(CANCER RESEARCH 48, 6977-6985, December 15, 1988]

Perspectives in Cancer Research

Oncological Applications of Somatostatin Analogues1

Andrew V. SchallyEndocrine, Polypeptide, and Cancer Institute, Veterans Administration Medical Center, and Section of Experimental Medicine, Tulane University School of Medicine,New Orleans, Louisiana 70146

Background

The cyclic tetradecapeptide somatostatin is widely distributedin the body, being found in high concentrations in the hypothalamus, in other areas of the brain, and in the stomach, thepancreas, and the intestine (1, 2). Somatostatin has a broadspectrum of biological actions, exerts suppressive effects on alarge variety of cells (1, 2), and appears to be an endogenousgrowth inhibitor (1, 3,4). The clinical potential of somatostatinhas been appreciated for more than 15 years. Various studiesdemonstrated inhibitory effects of somatostatin in patients withacromegaly, endocrine pancreatic tumors such as insulinomasand glucagonomas, ectopie tumors like gastrinomas, and VIP2producing tumors (1,2, 5-9). However, the therapeutic use ofsomatostatin is impractical because of its multiple actions andthe short duration of its antisecretory effects, half-life in circulation being about 3 min (1,6). Work was carried out by severalgroups to systematically design and synthesize somatostatinanalogues with selective enhanced and prolonged activities.Various phases of this endeavor were reviewed previously (1,5,6). Consequently, this work will be cited only very briefly.

Incorporation of o-amino acids into the somatostatin backbone to augment resistance to degradative enzymes and prolongactivity and derivatization of various functional groups or exchange of amino acids led to some analogues with greatlyincreased activities (10-12). Some of these analogues showedinhibitory activities in experimental models of chondrosarco-mas and ductal pancreatic cancers (6, 13-16). However, analogues of somatostatin 14 as well as those of its precursorsomatostatin 28 were expensive and not superactive in vivo (6,13-16). The era of modern analogues of somatostatin wasinitiated by the work of Veber et al. (17), who carried outconformational analysis and designed several analogues by replacing 9 of the 14 amino acids of somatostatin with a singleproline residue. Some of the resulting hexapeptide analogues,including cyclo(-Pro-Phe-D-Trp-Lys-Thr-Phe), and subsequently cyclo(yV-Me-Ala-Tyr-D-Trp-Lys-Val-Phe) were muchmore potent than somatostatin in inhibiting GH, insulin, andglucagon release (17, 18). However, their work was apparentlyaimed at producing analogues for the therapy of diabetes typeI, and our evaluation of some of these analogues in varioustumor models did not reveal antitumor activities (6, 15).

Bauer et al. (19) synthesized another series of highly potentoctapeptide analogues of somatostatin. They retained the sequence 7-10 of somatostatin, Phe-Trp-Lys-Thr, proposed asessential by Veber et al. (17), and incorporated it with the

Received 7/20/88; revised 9/6/88; accepted 9/16/88.' Some experimental work described in this paper was supported by USPHS

Grants DK07467, CA 40003. CA 40077, and CA 40004 and by the MedicalResearch Service of the Veterans Administration.

2The abbreviations used are: VIP, vasoactive intestinal peptide; LH-RH,luteinizing hormone-releasing hormone; GH, growth hormone; EGF, epidermalgrowth factor; IGF-1, insulin-like growth factor I or somatomedin C; PDGF,platelet-derived growth factor; TGF, transforming growth factor; BOP, /V-nitro-sobis(2-oxopropyl)amine; CCK, cholecystokinin; GRP, gastrin releasing peptide:ACTH, adrenocorticotropin hormone; 5-HIAA, S-hydroxyindoleacetic acid;SCLC, small cell lung carcinoma.

tryptophan residue in the D configuration, as in the originalhexapeptide of Veber et al. ( 17), into a series of cystine-bridgedanalogues of which D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol, containing a C-terminal amino alcohol, was the mostactive (19). This analogue, designated SMS-201-995, was longacting and 45-70 times more potent than somatostatin in testson inhibition of GH secretion and more selective, since itsuppressed insulin and glucagon less than GH. Initial clinicaltrials with SMS-201-995 included acromegalics, type I diabetics, and patients with endocrine tumors of the pancreas andintestine (19, 20).

