Biotherapy 4: 31-36, 1992. © 1992 Kluwer Academic Publishers. Printed in the Netherlands.
Somatostatin and growth hormone regulation in cancer Andrea Manni Department of Medicine, Division of Endocrinology, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, PA 17033, USA Received 18 March 1991; accepted 19 April 1991
Key words: cancer modulation, growth hormone, somatostatin Abstract
Somatostatin analogues are used clinically in a variety of pituitary and gastroenteropancreatic tumours. In addition, they may influence breast and prostate growth either directly through somatostatin receptors or indirectly through inhibition of growth hormone and prolactin release. Somatostatin analogues may interfere with EGF/TGFa-stimulated growth of these tumours and can suppress circulating levels of IGF-I in addition.
Introduction
Somatostatins are naturally occurring polypeptides with diverse biologic functions (Table 1) [1]. Although many therapeutic applications could be envisioned for native somatostatin, its
short plasma half-life (2-3 min) limits its practical use. The development of long acting somatostatin analogues has been a major advance in overcoming this obstacle [1-4]. In general, such analogues have similar qualitative effects to those of native somatostatin but differ in
Table 1. Systemic regulatory effects of somatostatin.
Hormonal inhibition
Secretory inhibitory activity
Growth hormone Thyroid-stimulating hormone
Gastric acid secretion Gastric motility Gastrin secretion Gastrointestinal blood flow Intestinal absorption (glucose, AA) Pancreatic bicarbonate secretion Pancreatic enzyme secretion Splanchnic blood flow VIP-stimulated water/ion transport
Gastrointestinal tract Enteroglucagon Gastrointestinal polypeptide Gastrin Motilin Secretin Vasoactive intestinal peptide Pancreatic Glucagon Insulin Pancreatic polypeptide Somatostatin Genitourinary tract Aldosterone Renin VIP = vasoactive intestinal peptide. Reproduced with permission from [1].
32 Table 2. Diseases where octreotide is undergoing clinical testing. Pituitary tumors Acromegaly TSH-secreting tumors Gastroenteropancreatictumors Carconoid tumors Gastrinomas Insulinomas Vipoma Glucagonomas Non malignantdiseasesof the gastrointestinal tract Secretorydiarrhea Ileostomy diarrhea GI fistulas Pancreatitis Dumping syndrome Bleeding esophageal varices Nonvariceal upper GI bleeding Diabetes mellitus Autonomic neuropathy Solid tumors Breast cancer Prostate cancer Pancreatic cancer
degrees of potency and antihormonal specificity. Among these, octreotide has been most extensively tested in clinical trials [3,4]. Animal studies show that octreotide is 70 times more potent than native somatostatin in inhibiting growth hormone secretion, 23 times more potent in inhibiting glucagon secretion and 3 times more effective in suppressing secretion of insulin [5]. Although octreotide is approved by the FDA only for treatment of the carcinoid syndrome and vipomas, this analogue is undergoing clinical investigation in a variety of disorders (Table 2). Detailed discussion on the use of octreotide in these conditions, is available in recent comprehensive reviews [1-4]. The focus here is on the potential usefulness of octreotide in the treatment of breast and prostate cancer, the potential mechanisms of antitumor action and the results of pilot clinical trials so far published.
