
A slow-release formulation (Somatuline-SR®) is also available for the other somato-statin analog, lanreotide. This formulationhas been studied in healthy volunteers [82]and acromegalic patients [83]. The maximumlanreotide concentration (Cmax) in plasma(38.3 B 4.1 ng/ml) was obtained 2 h followinginjection. The levels then progressively de-creased, remaining above 1.5 ng/ml until day11 and reaching 0.92 B 0.28 ng/ml 2 weeksafter injection. The apparent plasma half-lifeand mean residence time were 4.52 B 0.50and 5.48 B 0.51 days, respectively [81].
Studies with Somatuline-SR have beencarried out by several European centers [83–88] on a few groups of acromegalic patients,often selected on the basis of their previousresponsiveness to octreotide therapy. An Ital-ian multicenter study [89] evaluated the toler-ability and effectiveness of this formulation ina large number of acromegalic patients withactive disease, unselected in terms of their
previous responsiveness to octreotide, andfound that 30 mg of the compound, adminis-tered every 14 days, provided an effectivetreatment in the majority. After drug admin-istration, an inverse correlation was foundbetween lanreotide and GH plasma levels(fig. 8).
Both octreotide and lanreotide slow-re-lease formulations, administered monthlyand every 10–14 days, respectively, proved tobe effective in controlling symptoms associat-ed with neuroendocrine gut tumors, provid-ing – in addition – a substantial improvementin patient compliance [90–95].
A slow-release formulation of vapreotidewas developed more than 10 years ago [96]whereas a long-term delivery system has beenproduced only recently [97]. This injectable,biodegradable depot formulation ensures sa-tisfactory peptide blood levels in rats for over250 days. No pharmacokinetic data withthese formulations have yet been published inhumans.
Radiopharmaceuticals for SomatostatinReceptor ScintigraphyThe diagnosis and staging of neuroendo-
crine tumors is often difficult and time con-suming. Blood levels of hormonal markers arefrequently elevated and allow a presumptivediagnosis [98] but, since tumors are frequent-ly small, standard imaging techniques such asultrasonography or computed tomographycannot accurately localize the tumor [99]. Ar-teriography and selective venous sampling aremore specific, but technically demanding andnot always accurate [100]. Somatostatin re-ceptor-expressing tumors and their respectivemetastases are attractive targets for diagnosticimaging with gamma emitter-labelled syn-thetic analogs. Indeed, somatostatin receptordetection can be accomplished by injecting aradiolabelled peptide analog and imaging tis-sue uptake of the compound via scintigraphy.Selective radioactive uptake will occur in pro-portion to the density and affinity of thereceptor population. Octreotide binds withhigh affinity to the SSTR-2, while this analoghas a relatively low affinity for SSTR-3 andSSTR-5 and shows no binding to SSTR-1 andSSTR-4 (see above). Octreotide scintigraphy(OctreoScan®) is, therefore, based on the vi-sualization of (an) octreotide-binding so-matostatin receptor(s), most probably SSTR-2 and SSTR-5 [18–21]. Visualization ofSSTR-positive tumors is widely used in tumorstaging and may also predict therapeutic re-sponse to octreotide. A number of studies[101, 102] have suggested that somatostatinreceptor scintigraphy can be used to selectpatients with malignant carcinoid tumorssuitable for somatostatin analog treatmentand exclude those that will not benefit fromsuch medication since most hormone-secret-ing tumors react in vitro to octreotide with aninhibition of hormone release and possibly
inhibition of growth. It has been shown, forinstance, that in patients with carcinoids,there was a complete agreement between thepresence of mRNA for SSTR-2 detected by insitu hybridization and therapeutic response tooctreotide [103]. In those patients with patho-logical tracer accumulation without expres-sion of somatostatin SSTR-2 mRNA, otherSSTRs may be present that can bind thesomatostatin analog but not inhibit hormonesecretion. However, octreotide scintigraphyalone may not be sufficient in determining thepatients with neuroendocrine tumors who canbenefit from chronic treatment with somatos-tatin analogs, because almost 20% of patientswith pathological somatostatin scintigraphyfail to respond to such treatment and further,in rare cases, octreotide treatment results inclinical improvement in spite of octreotidescintigraphy failure to demonstrate any tumorlocalization [58, 59].