Our analogues were designed specifically for antitumor activity. In our early studies in various animal tumor models weused analogues of somatostatin 14 and detected a significantantitumor activity for some analogues which contained disulfidelinkages (6,13-16). We decided therefore to synthesize a seiof octapeptide analogues with disulfide linkages, whichspeculatively considered necessary for antitumor activity. Wealso used a C-terminal amide, since having successfully developed microcapsules of D-Trp6-LH-RH in poly(DL-lactide-co-

glycolide) for once a month i.m. administration (21), weplanned to encapsulate our somatostatin analogues and wereconsequently not too interested in oral activity. Thus, nearly300 analogues of somatostatin which belonged to 3 differentseries were synthesized by us by solid-phase methods (22, 23).In series I, the analogue D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Trp-NH2 (RC-95-I) was 53 times more potent than somatostatin (22). In series II, the activity of some somatostatinanalogues was enhanced by incorporation of tyrosine and valinein positions corresponding to residues 7 and 10, respective-ly, of somatostatin 14 (22). Thus the analogues D-Phe-

Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (RC-121) and D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NHz (RC-160) were199 times and 135 times more potent, respectively, than somatostatin 14 in tests for inhibition of growth hormone releasein vivo in rats and possessed a prolonged duration of action.Analogues of series III had related structures, but an NH2-terminal tryptophan residue (23). All these analogues wereselective for suppressing GH secretion, the inhibitory potenciesfor insulin and glucagon release in rats being much smaller (22,23). These analogues also inhibited gastric acid secretion andrelease or action of gastrin, secretin, and CCK (6, 22-24).

The somatostatin analogues recently reported by Murphy etal. (25) were also cyclic octapeptides related to our analogues(22, 23) and the analogue of Bauer et al. (19).

Possible Mechanisms of Antitumoral Action of SomatostatinAnalogues

It is likely that somatostatin analogues, by virtue of having awide spectrum of activities which include the suppression ofthe secretions of the pituitary, pancreas, stomach, and intestine(1, 2, 5, 6, 24), interference with growth factors, and possibledirect antiproliferative effects on some tissues (3, 4, 26, 27),

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would prove to inhibit various tumors through multiple mechanisms. These processes will be discussed in greater detail foreach specific tumor. However, the principles of these mechanisms will be set forth below. Among the major actions ofsomatostatin is the inhibition of the release of the pituitary GHand, under certain conditions, of prolactin (1, 4, 6, 28, 29).Prolactin could be involved in prostate cancer as a cofactor andboth prolactin and GH have been implicated in the growth ofhuman breast cancers (29-31). The reduction in prolactin levelsproduced by the administration of a somatostatin analogue maycontribute to the inhibition of the growth of breast and prostatetumors (28). The fall in GH levels induced by somatostatinanalogues could, through mechanisms involving endogenousgrowth factors, be of major importance for the inhibition ofgrowth of various tumors (4, 28). GH stimulates cell differentiation directly and clonal expansion indirectly through localproduction of IGF-1 (32-35).

A family of IGF polypeptides, also called somatomedins, andother growth factors including EGF, PDGF, fibroblast growthfactor, and TGF appear to be involved in the proliferation ofboth normal and neoplastic cells (36-40). In addition, aTGF,PDGF, and other growth factors are implicated in phenotypictransformation of cells (41).

Mascardo and Sherline (3) showed that somatostatin has adirect antiproliferative effect and inhibits DNA synthesis andcell replication induced by EGF in gerbil fibroma and HeLacells. Somatostatin exerts this action by blocking EGF-induced

centrosoma! separation, a biological marker of the Gl phase ofthe cell cycle, which is necessary for DNA synthesis and cellreplication (3). The mechanism by which somatostatin preventscentrosoma! separation is not clear, but somatostatin mayinterfere with the movement of microfilamcnts and preventmicrotubule disassembly induced by EGF or inhibit a calciuminflux (3).

Direct antiproliferative actions of somatostatin analoguescould be mediated by specific receptors located on tumor cells.High affinity binding sites for somatostatin and its analogueshave been found in normal tissues and in tumors (2, 6, 24, 26,27). (See also sections below on specific tumors.) In the MIAPaCa-2 human pancreatic cancer cell line, somatostatin reverses the stimulatory effect of EGF on the phosphorylation ofthe tyrosine kinase portion of the EGF receptor and of tyrosineacceptor proteins (26) and on cell growth (27). Binding ofsomatostatin to the membrane receptor in the MIA PaCa-2 cellline activates dephosphorylation of EGF receptor, a M, \ 70,000phosphotyrosyl membrane protein the phosphorylation ofwhich is promoted by EGF (26). Superactive analogues RC-160 and RC-121 exhibit even higher activity than somatostatinon dephosphorylation of EGF receptor in Mia PaCa-2 line.3Analogue RC-160 also inhibits the EGF-induced growth ofcultured pancreatic cancer cells more powerfully than somatostatin 14.' Thus, somatostatin and its superactive ana

logues RC-121 and RC-160 can nullify in these conditions theeffect of EGF, apparently through activation of dephosphorylation (4, 6, 26). This reduction in phosphorylation in vitroshows a correlation with the decrease in pancreatic tumorweight and volume induced by analogue RC-160 in vivo (42)and thus may reflect cellular biochemical events associated withtumor regression. Somatostatin and its analogues could similarly inhibit the action of other endogenous growth factors bymechanisms involving interference with transmission of intra-cellular signals that regulate cell growth (3, 26, 27, 37-41).