antitumor action involves inhibition of growth hormone and, under certain conditions, also of prolactin release [6-10] although consistent prolactin suppression can best be achieved in patients by concomitant administration of dopaminergic drugs such as bromocriptine [11]. In humans, growth hormone is lactogenic and, together with prolactin, could be involved in the growth of both breast [12, 13] and prostate cancer [7, 9, 10, 14, 15]. Suppression of circulating levels of IGF-I, the production of which is growth hormone-dependent, could also be instrumental in inducing tumor regression. IGF-1 is known to exert a potent stimulatory effect on breast cancer growth [16, 17] and its action has been recently shown to be greatly amplified by estrogens [18]. Somatostatin analogues could also interfere with E G F / T G F - a stimulated breast and prostate cancer cell proliferation and considerable evidence indicates that these growth factors may be important effectors of tumor growth in both of these malignancies [19, 20]. Plasma concentrations of EGF have been found to be suppressed in patients treated with somatostatin analogue therapy [21]. In addition, in different experimental systems, somatostatin has been shown to inhibit EGF stimulated proliferation [22,23], possibly by reversing the stimulatory effects of EGF on the phosphorylation of the tyrosine kinase portion of the EGF receptor [24]. Finally, somatostatin analogues could also exert a direct inhibitory effect on tumor growth as shown for the MCF-7 breast cancer celt line in liquid culture [25]. The presence of somatostatin receptors in a significant fraction of human breast cancer specimens provides support for this potential mechanism of antitumor action [26, 27]. It has recently been reported that different somatostatin analogues differ in their binding affinities for various tumors [28]. If confirmed, these findings suggest that some analogues could be therapeutically superior to others in the treatment of cancer.
Potential mechanisms of antitumor action
Somatostatin analogues could influence breast and prostate cancer growth indirectly by affecting the endocrine milieu of the host and directly at the tumor level. A potential mechanism of
Clinical trials in breast cancer
Table 3 summarizes the published pilot clinical trials testing the role of octreotide in the treat-
33 Table 3. Summary of pilot clinical trials testing the role of octreotide in the treatment of advanced breast cancer. Author
No. of patients
Treatment schedule
No. of responders
Duration of response
Endocrine effects
[11]
10
100-200/xg s.c. BID +
1~
7 months
-
~ 4 months b _
bromocriptine 2.5 mg BID po
[29] [30]
14 8¢
100/xg s.c. BID 400/~g s.c. TID
3" 9
[31]
10
750/xg i.v. TID x 10 days -+500 ixg i.m. BID x 5 days
3d
G H ~ in 7/9 SM-C + i n 6 / 9 ( - 3 0 % ) PRL ,~ i n 8 / 9 No effect on gonadotropins, estrogens, cortisol, thyroid hormones - SM-C $ in 8/12 ( ~ 3 0 % ) ;GH - $ SM-C ( - 5 0 % ) - endocrine studies not performed -
" O n l y disease stabilization was observed in these patients. b Treatment was discontinued in the absence of tumor regression despite lack of progression. c This group includes patients with pancreatic, ovarian, breast, kidney and colon cancer. The exact distribution of patients among the various tumor types was not reported. d All these patients were previously untreated, ° Duration of response not reported since the treatment was discontinued after 15 days.
ment of advanced breast cancer [11, 29-31]. Overall, these studies indicate that moderate suppression of growth hormone and somatomedin-C production can be achieved in most but not all patients. The ability of octreotide to suppress growth hormone secretion in non-acromegalic patients is not well established. While some studies have suggested significant growth hormone suppression following the administration of this compound [32], others have shown no effect [33], probably as a result of different experimental conditions such as timing of injection. For instance, one study [34] clearly showed that administration shortly before onset of sleep is critical for suppression of the nocturnal growth hormone rise which accounts for a major portion of the 24 hour growth hormone output. Thus, additional efforts need to be placed in determining the optimal schedule of administration of the drug to maximize its endocrine effects. Since most clinical trials to date included heavily pretreated patients, the therapeutic potential of somatostatin analogue therapy in advanced breast cancer cannot be adequately assessed. The only patients reported to have obtained objective tumor regression were those who were previously untreated (Table 3) [31].
Following our published report [11], we have treated 7 additional patients with the combination of octreotide and bromocriptine. Of these, one obtained objective tumor regression consisting of a decrease in the size of metastatic skin lesions and healing of lytic bone matastasis for a 6-month duration. Larger clinical trials involving a more favorable category of patients are needed to establish the therapeutic efficacy of somatostatin analogues, either alone or in combination with standard therapy, in the treatment of metastatic breast cancer.