A radioiodinated analog of somatostatin,[123I-Tyr3]octreotide (fig. 9), was first used todetect somatostatin receptor-positive tumors[104]. However, despite the successful visuali-zation with this radiopharmaceutical of a va-riety of somatostatin receptor-positive tumorsin more than 100 patients, this method of invivo imaging had several drawbacks, amongstwhich are the limited availability of chemical-ly pure 123I and the high abdominal back-ground of radioactivity, caused by clearanceof this analog via the liver [104]. Therefore, an111In-labelled somatostatin analog was devel-oped. [Diethylenetriamine pentaacetic acid(DTPA)-D-Phe1]-octreotide was shown tobind 111In efficiently in a single step proce-dure. The binding as well as the biologicalactivity of this new labelled peptide wereshown to be similar to that of octreotide, mak-ing it a good radiopharmaceutical for in vivoimaging of somatostatin receptor-positive tu-mors [105]. The 111In-labelled octreotide isexcreted mainly via the kidneys, 90% of the
Somatostatin Analogs for CancerTreatment and Diagnosis
Chemotherapy 2001;47(suppl 2):1–29 15
Fig. 9. Chemical structures of oc-treotide, [Tyr3]-octreotide, DTPAand DOTA.
dose being present in the urine 24 h afterinjection. Because of its relatively long effec-tive half-life, [111In-DTPA-D-Phe1]-octreo-tide is a radiopharmaceutical which can beused to visualize somatostatin receptor-bear-ing tumors efficiently after 24 and 48 h, wheninterfering background radioactivity is mini-mized by renal clearance [104]. The synthe-sis and biological properties of 99mTc-hydra-zinonicotinyl-Tyr3-octreotide (HYNIC-TOC)using different coligands for radiolabeling wasreported quite recently by Decristoforo et al.[106]. HYNIC-TOC was radiolabelled at highspecific activities using tricine, ethylenedi-aminediacetic acid, and tricine-nicotinic ac-id as coligand systems. All 99mTc-labelledHYNIC peptides showed retained somato-statin receptor binding affinities (Kd !2.65nM). Protein binding and internalizationrates were dependent on the coligand used.Specific tumor uptake between 5.8 and 9.6%of the injected dose/g was found for the 99mTc-labelled peptides compared with 4.3% in-jected dose/g for [111In-DTPA-D-Phe1]-oc-treotide [106]. The high specific tumor up-take, rapid blood clearance, and predomi-
nantly renal excretion make [99mTc-EDDA-HYNIC-TOC] a promising candidate as analternative to [111In-DTPA-D-Phe1]-octreo-tide for tumor imaging.
The major limitation of somatostatin re-ceptor scintigraphy using radiolabelled li-gands of octreotide is that the technique willonly allow detection of those tumors express-ing hSSTR-2 and hSSTR-5 and possibly thoseneoplasms expressing hSSTR-3 in sufficientdensity to allow visualization. Radioligandsof lanreotide or vapreotide might be moreuseful than radiolabelled ligands of octreotidein visualizing those tumors that expresshSSTR-4, but not hSSTR-2 and hSSTR-5. Vi-sualization of tumors by lanreotide or vapreo-tide scintigraphy but not by octreotide scin-tigraphy may provide a rationale for the selec-tion of patients that are likely to benefit fromtherapy with these analogs but this hypothesisrequires confirmation in prospective con-trolled trials.