3C. Liebow. M. Hieroski, and A. V. Schally, manuscript in preparation.

Somatostatin and its analogues also suppress the release oraction of gastrointestinal hormones, gastrin, CCK, and secretin(1, 2, 6, 9, 24). Consequently somatostatin analogues could beof value for impeding the growth of cancers, such as pancreaticand colorectal in which gastrointestinal hormones as well asgrowth factors might be involved (14, 28, 42). In addition, thesecretion of bombesin and GRP, which are autocrine growthfactors for small cell lung carcinomas (43-45), might be reducedby somatostatin. Another possible mechanism by which somatostatin analogues might inhibit tumor growth is the interference with the synthesis of autocrine growth factors by tumorcells. Thus, the action of somatostatin analogues might involvethe inhibition of not only endocrine, but also paracrine andautocrine mediated effects of growth factors (35, 38, 39).

Somatostatin analogues could also inhibit oncogene products, several of which are similar to growth factors or theirreceptors (46-48). Growth factors or aberrant receptors generated by the oncogenes (37) could be responsible for promotingtumor cell growth (49). One protooncogene, c-sis, was found tocode for the B-chain of PDGF (46, 47). The product of viraloncogene erbB is a truncated receptor for EGF (48). Thesequence encoded in erbB corresponds to the transmembraneand cytoplasmic portions of the EGF receptor (48). Althoughthe erbB oncogene may have been derived from the cellulargene for the epidermal growth factor, the gene segment codingfor the EGF binding region was apparently not acquired by thevirus (48). In the case of the erbB oncogene, since its productslack the binding region for growth factors, they could create acondition whereby the cells are maintained in a continuous stateof division (48). Activation oncogenes and EGF receptors havebeen found in the human bladder and lung cancer cell lines (36,37). At present, it is still not known whether the uncontrollablegrowth of cancer cells could be the result of the interactionamong growth factors, oncogenes, or their products and thereceptors (37). In conclusion, oncological application of somatostatin analogues could be based on multiple effects, andseveral mechanisms of action are possible. Somatostatin analogues should be subjected to further experimental studies andclinical trials aimed at the exploration of their inhibitory effectson the processes of malignant growth (4, 6). This review willnow focus on specific neoplasms and cite studies, both experimental and clinical, performed thus far with somatostatin analogues. Mention will also be made of other tumors, the treatment of which could benefit from such research.

Pituitary Tumors

Pituitary tumors are rarely life threatening and are presentlytreated by neurosurgery, radiotherapy, or dopamine agonistssuch as 2-bromo-a-ergocriptine (bromocriptine). Bromocrip-tine is more effective for prolactinomas than for tumors associated with acromegaly. Various studies in animals and humanshave established that somatostatin 14 can decrease the releaseof GH, thyroid stimulating hormone, prolactin, and ACTHfrom the pituitary (5, 9). In the first clinical trial with somatostatin 14, we were able to demonstrate a fall in elevatedGH levels in acromegalics (50). These findings have not beenimplemented therapeutically because clinical use of somatostatin is impractical. Subsequently, various early analoguesof somatostatin such as Phe4-somatostatin, p-NH2-Phe4-r>Trp8-somatostatin, Ala2-D-Trp8-Cys'4-somatostatin, and L-5F-Trp8-somatostatin were administered to normal subjects and

acromegalie patients and shown to inhibit the basal or argininestimulated GH levels, but the effects were short-lived and

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persisted only during the infusion of these analogues (6). Workin animal models of pituitary tumors indicated that so-matostatin analogues inhibited the growth of the prolactin andACTH secreting pituitary tumor 7315a in rats, but not the GHand prolactin secreting pituitary GH3 tumor (6).

Subsequent clinical trials revealed that the Bauer SMS-201-995 octapeptide was suitable for the clinical management ofacromegaly (51-54). Plewe et al. (51) showed that a simple s.c.injection of 50 ¿igof SMS-201-995 markedly reduced serumGH levels in six of seven acromegalics, the effect lasting for atleast 9 h. Some reduction in serum glucagon also occurred, butno side effects were observed. Lamberts et al. (52, 53) reportedsimilar results. Chronic therapy of 10 acromegalie patients for1-2 years with 100 ng SMS-201-995 every 8-12 h s.c. resultedin a rapid improvement and virtual disappearance of the clinicalsigns and symptoms of this disease. Circulating somatostatinC levels normalized in 5 of 10 patients (52, 53). GH levels alsodeclined. Some tumor shrinkage was observed by computerizedtomography of the pituitary in three of the six patients in whomthis could be evaluated, the decrease in tumor size being about20-30%. These and other results (54) indicate that analogueSMS-201-995 is effective in treatment of acromegaly. Ouranalogue RC-160 was also demonstrated to significantly depress GH levels in acromegalics in doses of 25-250 tig s.c. (55)and clinical trials with delayed delivery systems (microcapsules)of this analogue are in progress. Recently, five patients withthyrotropin secreting pituitary adenomas were treated withanalogue SMS-201-995, s.c. in doses of 50-100 »gevery 8 to12 h, and showed a reduction in serum levels of thyrotropin(56). Prolactinomas are insensitive to SMS-201-995, but prolactin secretion from mixed GH/prolactin secreting adenomasis inhibited (57). In conclusion, modern analogues of somatostatin like SMS-201-995 and RC-160 can be used clinically for the treatment of GH secreting pituitary tumors andcertain adenomas.