Clinical trials in prostate cancer
The potential usefulness of somatostatin analogues in the treatment of prostate cancer is suggested by the recent finding that these compounds inhibit the growth of Dunning R 3327 tumors in rats [7]. Also that the combination of LHRH superagonist therapy with somatostatin analogue treatment resulted in a synergistic potentiation of inhibition of tumor growth [7]. Dupont et al. [35] have published a preliminary report where octreotide and bromocriptine were administered to patients with stage D2 prostate cancer who relapsed following treat-
34 ment with flutamide and castration. Octreotide was administered subcutaneously under constant pump infusion and it is reported that the decrease in plasma growth hormone concentration was not significant despite the daily administration of an average of 1350/zg of octroetide and 5 mg of bromocriptine. In contrast, a significant decrease in serum prolactin and IGF-I was observed for up to 3 months of treatment. None of 10 evaluable patients obtained an objective response according to the NPCP criteria. As in the case of breast cancer, the therapeutic potential of this treatment needs to be assessed in less heavily pretreated patients. Again the optimal treatment schedule needs to be determined if we are to maximize the endocrine effects.
to improve in diabetics and acromegalics treated with octroetide, probably as a result of growth hormone and/or glucagon suppression [40,41]. Perhaps of more concern is the development of cholelithiasis. Ho et al. [4] reported development of gallstones after 12 months of octreotide treatment in 4 of 9 patients who had normal gallbladder ultrasound examination before initiation of therapy. In addition, gallstones were detected in 5 of another 9 patients who did not have ultrasonography at the start of treatment. Overall, toxicity from octreotide seems to be acceptable although patients should be closely monitored for development of adverse reactions in view of the limited clinical experience with the use of this agent.
Toxicity of somatostatin analogues Acknowledgements Somatostatin analogue therapy with octreotide has generally been reported to be free of major toxicity [1-4]. Nevertheless, a variety of sideeffects have been reported in some patients (Table 4). The majority of complaints are gastrointestinal and consists of abdominal pain, cramping, loose stools, and steatorrhea. These symptoms, however, are usually transient and frequently subside despite continuation of treatment. Glucose intolerance, when present, is mild and clinically insignificant [36-39]. There has been no report of the development of frank diabetes or an increase in glycosylated hemoglobin. Glucose tolerance has actually been shown Table 4. Toxicity reported with the use of somatostatin analog therapy."
Pain at the injection site Transient abdominal pain, cramping and loose stools Transient steatorrhea Glucose intolerance Elevation in serum transaminase concentration Skin rash due to hypersensitivity reaction Water retention and hyponatremia b Cholelithiasis Phamacokinetic interaction with cyclosporine~ "See [1-4] for detailed description of these side effects and additional specific references. b Observed only with i.v. infusion of native somatostatin, not octreotide. A decline in previously stable concentrations of cyclosporine has been observed following institution of octreotide treatment.
This work is supported by a grant from the National Cancer Institute, PO1 CA40011. The author wishes to thank Mrs. Carrie Leitzell for her excellent secretarial assistance.