Taking the above considerations into ac-count, radiolabelled derivative of both lanreo-tide [111In-DOTA-lanreotide] and vapreotide[111In-DTPA-D-Phe1]-RC-160 have been de-
veloped [107–109]. However, while labelledlanreotide showed a high tumor uptake for avariety of different human tumor types anda favorable dosimetry over labelled octreo-tide [107], with [111In-DTPA-D-Phe1]-RC-160 blood radioactivity (background) washigher, resulting in a lower tumor to blood(background) ratio [108]. This radiopharma-ceutical should, therefore, have no advantageover [111In-DTPA-D-Phe1]-octreotide for thevisualization of somatostatin receptors whichbind both analogs. However, recent reportssuggest the existence of different somatostatinreceptor subtypes on some human cancers,which differentially bind the synthetic so-matostatin analogs [60]. These tumors in-clude cancers of the breast, ovary, exocrinepancreas, prostate and colon. Radiolabelledlanreotide or vapreotide might be of interestfor future use in such cancer patients as aradiopharmaceutical for imaging somatosta-tin receptor-positive tumors, which do notbind octreotide. Compared with the parentpeptide (i.e. lanreotide), DOTA-lanreotideseems to display a distinct binding pattern,since it binds all transfected hSSTR subtypesas well as a large variety of primary humantumors [107]. As a consequence, the radio-pharmaceutical is claimed to be a ‘universal’SSRT ligand. A multicenter study (calledMulticentre Analysis of a Universal ReceptorImaging and Treatment Initiative: a Euro-pean Study) was recently started, for whichthe acronym MAURITIUS has been coined.[DOTA]-lanreotide was then renamed MAU-RITIUS. In a preliminary report 111In-MAU-RITIUS was used in a series of 25 patientswith advanced malignancies refractory toconventional antineoplastic treatment and inall of them at least one tumor site could bevisualized at scintigraphy [110]. Interestinglyenough, some neoplasms, which were re-peatedly negative by the conventional Oc-treoScan, could be visualized by means of this
new radiopharmaceutical, thus suggestingthat somatostatin receptors other thanhSSTR-2 and hSSTR-5 are responsible forbinding.
While single photon emission computedtomography seems to improve accuracy ofsomatostatin receptor scintigraphy [111], in-traoperative gamma detection reveals ab-dominal endocrine turmors more efficientlythan conventional OctreoScan [112–114] andmay allow improvement in surgical manage-ment allowing radioimmunoguided surgery[115]. In vitro and in vivo studies [116]showed that a recently developed terbium-161-labelled derivative, i.e. [161Tb-DTPA-D-Phe1]-octreotide, represents a promising phar-maceutical for intraoperative scanning andradiotherapy.
Octreotide has also been labelled with posi-tron-emitting 67Ga [117], 64Cu [118, 119] or18F [120]. Some of these radiolabelled deriv-atives ([2 - 18F - fluoropropionyl - D - Phe1]-octreotide, [64Cu-TETA-D-Phe1]-octreotideand [67Ga]-DFO-B-succinyl-D-Phe1]-octreo-tide) have, therefore, been used for PET imag-ing [120]. However, the hepatobiliary excre-tion of these compounds complicates the in-terpretation of the images arising from ab-dominal tumors [120]. In contrast, [64Cu-TETA-D-Phe1]-octreotide binds to somatos-tatin receptor with five times the affinity of[111In-DTPA-D-Phe1]-octreotide, has desira-ble clearance properties (renal clearance withrapid excretion) and is a potential agent forPET imaging of somatostatin receptors. Atpresent, however, other labelled compounds(e.g. 11C-5-HTP or 11C-labelled-L-DOPA) arepreferred for PET scanning of neuroendo-crine tumors [121].
The detection of heterogenous metastases(with regard to the expression of differentpeptide receptors or the accumulation of oth-er radioligands) becomes possible if a combi-nation of different radiolabelled peptides or
Somatostatin Analogs for CancerTreatment and Diagnosis
Chemotherapy 2001;47(suppl 2):1–29 17
of a radiolabelled peptide with other radioli-gands (all labelled with different radionu-clides) can be used. Simultaneous use of 111In-octreotide and 131I-MIBG (metaiodobenzyl-guanidine) scintigraphy in patients with me-tastasized pheochromocytoma [22] representsa successful example of such an approach.
Radiopharmaceuticals for SomatostatinReceptor-Targeted RadiotherapyA new and fascinating application of radio-
labelled peptides is represented by their use inthe so-called peptide receptor radiotherapy[122]. The success of this therapeutic strategyrelies upon the concentration of the radioli-gand within tumor cells which will depend onthe rates of internalization, degradation andrecycling of both ligand and receptor.
Binding of several peptide hormones tospecific surface receptors is generally followedby internalization of the ligand-receptor com-plex via invagination of the plasma mem-brane [123]. The resulting intracellular vesi-cles, termed endosomes, rapidly acidify, thuscausing dissociation of the ligand from thereceptor. The ligand may be delivered to lyso-somes and the receptor recycles back to plas-ma membrane. The whole process takes ap-proximately 15 min and a single receptor candeliver numerous ligand molecules to the ly-sosomes [124].