Endocrine Tumors of the Gastroenteropancreatic System

The gastroenteropancreatic neuroendocrine tumors are rare,slow growing, and often metastatic, primarily to the liver (58).They are frequently refractory to surgery and/or chemotherapy.Various gastroenteropancreatic endocrine tumors derive fromneuroendocrine cells/tissue (58-60). These tumors are normallyclassified according to their secretory products, although someare mixed. Entopic pancreatic tumors include insulinomas,glucagonomas, somatostatinomas, and pancreatic polypeptideislet cell tumors (pancreatic polypeptide apudomas) (60). Car-cinoid tumors can elaborate various polypeptides of the amineprecursor uptake and decarboxylation system in addition toserotonin, dopamine, histamine, or another amine (60). Amongthe chief ectopie endocrine tumors of the pancreas are gastri-nomas associated with Zollinger-Ellison syndrome and VIP-omas (VIP producing tumors) which result in Verner-Morrisonwatery diarrhea syndrome. Other gastrointestinal tumors canproduce ACTH and parathyroid hormone or multiple hormones (60). Complete surgical excision of gastrinomas or otherresectable endocrine tumors is the treatment of choice, but inmany patients such treatment is not possible (60). Chemother-apeutic agents such as streptozotocin or irradiation have beenused for the management of endocrine pancreatic tumors (60),but these measures are not always effective. Somatostatin analogues offer a promising new therapeutic modality for thesetumors. The responsiveness of gastrointestinal tumors to somatostatin analogues may be explained by the presence of high

levels of membrane receptors for somatostatin in these tumors(57).

Carcinoid Tumors

Of all the endocrine gastroenteropancreatic tumors, abouthalf are carcinoids (58-61). These malignant tumors derivedfrom enterochromaffin cells arise usually in the ileum and afterhepatic métastasescan cause carcinoid syndrome (flushing,diarrhea, cardiac valvular lesions) (58-61). Some carcinoidtumors can be of nongastrointestinal origin, e.g., lungs or ovary.Chemotherapy can produce objective tumor responses in 20-40% of patients with carcinoid syndrome, but drug toxicity is aproblem (61). Interferon has also been used for treatment ofthe carcinoid syndrome and led to symptomatic improvementand some reduction in 5-HIAA acid excretion (61).

Several recent studies indicate that modern analogues ofsomatostatin like SMS-201-995 or RC-160 can be effectivelyused for treatment of carcinoid tumors (61-64). Kvols et al.(61, 62) evaluated the effects of SMS-201-995 in 25 patientswith histologically proved metastatic carcinoid tumors and thecarcinoid syndrome. This peptide was given s.c. at a dose of150 Mg,three times daily. Flushing and diarrhea were promptlyrelieved in 22 patients. All 25 patients had elevated urinarylevels of 5-HIAA before the treatment and 18 patients showeda decrease of 50% or greater in 5-HIAA levels. The mediumduration of response was more than 12 months. Some patientsshowed steatorrhea but no serious toxicity was observed (62).Similarly Mathéet al. showed that administration of analogueRC-160 in doses of 100-400 Mg 3 times daily to 21 patientswith carcinoid tumors caused a complete relief of flushing,diarrhea, and abdominal pain and reduced 5-HIAA and serotonin levels, but no changes in tumor size were seen (64). Theseresults suggest that somatostatin analogues are effective palliative agents in patients with malignant carcinoid tumors andwarrant the continuation of clinical trials with delayed deliverysystems of these analogues.

Insulinomas

Insulinomas are usually benign, readily detected, and treatedby surgical resection (65). The reduction in insulin levels inpatients with insulinomas in response to somatostatin 14 orearly analogues of somatostatin was reported previously byseveral groups (6, 9, 66). Modern somatostatin analogues maybe of value for malignant insulinomas or when the tumor cannotbe located. Recently, a reduction in serum insulin levels and arise in blood glucose were reported in a patient with malignantinsulinoma after the injection of 50 ng SMS-201-995 (67).