References 1. Longnecker SM. Somatostatin and octreotide: literature review and description of therapeutic activity in pancreatic neoplasia. Drug lntell Clim Pharm 1988; 2: 99106, 2. Katz MD, Estad BL. Octreotide, a new somatostatin analogue. Clin Pharm 1989; 8: 255-73. 3. Gorden P, Comi RJ, Maton PN, Go VLW. Somatostatin and somatostatin analogue (SMS 201-995) in treatment of hormone-secreting tumors of the pituitary and gastrointestinal tract and non-neoplastic diseases of the gut. Ann Int Med 1989; 110: 35-50. 4. Ho KY, Weissberger A J, Marbach P, Lazarus L. Therapeutic efficacy of the somatostatin analog SMS 201-995 (octreotide) in acromegaly: effects of dose and frequency and long-term safety. Ann Int Med i990; 112: 173-81. 5. Bauer W, Briner U, Doepfner W, Hailer R, Huguenin R, Marbach P, Petcher J, Pless J. SMS 201-995: a very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci 1982; 31: 1133-40. 6. Schally AV, Coy DH, Meyers CA. Hypothalamic regulatory hormones. Annu Rev Biochem 1978; 47: 89-128. 7. Schally AV, Redding TW. Somatostatin analogs as adjuncts to agonists of luteinizing hormone-releasing hormone in the treatment of experimental prostate cancer. Proc Natl Acad Sci USA 1987; 84: 7275-9.
35 8. Schally AV, Cai RZ, Torres-Aleman I, Redding TW, Szoke B, Fu D, Hierowski MT, Colaluca J, Konturek S. Endocrine, gastrointestinal and antitumor activity of somatostatin analogs. In: Moody TW, ed. Neural and endocrine peptides and receptors. New York: Plenum Publishing Corp., 1986: 73-83. 9. Schally AV, Redding TW, Cai RZ, Paz JI, Ben-David M, Comaru-Schally AM. Somatostatin analogs in the treatment of various experimental tumors. In: Klijn JGM, ed. International symposium on hormonal manipulation of cancer: peptides, growth factors and new (anti) steroidal agents. New York: Raven Press, 1987: 431-40. 10. Schally AV, Redding TW, Paz-Bouza JI, Comaru-Schally AM, Mathe G. Current concept for improving treatment of prostate cancer based on combination of LH-RH agonists with other agents. In: Murphy GP, Khoury S, Kuss R, Chatelain C, Denis L, eds. Prostate cancer, part A. New York: Alan R. Liss, 1987: 173-97. 11. Manni A, Boucher AE, Demers LM, Harvey HA, Lipton A, Simmonds MA, Bartholomew M. Endocrine effects of combined somatostatin analog and bromocriptine therapy in women with advanced breast cancer. Breast Cancer Res Treat 1989; 14: 289-98. 12. Manni A, Wright C, David G, Glenn J, Joehl R, Feil P. Promotion by prolactin of the growth of human breast neoplasms in vitro in the soft agar clonogenic assay. Cancer Res 1986; 46: 1669-72. 13. Malarkey WB, Kennedy M, Allred LE, Milo G. Physiological concentrations of prolactin can promote the growth of human breast tumor cells in culture. J Clin Endocrinol Metab 1983; 56: 673-7. 14. Schally Av, Comaru-SchaUy AM, Redding TW. Antitumor effects of analogs of hypothalamic hormones in endocrine-dependent cancers. Proc Soc Exp Biol Med 1984; t75: 259-81. 15. Johnson MP, Thompson SA, Lubaroff DM. Differential effects of prolactin on rat dorsolateral prostate and R3327 prostate tumor subtines. J Urol 1985; 133: 111220. 16. Huff KK, Knabbe C, Lindsey R, Kaufman D, Bronzert D, Lippman ME, Dickson RG. Multihormal regulation of insulin-like growth factor-I-related protein in MCF-7 human breast cancer cells. Molec Endocr 1988; 2: 200-8. 17. Glikman PL, Manni A, Bartholomew M, Demers L. Polyamine involvement in basal and estradiol-stimulated insulin-like growth factor I secretion and action in breast cancer cells in culture. J Steroid Biochem Molec Biol 1990; 37: 1-10. 18. Steward AJ, Johnson MD, May FEB, Westley BR. Role of insulin-like growth factors and the Type I insulin-like growth factor receptor in the estrogen-stimulated proliferation of human breast cancer cells. J Biol Chem 1990; 265; 21172-8. 19. Bates SE, Davidson NE, Valverius EM, Freter CE, Dickson RB, Tam JP, Kudlow JE, Lippman ME, Salomon DS. Expression of transforming growth factor a and its messenger ribonucleic acid in human breast cancer: its regulation by estrogen and its possible functional significance. Molec Endocrinol 1988; 2: 543-55.