Receptor-mediated endocytosis of so-matostatin analogs is especially importantwhen radiotherapy of somatostatin-positivetumors using radiolabelled analogs is consid-ered. Human neuroendocrine tumor cells in-ternalize the radioligand [111In-DTPA-D-Phe1]-octreotide. However, this radioligandmay not be the most suitable compound tocarry out radiotherapy because 111In, whichemits Auger (as well as conversion) electrons,is probably not the optimal radionuclide.Moreover, since a stable coupling of ·- and ß-emitting isotopes to [DTPA-D-Phe1]-octreo-
tide has not been feasible, a novel compound[tetraazacyclododecane tetraacetic acid(DOTA), Tyr3]-octreotide (compound codedas SDZ-SMT 487, fig. 9) in which the DTPAmolecule is replaced by another chelator,DOTA, allowing a stable bind with the ß-emitter yttrium-90, has been synthesized[125]. It was recently shown that iodinated[DOTA, Tyr3]-octreotide is internalized in alarge amount by mouse AtT20 pituitary tu-mor cells as well as by human insulinoma cells[126]. The high internalization rate of thisligand in vitro was also evident from the veryhigh uptake of this radioligand in vivo bysomatostatin receptor-positive organs in rats[126]. Along with the high internalization ofthe iodinated molecule, de Jong et al. [127]recently showed that the amount of [90Y-DOTA, Tyr3]-octreotide internalized by so-matostatin receptor-positive pancreatic tu-mor cells was higher than that of [111In-DOTA, Tyr3]-octreotide and of [111In-DTPA-D-Phe1]-octreotide (1.8- and 3.5-fold, respec-tively). In vitro, SMT 487 binds selectivelywith nanomolar affinity to the somatostatinreceptor subtype 2 (IC30 = 0.39 B 0.02 nM).In vivo, [90Y-DOTA, Tyr3]-octreotide shows arapid blood clearance (t½· !5 min) and highaccumulation in somatostatin subtype 2 re-ceptor-expressing tumors [128]. The in vivoadministration of this radiopharmaceuticalinduces a rapid tumor shrinkage in three dif-ferent somatostatin receptor-positive tumormodels, namely CA20948 rat pancreatic tu-mors grown in normal rats, AR42J rat pan-creatic tumors and NCI-H69 human smallcell lung cancer both grown in nude mice. Theradiotherapeutic efficacy of 90Y-SMT 487 wasenhanced when used in combination withstandard anticancer drugs, such as mitomycinC, and resulted in a tumor decrease of 70% ofthe initial volume. In the CA20948 syngeneicrat tumor model, a single treatment with 10ÌCi/kg [90Y-DOTA, Tyr3]-octreotide resulted
in the disappearance of 5 out of 7 tumors.Thus the new radiotherapeutic agent showedits curative potential for the selective treat-ment of SRIF receptor-expression tumors[128]. According to these data, [90Y-DOTA,Tyr3]-octreotide would appear to be a suitableradiopharmaceutical for somatostatin recep-tor-targeted radiotherapy.
To achieve an optimal radiotherapeutic ef-fect, the radiopharmaceutical should also beretained within tumor cells to allow intracel-lular radioactivity exerting its antineoplasticactivity. Therefore ‘trapping’ of radioligandsinto the tumor cells may be an addition-al important mechanism determining theamount of uptake of the radiopharmaceuticalwhich is used for somatostatin receptor scin-tigraphy and/or targeted radiotherapy. Whileprevious investigations [124] have shown that[111In-DTPA-D-Phe1]-octreotide is deliveredin vivo to lysosomes of pancreatic tumor cells,the intracellular fate of [90Y-DOTA, Tyr3]-octreotide is presently unknown.
Although being not the ideal radioligand,[111In-DTPA-D-Phe1]-octreotide has beenused for radionuclide therapy in patients withsomatostatin receptor-positive tumors andproved the feasibility of the approach [129].The trial did show a tendency towards betterresults in patients whose tumors had a higheraccumulation of the radioligand. In a recentpreliminary study, Otte et al. [130] reportedencouraging results after treatment with [90Y-DOTA, Tyr3]-octreotide (OctreoTher®) in 10patients with different somatostatin receptor-positive tumors. In addition, a case report[131] described a favorable response of a met-astatic gastrinoma to treatment with another90Y-labelled somatostatin analog, namely[90Y-DOTA]-lanreotide [132].