Glucagonomas

The treatment of inoperable or metastatic glucagonomas isunsatisfactory (68). The suppression of plasma glucagon levelsand a fall in plasma glucose during an infusion of somatostatin14 were first shown in 1974 (7). These observations were thenextended in other studies (6, 66). Recently, it was reported thatthe treatment of a diabetic patient with inoperable glucagonomas using 50-100 Mg SMS-201-995 s.c. twice a day for 8months led to a normalization of plasma glucagon levels, anincrease in body weight, and disappearance of characteristicskin rashes (68). However, the tumor size was not affected.

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Gastrinomas

Gastrinomas are usually malignant and treated by surgery(resection, gastrectomy) or administration of H2 receptor blockers (65). Inhibition of serum gastrin and suppression of gastricacid secretion by administration oíso mat ostati n 14 in a patientwith gastrin producing pancreatic tumor were described morethan 10 years ago (8). Subsequently, various early somatostatinanalogues were also shown to suppress plasma gastrin levels inpatients with gastrinomas (6, 66). During the past few yearsanalogue SMS-201-995 was evaluated by several groups inpatients with gastrinomas (63, 67, 69, 70). In most patientsdoses of 50-100 ng s.c. 1-2 times/day inhibited gastric secretion, lowered serum gastrin, and reduced epigastric pain. Thisanalogue also inhibited gastric secretion stimulated by secretinor calcium (69). Since analogue RC-160 also strongly inhibitsgastrin and gastric acid secretion (6, 22), modern somatostatinanalogues could provide a new therapeutic modality for thetreatment of gastrinomas.

VIPomas

VIP-producing non-0-islet cell tumors are associated withelevated plasma VIP and peptide histidine isoleucine levels andsevere watery diarrhea and hypokalemia (65). This syndrome isalso known as pancreatic cholera (71). Inhibition of VIP secre

tion from pancreatic tumors in the Verner-Morrison syndromeby administration of somatostatin or its analogue has beendemonstrated previously (6, 9, 66). Recently, it was reportedthat SMS-201-995 octapeptide, used for a period of 8 monthsin a patient with VIPoma, not only reduced VIP secretion andprevented torrential diarrhea but also led to a reduction in thesize of hepatic métastases(70, 72, 73). Other investigators havealso used this superactive Sandoz analogue in patients withVIPomas and obtained decreases in VIP levels, reduction instool weight, and improvement in electrolyte imbalance (67,71, 74). The overall results indicate that modern somatostatinanalogues could benefit those patients with endocrine gastroen-teropancreatic tumors who do not respond to conventionaltreatment (75).

Carcinoma of the Exocrine Pancreas

Carcinoma of the pancreas causes over 20,000 deaths/yearin the United States (76). About 80-90% of the cases ofpancreatic adenocarcinoma are ductular in appearance. Cancerof the pancreas has a poor prognosis and the 5-year survivalrate is very low (77, 78). The median duration of survival forpatients with pancreatic cancer was reported to be only 2.5months (78). The resectability is about 15-20% and radiotherapy and chemotherapy are usually ineffective (77-79).

Various experimental and clinical findings suggest that itmight be possible to develop a new hormonal therapy forexocrine cancer of the pancreas based on new somatostatinanalogues, alone or in combination with LH-RH analogues orother drugs (6, 14, 15, 28, 42, 78-81). Somatostatin 14 and itsanalogues exert antisecretory effects on the endocrine and exocrine pancreas as well as on the stomach and intestine (6, 15,24). These actions include the suppression of the secretion and/or action of gastrin, secretin, and CCK. These gastrointestinalhormones, in addition to their secretory effects (6, 24), producehyperplasia and hypertrophy of the exocrine pancreas andincrease DNA, RNA, and protein content (82). The role thegastrointestinal hormones play in pancreatic tumorigenesis isnot fully established, but it is likely that they also influence the

growth of the malignant cells of the pancreas and phenotypictransformations (14, 79-80, 82-84). In vitro studies have shownthat CCK, secretin, and gastrin can stimulate the growth ofpancreatic adenocarcinoma cells (14, 15, 79). Caerulein, whichis structurally closely related to CCK, given together withsecretin, stimulated the in vivo growth of pancreatic ductaladenocarcinoma H-2-T in golden hamsters (83). Somatostatinanalogues might also inhibit the growth of pancreatic cancer bysuppressing the action or secretion of growth factors (79), whichare thought to be involved in neoplastic processes (32-49).PANC-1 and MIA PaCa-2 human pancreatic cancer cell lines

have receptors for EGF (26,27,85). EGF stimulates the growthof MIA PaCa-2 pancreatic cancer cells in culture and may actas autocrine growth factor (27). EGF also augments pancreaticcarcinogenesis induced by BOP (86). Somatostatin reduces thelevels of IGF-1 and EGF (4, 28, 57) and nullifies the growth ofMIA PaCa-2 cells induced by EGF (27). In the MIA PaCa-2

line, somatostatin reverses the stimulatory effect of EGF on thephosphorylation of the tyrosine kinase portion of the EGFreceptor (26). Superactive analogues RC-160 and RC-121 inhibit growth of the MIA PaCa-2 line and stimulate dephospho-rylation of the EGF receptor much more powerfully than somatostatin 14.3