20. Wilding G, Valverius E, Knabbe C, Gelmann EP. Role of transforming growth factor-a in human prostate cancer cell growth. Prostate 1989; I5: 1-12. 21. Chirlanda G, Uccioli L, Perri F, Altomonte L, Bertoi A, Manna R, Frati L, Greco AU. Epidermal growth factor, somatostatin and psoriasis. Lancet t983; i: 65. 22. Viguerie N, Tahiri-Jouti N, Ayral AM, Cambillau C, Scemama JL, Bastie MJ, Knuhtsen S, Esteve JP, Pradayrol L, Susini C, Vaysse N. Direct inhibitory effects of a somatostatin analog, SMS 201-995, on AR4-2J cell proliferation via pertussis toxin-sensitive guanosine triphosphate-binding protein-independent mechanism. Endocrinology 1989; 124: 1017-25. 23. Mascardo RN, Sherline P. Somatostatin inhibits rapid intrasomal separation and cell proliferation induced by epidermal growth factor. Endocrinology 1982; 111: 13946. 24. Hierowski MT, Leibow C, Sapin K, Schally AV. Stimulation by somatostatin of dephosphorylation of membrane proteins in pancreatic cancer MIA PaCa-2 cell line. FEBS Lett 1985; 179: 252-6. 25. Setyono-Han B, Henkelman MS, Foekens JA, Klijn JGM. Direct inhibitory effects of somatostatin (analogues) on the growth of human breast cancer cells. Cancer Res 1987; 47: 1566-70. 26. Reubi JC, Waser B, Foekens JA, Klijn JGM, Lamberts SWJ, Laissue J. Somatostatin receptor incidence and distribution in breast cancer using receptor autoradiography: relationship to EGF receptors. Int J ancer 1990; 46: 416-20. 27. Fekete M, Wittlif JL, Schally AV. Characteristics and distribution of receptors for [D-TRpr]-luteinizing hormone-releasing hormone, somatostatin, epidermal growth factor, and sex steroids in 500 biopsy samples of human breast cancer. J Clin Lab Analysis 1989; 3: 137-47. 28. Srkalovic G, Cai R-Z, Schally AV. Evaluation of receptors for somatostatin in various tumors using different analogs. J Clin Endocrinol Metab 1990; 70: 661-9. 29. Vennin PH, Peyrat JP, Bonneterre J, Llouchez MM, Harris AG, DemaiUe A. Effect of the long-acting somatostatin analogue SMS 201-995 (Sandostatin) in advanced breast cancer. Anticancer Res 1989; 9: 153-6. 30. Pollak MN, Polychronakos C, Guyada H. Somatostatin analogue SMS 201-995 reduces serum IGF-I levels in patients with neoplasms potentially dependent on IGF-I. Anticancer Res 1989; 9: 889-92. 31. Stolfi R, Parisi AM, Natoli C, IaobeUi S. Advanced breast cancer: response to somatostatin. Anticancer Res 1990; 10: 203-4. 32. del Pozo E, Neufeld M, Schulter K, Tortosa F, Clarenbach P, Bieder E, Wendel L, Nuesch E, Marbach P, Cramer H, Kerp L. Endocrine profile of a long-acting somatostatin derivative SMS 201-995. Study in normal volunteers following subcutaneous administration. Acta Endocrinol 1986; 111: 433-9. 33. Davies RR, Miller M, Turner SJ, Goodship THJ, Cook DB, Watson M, McGill A, Orskov H, Alberti KGMM, Johnston DG. Effects of somatostatin analogue SMS
36
34.
35.
36.
37.