The concept of targeted radiotherapy oftumors using radioligands of somatostatinanalogs remains a very attractive approachfor the treatment of neoplasia. The very fact
that it is over 12 years since the concept ofoctreotide targeted radiotherapy of neoplasiawas first proposed and we are still awaitinggood phase 2 clinical trials on the efficacy andtolerability of this appealing treatment high-lights the practical difficulties involved in de-veloping this technique.
Safety and Tolerability ofSomatostatin Analogs
The safety profile of Sandostatin is wellestablished [17]. Most adverse reactions tooctreotide are merely a consequence of itspharmacological activity and consist mainlyof gastrointestinal complaints, cholelithiasisand effects on glucose metabolism. The re-ported cases of toxicity unrelated to the drug’spharmacological profile include reactions atthe injection site, allergic reactions, and a fewcases of reversible hepatic dysfunction. Al-though the kind of adverse events associatedwith Sandostatin is well known, their true fre-quency has not been accurately estimated.34.4% of patients reported one or more sideeffects, most of which (93.2%) were of littleclinical relevance [17]. For this reason, ad-verse events are only seldom mentioned inpublished series and are rarely reported to themanufacturer. In contrast, most reports re-ceived by the Novartis PharmacosurveillanceUnit pertained to events occurring in patientswith severe underlying diseases and multipledrug treatment; therefore, a cause-effect rela-tionship with octreotide could only seldom beestablished.
The tolerability of octreotide LAR appearsto be comparable to that of the subcutaneousformulation [77]. Here again, gastrointestinaladverse events predominate: abdominal pain,flatulence, diarrhea, constipation, steator-rhea, nausea and vomiting occurred in up to50% of patients with acromegaly who re-
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Chemotherapy 2001;47(suppl 2):1–29 19
Fig. 10. Adverse events observedin acromegalic patients (n = 93–101) after a single intramuscularinjection of Sandostatin LAR (10–30 mg) or multiple injections (30injections at 4-week intervals) ofthe same formulation (20–40 mg)[from 77].
ceived 1–3 intramuscular doses of octreotideLAR (10–30 mg). Representative results fromthe largest clinical trial are depicted in fig-ure 10. Gastrointestinal symptoms tended tobe mild to moderate and often disappeared
within 1–4 days of the injection. Further-more, the incidence of these events decreasedwith long-term (up to 7 months) treatments.In addition, there was no evidence that tolera-bility worsened with increasing dose.
Injection site events (pain, burning, red-ness and swelling at injection site) occurred insome patients receiving intramuscular octreo-tide LAR, but were generally mild and ofshort duration [77]. These phenomena arethought to be caused by the acidic vehicle ofSandostatin formulations and can be mini-mized by simple precautions, i.e. to allow re-frigerator-cold vials to reach room tempera-ture before administration, and to rotate thesites of injections.
Although the risk of cholelithiasis increasesin patients receiving octreotide [17], simulta-neous bile acid administration strongly reducesits incidence [77]. Although diabetes mellitusmay occur as a result of reduced glucose toler-ance, the net effect of drug-induced changes isusually mild and not clinically relevant [17,77]. Finally, few patients developed moderateto severe hair loss [77]. The spectrum and inci-dence of adverse events reported after lanreo-tide, either immediate and slow release formu-lations, are similar to those reported afteroctreotide [87, 88, 93, 94], the majority of poor-ly tolerant patients experiencing untowardreactions to both compounds [87].
Synthetic somatostatin analogs are, there-fore, safe drugs for long-term use. While im-mediate release preparations are the drugs ofchoice in the short term, long-acting formu-lations are better indicated, on an outpa-tient basis, for the long-term management ofchronic conditions.