Sex steroids may also play a role in the growth of thecancerous pancreas (79-81, 87). The presence of specific receptors for estrogen and androgen was demonstrated in normalpancreas and pancreatic cancer cell lines (79, 81, 87). Clinicaltrials indicate that some patients with pancreatic cancer respondto antiestrogen tamoxifen or LH-RH agonists, which producea state of sex hormone deprivation (14, 15, 79, 80) with prolongation of survival (78, 88). Our experimental studies (14, 15,26, 28, 42, 89) and those of others (27, 81-87) are consistentwith the view that the exocrine pancreatic carcinomas aresensitive to gastrointestinal hormones, sex steroids, and growthfactors.

Inhibition of growth of pancreatic carcinomas in animalmodels by analogues of hypothalamic hormones was first reported by us in 1984 (14). Chronic administration of earlysomatostatin analogues inhibited the growth of transplantedacinar pancreatic tumors in rats and of ductal cancers in hamsters (14). The agonist D-Trp6-LH-RH, injected once a month

in the form of microcapsules, also significantly decreased tumorweight and volume and suppressed serum testosterone levels(14). We then showed that modern somatostatin analoguessuch as RC-160 inhibited the growth of transplanted or BOPinduced ductal pancreatic cancers in male or female hamsters(42). Recently, we reported marked inhibition of tumor growthand clear evidence of histological regression of the BOP inducedpancreatic cancer in hamsters after treatment with microcap-sules of somatostatin analogue RC-160 or D-Trp6-LH-RH (89).

The combination of both peptides produced the best results interms of prolongation of survival, elimination of ascites, andhistological regression signs which were as high as 67%.4

In cooperative trials, D-Trp6-LH-RH and RC-160 are being

tried clinically as single drugs in patients with inoperable pancreatic cancer. Preliminary results indicate clinical improvement, reduction in tumor mass, and increased survival rate insome patients (64, 79, 88). In an ongoing trial with D-Trp6-LH-

RH, a subjective improvement including a decrease in abdominal pain, reduction in serum bilirubin levels, and increase inappetite and hemoglobin values was observed in 13 of 16patients with stage IV disease. At present, the mean survival

4 A. Zalatnai and A. V. Schally, submitted for publication.

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time for that group is 7.4 months.5 The combination of so-matostatin analogues and D-Trp6-LH-RH should be even more

efficacious clinically in treating patients with cancer of thepancreas than single peptides. Although, the clinical efficacy ofthis new approach to the treatment of pancreatic cancer remainsto be assessed by further clinical trials, it is conceivable that thecombined administration of LH-RH analogues and so-matostatin analogues might prolong survival and improve quality of life in patients afflicted with this malignancy that isvirtually untreatable at present.

Colorectal Cancer

It is estimated that about 60,000 Americans die of colon andrectum cancers every year (90, 91). Colon tumors are presentlytreated by surgical ablation (91). Chemotherapy and radiotherapy are of limited use (92). New treatment modalities are neededfor treatment of advanced colorectal cancer. Various reportsindicate the possible involvement of sex steroids and gastrointestinal hormones, especially gastrin and growth factors suchas EGF, IGF-1, and aTGF in the tumorigenesis of the colon(90-97). The incidence of colon cancer is increased in acrome-galics suggesting that excessive secretion of GH or IGF-1 maybe a factor. IGF-1 receptors were found in human colon carcinomas (96). An approach similar to that on pancreatic cancerand based on hormonal manipulations such as the combineduse of analogues of somatostatin and LH-RH analogues couldalso be envisioned for colorectal cancer.

Osteosarcomas and Chondrosarcomas

Clinical management of osteosarcomas and chondrosarco-mas is difficult and therapeutic modalities should be improved(15, 16, 98-101). The incidence of osteosarcomas may beinfluenced by growth hormone (15, 28, 98). Hormonal factorsare also involved in the growth of malignant cartilage tissue(13). Rat chondrosarcomas are dependent upon GH, somato-medins, glucocorticoids, and insulin (99, 100). Consequently,we made attempts at experimental endocrine management ofthese tumors and have demonstrated that somatostatin analogues could have potential therapeutic applications in thetreatment of these neoplasms (13, 15, 16, 28). Our studiesshowed that in rats bearing Swarm chondrosarcoma, administration of various analogues of somatostatin 14 significantlyreduced tumor weights and/or volume (13). These findings wereconfirmed by Reubi (102), using analogue SMS-201-995. D-Trp6-LH-RH administered alone or with somatostatin ana