201-995 in normal man. Clin Endocrinol 1986; 24: 66574. Johnston DG, Davies RR, Alberti KGMM, Miller M, Turner SJ, Watson M. Effects of SMS 201-995 on intermediary metabolism and endocrine status in normal and diabetic humans. Amer J Med 1986; 81: 88-93. Dupont A, Boucher H, Cusan L, Lacourciere Y, Emod J, Labrie F. Octreotide and bromocriptine in patients with stage D2 prostate cancer who relapsed during treatment with flutamide and castration. Eur J Cancer 1990; 26; 770-1. Kvols LK, Moertel CG, O'Connell MJ, Schutt A J, Ruin J, Hahn RG. Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. N Engl J Med 1986; 315; 663-6. Kvols LK, Buck M, Moertel CG, Schutt AJ, Rubin J, O'ConneU MJ, Hahn RG. Treatment of metastatic islet cell carcinoma with a somatostatin analogue (SMS 201995). Ann Int Med 1987; 107: 162-8.
38. Boden G, Ryan IG, Eisenschmid BL, Shelmet JJ, Owen OE. Treatment of inoperable glucagonama with the long-acting somatostatin analogue SMS 201-995. N Engl J Med I986; 314: 1686-9. 39. Maton PN, O'Dorisio TM, Howe BA, McArthur KE, Howard JH, Cherner JA, Malarkey TB, Collen MJ, Gardner JD, Jensen RT. Effect of a long-acting somatostatin analogue (SMS 201-995) in a patient with pancreatic cholera. N Engl J Med 1985; 312: 17-21. 40. Barnard L, Grantham WG, Lamberton P, O'Dorisio TM, Jackson I. Treatment of resistant acromegally with a long-acting somatostatin analogue (SMS 201-995). Ann Int Med. 1986; 105: 856-61. 41. Chiodini PG, Cozzi R, Dallabonzana D, Oppizzi G, Verde G, Petroncini M, Liuzzi A, Pozo ED. Medical treatment of acromegaly with SMS 201-995, a somatostatin analog: a comparison with bromocriptine. J Clin Endocrinol Metab 1987; 64: 447-53.
Somatostatin and growth hormone regulation in cancer Andrea Manni Department of Medicine, Division of Endocrinology, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, PA 17033, USA Received 18 March 1991; accepted 19 April 1991
Key words: cancer modulation, growth hormone, somatostatin Abstract
Somatostatin analogues are used clinically in a variety of pituitary and gastroenteropancreatic tumours. In addition, they may influence breast and prostate growth either directly through somatostatin receptors or indirectly through inhibition of growth hormone and prolactin release. Somatostatin analogues may interfere with EGF/TGFa-stimulated growth of these tumours and can suppress circulating levels of IGF-I in addition.
Introduction
Somatostatins are naturally occurring polypeptides with diverse biologic functions (Table 1) [1]. Although many therapeutic applications could be envisioned for native somatostatin, its
short plasma half-life (2-3 min) limits its practical use. The development of long acting somatostatin analogues has been a major advance in overcoming this obstacle [1-4]. In general, such analogues have similar qualitative effects to those of native somatostatin but differ in
Table 1. Systemic regulatory effects of somatostatin.
Hormonal inhibition
Secretory inhibitory activity
Growth hormone Thyroid-stimulating hormone
Gastric acid secretion Gastric motility Gastrin secretion Gastrointestinal blood flow Intestinal absorption (glucose, AA) Pancreatic bicarbonate secretion Pancreatic enzyme secretion Splanchnic blood flow VIP-stimulated water/ion transport
Gastrointestinal tract Enteroglucagon Gastrointestinal polypeptide Gastrin Motilin Secretin Vasoactive intestinal peptide Pancreatic Glucagon Insulin Pancreatic polypeptide Somatostatin Genitourinary tract Aldosterone Renin VIP = vasoactive intestinal peptide. Reproduced with permission from [1].