Somatostatin Analogs for CancerDiagnosis and Treatment: A Lookinto the Future
New Somatostatin Analogs and RegimensThe principal challenge in somatostatin re-
search derives from the fact that the five basicsomatostatin receptor subtypes have highstructural similarities and different tissue dis-
tributions. The strong functional similarityamong the five receptor types is exhibited intheir common inhibitory effect on adenylylcyclase activity. Therefore, it is understand-able that somatostatin, which binds with highaffinity to each receptor type, has multiplephysiological actions. To explore the specificbiological function of each subtype, receptor-specific synthetic analogs, agonists (as well asantagonists) are being developed. New com-pounds in the early phase of developmentinclude receptor-selective and ‘universal’ ana-logs. The receptor-selective analogs bind toone, possibly two somatostatin receptor sub-types [133, 134] while the universal analogsbind to most or all of the five known SSTRs.
The elucidation of the 3-dimensional struc-tures of receptor subtype-selective somatosta-tin agonists has aided and will considerablyenhance the rational design of novel analogsincluding non-peptide compounds [135–137].Development of potent non-peptide somatos-tatin analogs is important because they maydisplay a good bioavailabilty [138] followingoral administration. Continuing research onsomatostatin receptors and somatostatin ana-logs will help to characterize better the func-tional somatostatin receptor models. Recentavailability of the five transfected cell lines hasenabled the use of more rational researchmethods. This will help to develop novel drugcandidates beyond the clinically used octreo-tide-type analogs. Newly developed analogs(BIM 23190 and BIM 23197) show higherplasma levels, greater distribution to target tis-sues and longer in vivo stability [139]. Theymay prove to be superior to the currently avail-able compounds for the treatment of acromeg-aly and some types of cancer.
Future investigations should also be aimedat further exploring the use of long-actingsomatostatin analogs as antineoplastic agents,either alone or in combination with otherdrugs. In this respect, it will be important to
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Chemotherapy 2001;47(suppl 2):1–29 21
better define the dose-response relationshipand to ascertain whether higher doses areassociated with more disease stability or withgreater response rate or survival [16].
Somatostatin Receptor-TargetedChemotherapyIt is now well established that chemothera-
peutic compounds and toxins can be cova-lently attached to various carriers, includinghormones, for which receptors are present oncancer cells or to antibodies that preferen-tially recognize tumor cells [140]. Such conju-gates are designed to deliver cytotoxic agentsmore selectively to cancer cells. Ideally, tumorcells that bind these conjugates would bekilled while normal cells that do not have thereceptors would be spared [141].
Like targeted radiotherapy, somatostatinreceptor-targeted chemotherapy representsan appealing approach to treatment of SSTRexpressing tumors. By synthesizing conju-gates of somatostatin analogs and cytotoxicdrugs (such as methotrexate or doxirubicin)[142, 143], selective accumulation of cyto-toxic radicals in somatosatin receptor-posi-tive tumor cells would be possible. Obviously,with the currently available somatostatin ana-logs, targeted chemotherapy would be limitedto the treatment of SSTR-2- and SSTR-5-expressing tumors. Experimental studies[142, 143] have actually shown that thesederivatives are less toxic and more effectivethan the parent cytotoxic drugs in inhibitingtumor growth in vivo. A recent study [144]demonstrated a high efficacy of SSTR-tar-geted chemotherapy in a model of dissemi-nated human androgen-independent prostat-ic carcinoma. The use of cytotoxic somatosta-tin analog AN-238 (fig. 11) could provide aneffective therapy for patients with advancedhormone-refractory prostatic carcinoma.Other studies in progress show that growth ofvarious human pancreatic, colorectal and gas-
Fig. 11. Molecular structure of the cytotoxic somato-statin analog AN-238. The somatostatin analog RC-121 is linked through the ·-aminogroup of it D-Phemoiety and a glutaric acid spacer to the 14-OH groupof 2-pyrrolinodoxorubicin [from 142].
tric cancers in nude mice as well as glioblasto-mas and non-SCLC can be suppressed bycytotoxic somatostatin analogs [141]. Thusthese somatostatin analogs might find appli-cations for the therapy of different types ofhuman malignancies.