logues also reduced the growth of chondrosarcomas (13). Inmice with Dunn osteosarcomas (101), analogues of so-matostatin 14 or more modern analogues, e.g., Ac-p-Cl-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2 (RC-15) and D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160-2H), appeared to have antitumor activities as shown by an increasedsurvival rate and decrease in serum alkaline phosphatase levels(15,16, 28). The inhibitory effect of somatostatin analogues onthe growth of chondrosarcomas and osteosarcomas might beexplained by a reduction in GH and IGF-1 levels and effects onother growth factors (13, 15, 16, 28, 102). D-Trp6-LH-RH

induces the state of sex hormone deprivation, which mightaffect estrogen or testosterone-dependent proteins in bone andcartilage (28). Inhibition of the animal models of chondrosar-comas and osteosarcomas by analogues of somatostatin and

' D. Gonzales-Barcena. manuscript in preparation.

LH-RH agonists suggests that these peptides might be considered for the development of a new endocrine therapy for theseneoplasms. In patients with osteogenic malignancies for whomconventional therapy has failed, treatment with analogues ofsomatostatin alone or combined with D-Trp6-LH-RH could

perhaps be of value.

Lung Cancer

SCLC accounts for 15-25% of all cases of lung cancer (103).The current poor prognosis for most patients with SCLC makesimperative the search for new forms of treatment (103). Thedevelopment of endocrine therapy could be considered sincerecent evidence indicates that SCLC may be hormone dependent (43-45). SCLC produces peptides such as bombesin orGRP which act as autocrine growth factors and which stimulatethe growth of this malignancy (43-45). It was also reportedthat IGF-1 may be a mitogen for human SCLC (104). Oneexperimental approach consists of synthesis of bombesin/GRPreceptor antagonists (43, 103). In addition, somatostatin analogues should also be investigated as possible inhibitors ofSCLC since they reduce the secretion of bombesin and GRPand might also inhibit tumor growth by interfering with thesynthesis of autocrine growth factors by tumor cells (4, 64).Recently an octapeptide analogue of somatostatin was reportedto inhibit the growth of SCLC H-69 line in vivo and in vitro(105).

Brain Tumors

Therapeutic modalities for primary brain tumors like malignant astrocytomas (glioblastomas) are not very effective. Recently, various brain tumors including astrocytomas and menin-giomas have been found to contain significant levels of highaffinity receptors for somatostatin (57, 106). The presence ofreceptors for EGF and IGF-1 and II in human brain tumorswas also established (107, 108). Thus, growth factors may beinvolved in the proliferation of brain tumors. These findingssuggest the merit of investigations to determine whether super-active somatostatin octapeptide analogues could inhibit thegrowth of brain tumors in experimental models. In the case ofpositive results, since these octapeptides would probably penetrate the blood-brain barrier (109), they could be then considered for the development of new approaches to the treatmentof some brain tumors.

Breast Cancer

About one-third of all breast cancers are estrogen dependent(110). Endocrine manipulations used for the treatment of met-astatic breast carcinoma include antiestrogens and LH-RHanalogues (15, 28). In addition prolactin, growth hormone, andvarious growth factors such as IGF-1, EGF, and aTGF may bealso involved in growth and malignant transformation of humanbreast cancer cells (30, 31, 39, 96, 98, 110). Human breasttumors and cancer lines such as MCF-7 have receptors for IGF-1 and EGF (39, 96, 110-112). Both IGF-1 and EGF stimulatethe growth of breast cancer cells in culture and may act asautocrine and paracrine growth factors (39, 110-113). EGFmay play a role in onset and growth of mammary cancer inmice (114). The presence of EGF receptors is associated withpoor prognosis and advanced disease in patients with breastcancer (111). Somatostatin analogues reduce the levels of IGF-1 and EGF (4, 52, 53, 57, 112). Thus somatostatin analogues