32 Table 2. Diseases where octreotide is undergoing clinical testing. Pituitary tumors Acromegaly TSH-secreting tumors Gastroenteropancreatictumors Carconoid tumors Gastrinomas Insulinomas Vipoma Glucagonomas Non malignantdiseasesof the gastrointestinal tract Secretorydiarrhea Ileostomy diarrhea GI fistulas Pancreatitis Dumping syndrome Bleeding esophageal varices Nonvariceal upper GI bleeding Diabetes mellitus Autonomic neuropathy Solid tumors Breast cancer Prostate cancer Pancreatic cancer
degrees of potency and antihormonal specificity. Among these, octreotide has been most extensively tested in clinical trials [3,4]. Animal studies show that octreotide is 70 times more potent than native somatostatin in inhibiting growth hormone secretion, 23 times more potent in inhibiting glucagon secretion and 3 times more effective in suppressing secretion of insulin [5]. Although octreotide is approved by the FDA only for treatment of the carcinoid syndrome and vipomas, this analogue is undergoing clinical investigation in a variety of disorders (Table 2). Detailed discussion on the use of octreotide in these conditions, is available in recent comprehensive reviews [1-4]. The focus here is on the potential usefulness of octreotide in the treatment of breast and prostate cancer, the potential mechanisms of antitumor action and the results of pilot clinical trials so far published.
antitumor action involves inhibition of growth hormone and, under certain conditions, also of prolactin release [6-10] although consistent prolactin suppression can best be achieved in patients by concomitant administration of dopaminergic drugs such as bromocriptine [11]. In humans, growth hormone is lactogenic and, together with prolactin, could be involved in the growth of both breast [12, 13] and prostate cancer [7, 9, 10, 14, 15]. Suppression of circulating levels of IGF-I, the production of which is growth hormone-dependent, could also be instrumental in inducing tumor regression. IGF-1 is known to exert a potent stimulatory effect on breast cancer growth [16, 17] and its action has been recently shown to be greatly amplified by estrogens [18]. Somatostatin analogues could also interfere with E G F / T G F - a stimulated breast and prostate cancer cell proliferation and considerable evidence indicates that these growth factors may be important effectors of tumor growth in both of these malignancies [19, 20]. Plasma concentrations of EGF have been found to be suppressed in patients treated with somatostatin analogue therapy [21]. In addition, in different experimental systems, somatostatin has been shown to inhibit EGF stimulated proliferation [22,23], possibly by reversing the stimulatory effects of EGF on the phosphorylation of the tyrosine kinase portion of the EGF receptor [24]. Finally, somatostatin analogues could also exert a direct inhibitory effect on tumor growth as shown for the MCF-7 breast cancer celt line in liquid culture [25]. The presence of somatostatin receptors in a significant fraction of human breast cancer specimens provides support for this potential mechanism of antitumor action [26, 27]. It has recently been reported that different somatostatin analogues differ in their binding affinities for various tumors [28]. If confirmed, these findings suggest that some analogues could be therapeutically superior to others in the treatment of cancer.
Potential mechanisms of antitumor action
Somatostatin analogues could influence breast and prostate cancer growth indirectly by affecting the endocrine milieu of the host and directly at the tumor level. A potential mechanism of
Clinical trials in breast cancer
Table 3 summarizes the published pilot clinical trials testing the role of octreotide in the treat-
33 Table 3. Summary of pilot clinical trials testing the role of octreotide in the treatment of advanced breast cancer. Author
No. of patients
Treatment schedule
No. of responders
Duration of response
Endocrine effects
[11]
10
100-200/xg s.c. BID +
1~
7 months
-
~ 4 months b _
bromocriptine 2.5 mg BID po
[29] [30]
14 8¢
100/xg s.c. BID 400/~g s.c. TID
3" 9
[31]
10
750/xg i.v. TID x 10 days -+500 ixg i.m. BID x 5 days
3d
G H ~ in 7/9 SM-C + i n 6 / 9 ( - 3 0 % ) PRL ,~ i n 8 / 9 No effect on gonadotropins, estrogens, cortisol, thyroid hormones - SM-C $ in 8/12 ( ~ 3 0 % ) ;GH - $ SM-C ( - 5 0 % ) - endocrine studies not performed -
" O n l y disease stabilization was observed in these patients. b Treatment was discontinued in the absence of tumor regression despite lack of progression. c This group includes patients with pancreatic, ovarian, breast, kidney and colon cancer. The exact distribution of patients among the various tumor types was not reported. d All these patients were previously untreated, ° Duration of response not reported since the treatment was discontinued after 15 days.