Gene TherapyGene therapy is at an early phase, but
represents an exciting opportunity to prolonglife in some patients with advanced malignan-cies [145–149]. The key problems are gettingthe replacement gene to the appropriate cellu-lar target and once there persuading it tomake the normal gene product in sufficientquantities to correct the defect. With respectto somatostatin analog therapy there are anumber of areas in which effective gene thera-py may be used to potentiate the antineoplas-tic effects of these drugs. The most obviousapplication of gene therapy to somatostatinanalog treatment of neoplasia is the delivery
Fig. 12. Expression of the SSTR-2in pancreatic tumor cells sup-presses clonigenicity in vitro andtumorigenicity in nude mice by afeedback mechanism. According tothe findings in vitro and in vivo,the expression of this receptor sub-type leads to an increase in somato-statin ligand production and hencea constitutive receptor activation.Experimental data also suggest thatthe SSTR-2 expression is associat-ed with an increase in the endopro-teolytic processing of prosomato-statin [from 7].
of hSSTR-2 and hSSTR-5 genes together withthe genes that encode their membrane pro-teins to those cancers such as pancreatic, gas-tric and colorectal carcinomas that do notexpress these receptor subtypes. The somatos-tatin analogs currently available for clinicaluse (i.e. octreotide, lanreotide and vapreotide)all exert the majority of their antineoplasticeffects via hSSTR-2 and hSSTR-5 and it fol-lows, therefore, that effective transfer of genesencoding for hSSTR-2 and hSSTR-5 and theirmembrane proteins to cancers which do notexpress these receptor subtypes may renderthem responsive to the direct antineoplasticeffects of the current generation of somato-statin analogs.
Human pancreatic adenocarcinomas losethe ability to express SSTR-2, the somatostat-in receptor, which mediates the antiprolifera-tive effect of currently available somatostatinanalogs. Reintroducing SSTR-2 into humanpancreatic cancer cells by stable expressionevokes an autocrine negative feedback loopleading to a constitutive activation of the
SSTR-2 gene and an inhibition of cell prolifer-ation and tumorigenicity. In vivo studies[150], performed in athymic mice, confirmedthe antitumor bystander effects resulting fromthe transfer of the SSTR-2 gene into humanpancreatic cancer cell line BxPC-3. Mice wereseparately xenografted with control cells onone flank and with SSTR-2-expressing cellson the other flank. A distant antitumor effectwas induced: growth of control tumors wasdelayed by 33 days, the Ki67 index decreasedsignificantly, and apoptosis increased whencompared with control tumors that grewalone [150]. The distant bystander effect maybe explained in part by a significant increasein serum somatostatin-like immunoreactivitylevels resulting from the autocrine feedbackloop produced by SSTR-2 expressing cells(fig. 12) [151] and inducing an upregulation ofthe type 1 somatostatin receptor, SSTR-1,which also mediates the antiproliferative ef-fect of somatostatin [150].
Limitations to peptide receptor radiother-apy are principally due to poor tumor pene-
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Chemotherapy 2001;47(suppl 2):1–29 23
tration of the radioligand and insufficient ac-cumulation of radioactivity within the neo-plastic cell. In addition, low or variable ex-pression of tumor-associated receptors maylead to poor tumor localization of radiola-belled peptide agonists. An attempt to over-come these problems consists in the use ofbiological response modifiers to increase tar-get receptor expression [152]. In this connec-tion, replication-deficient adenoviral vectorswere constructed encoding the cDNA for thesomatostatin receptor subtype (SSTR-2). Invitro binding and in vivo tumor localizationwere observed with radiolabelled octreotideanalogs to cells infected with adenoviral vec-tors encoding the corresponding gene [152].Provided it is successful in humans, thismethod could be useful for increasing thetherapeutic efficacy of targeted radiotherapyin cancer patients.
Conclusions
Despite the explosion of knowledge in re-cent years in the somatostatin field, a greatdeal remains to be discovered. In particular,developing the potential of somatostatin ana-logs for cancer treatment will require a morecomplete understanding of their intracellularactions and interactions. Moreover, in spite ofthe ongoing clinical application of octreotideand its analogs in cancer management [153],the molecular mechanism and the beneficialeffects of these drugs need to be elucidated.
Twenty-seven years after its discovery, so-matostatin is still the subject of continuinginvestigations by researchers in both the in-dustry and the academia. In the future, thejoint effort of many scientists from differentfields will no doubt produce more specifictherapeutic agents that are likely to result inmajor improvements in clinical managementof various malignancies.
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