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might inhibit breast cancers by reducing the release of GH andprolactin and interfering with the action or secretion of endogenous growth factors. A regression of nitrosomethylurea-in-duced rat mammary carcinoma after administration of a so-matostatin analogue has been demonstrated (115), as well asdirect inhibitory effects of somatostatin analogues SMS-201-995 on the growth of MCF-7 human breast cancer cells incultures (112). We showed a direct inhibition of the MT-5 ratmammary tumor cell line by somatostatin analogue RC-160(116). In rats bearing estrogen and prolactin dependent MT/W9A mammary adenocarcinoma. administration of microcap-sules of analogue RC-160 significantly inhibited tumor growth(28). A significant synergism between D-Trp6-LH-RH and thesomatostatin analogue RC-160 in the inhibition of tumorgrowth was demonstrated when microcapsules of both peptideswere given together. One of the approaches for improving thetherapeutic response and its duration in breast cancer could bethus based on combining treatment with LH-RH agonists orantagonists with somatostatin analogues. Somatostatin analogues are being tried as adjuncts to agonistic analogues of LH-RH in the palliative treatment of breast cancer in women,depending upon the status of receptors (64). Somatostatinanalogues could be also tried alone in women with advancedbreast carcinoma and low or negative receptors for estrogenand progesterone who do not respond to estrogen ablationtherapy. In view of the observations that the side effects ofsomatostatin analogues consist mainly of steatorrhea (53, 57,62,64), which can be controlled, somatostatin analogues shouldbe less toxic than adjuvant chemotherapy, but their clinicalpalliative effectiveness in treatment of breast cancer remains tobe demonstrated.

Since growth factors might be also implicated in ovarianepithelial carcinoma (117), somatostatin analogues could bealso tried as adjuncts to therapy with D-Trp6-LH-RH which

induces some responses in advanced cases of this malignancy,probably by suppressing gonadotropins (118).

Prostate Cancer

About 70% of prostate cancers are testosterone dependent(15,28,29,119).The endocrine treatment of advanced prostaticcarcinoma is based upon the androgen dependence (15, 28, 29,119, 120). The approach based on microcapsule formulation ofD-Trp6-LH-RH and other LH-RH agonists could become the

method of choice for the palliative treatment of advancedprostate carcinoma (121). However, the duration of remissionin patients with prostate cancer may be limited, inasmuch ashormonal manipulations do not prevent the ultimate growth ofhormone-independent cells (4, 28, 29, 120, 122). Combinationof hormonal therapy with somatostatin analogues might forestall this phenomenon and prolong survival (4). Somatostatinanalogues could inhibit prostate cancers by reducing the releaseof GH and prolactin and interfering with the action, signaltransmission, or secretion of endogenous growth factors (4).Prolactin has been shown to stimulate prostate growth, toenhance metabolic processes in the prostate, and to potentiatethe response of the prostate to 5-dihydrotestosterone (4, 15,28, 29, 123). Consequently, prolactin could be involved inprostate cancer as a cofactor. The fall in GH induced bysomatostatin analogues could, through suppression of IGF-1levels, be important for the inhibition of prostate tumor growth.Other growth factors especially EGF could be implicated inneoplastic proliferation of the prostatic cells (36). Recently, ithas been shown that rat and human prostate contain high-

affinity binding sites for EGF (124, 125) and that in the ratandrogens regulate the levels of these receptors (124). Our ownstudies also revealed the presence of membrane EGF receptorsin normal human prostate, benign prostatic hyperplasia, andhuman prostate cancer specimens (126). We have also demonstrated that modern superactive octapeptide analogues of somatostatin, including RC-121, significantly decreased theweight and volume of Dunning R3327 prostate cancers and,when given in combination with D-Trp'-LH-RH microcapsules,potentiated the effects of the latter (4). Microcapsules of RC-160 designed for a controlled release of this analogue for 30days also inhibited the growth of Dunning prostate tumorswhen given alone. The view that some of the actions of somatostatin analogues might be exerted directly on prostatecancers is supported by the presence of high affinity bindingsites for somatostatin in Dunning tumors (126). The combination of microcapsules of D-Trp'-LH-RH with microcapsules ofRC-160 resulted in a synergistic potentiation of the inhibitionof prostate tumors (4). Serum GH, prolactin, and somatomedinC levels in serum of rats treated with somatostatin analogueRC-160, alone or in combination with D-Trp6-LH-RH, weresignificantly reduced as compared to controls. Histopathologi-cal evaluation of prostate cancers in rats that received thecombination treatment (RC-160 plus D-Trp6-LH-RH) showed

an inhibitory effect on tumors and regressive changes nearlyequivalent to those induced by chemotherapy with novantroneand D-Trp6-LH-RH (127). The combination of LH-RH ago

nists with somatostatin analogues could result in an increase inthe therapeutic response in patients with advanced prostatecancer. Somatostatin analogues could be also tried in patientswith prostate cancer who have relapsed to androgen ablationtherapy.

Conclusions

The potential of modern somatostatin analogues in treatmentof a variety of malignancies still remains to be established.However, much experimental and clinical evidence suggeststhat modern somatostatin analogues could provide a usefulpalliative form of treatment for some tumors. Somatostatinanalogues could be also considered for use as adjuncts totherapy with LH-RH analogues in breast cancer and prostatecancer.

Acknowledgments

I am grateful to my wife Ana Maria Comaru-Schally, M.D., toMichael N. Pollak, M.D., and to Dr. Charles Liebow for advice in thepreparation of this manuscript.

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