ment of advanced breast cancer [11, 29-31]. Overall, these studies indicate that moderate suppression of growth hormone and somatomedin-C production can be achieved in most but not all patients. The ability of octreotide to suppress growth hormone secretion in non-acromegalic patients is not well established. While some studies have suggested significant growth hormone suppression following the administration of this compound [32], others have shown no effect [33], probably as a result of different experimental conditions such as timing of injection. For instance, one study [34] clearly showed that administration shortly before onset of sleep is critical for suppression of the nocturnal growth hormone rise which accounts for a major portion of the 24 hour growth hormone output. Thus, additional efforts need to be placed in determining the optimal schedule of administration of the drug to maximize its endocrine effects. Since most clinical trials to date included heavily pretreated patients, the therapeutic potential of somatostatin analogue therapy in advanced breast cancer cannot be adequately assessed. The only patients reported to have obtained objective tumor regression were those who were previously untreated (Table 3) [31].
Following our published report [11], we have treated 7 additional patients with the combination of octreotide and bromocriptine. Of these, one obtained objective tumor regression consisting of a decrease in the size of metastatic skin lesions and healing of lytic bone matastasis for a 6-month duration. Larger clinical trials involving a more favorable category of patients are needed to establish the therapeutic efficacy of somatostatin analogues, either alone or in combination with standard therapy, in the treatment of metastatic breast cancer.
Clinical trials in prostate cancer
The potential usefulness of somatostatin analogues in the treatment of prostate cancer is suggested by the recent finding that these compounds inhibit the growth of Dunning R 3327 tumors in rats [7]. Also that the combination of LHRH superagonist therapy with somatostatin analogue treatment resulted in a synergistic potentiation of inhibition of tumor growth [7]. Dupont et al. [35] have published a preliminary report where octreotide and bromocriptine were administered to patients with stage D2 prostate cancer who relapsed following treat-
34 ment with flutamide and castration. Octreotide was administered subcutaneously under constant pump infusion and it is reported that the decrease in plasma growth hormone concentration was not significant despite the daily administration of an average of 1350/zg of octroetide and 5 mg of bromocriptine. In contrast, a significant decrease in serum prolactin and IGF-I was observed for up to 3 months of treatment. None of 10 evaluable patients obtained an objective response according to the NPCP criteria. As in the case of breast cancer, the therapeutic potential of this treatment needs to be assessed in less heavily pretreated patients. Again the optimal treatment schedule needs to be determined if we are to maximize the endocrine effects.
to improve in diabetics and acromegalics treated with octroetide, probably as a result of growth hormone and/or glucagon suppression [40,41]. Perhaps of more concern is the development of cholelithiasis. Ho et al. [4] reported development of gallstones after 12 months of octreotide treatment in 4 of 9 patients who had normal gallbladder ultrasound examination before initiation of therapy. In addition, gallstones were detected in 5 of another 9 patients who did not have ultrasonography at the start of treatment. Overall, toxicity from octreotide seems to be acceptable although patients should be closely monitored for development of adverse reactions in view of the limited clinical experience with the use of this agent.
Toxicity of somatostatin analogues Acknowledgements Somatostatin analogue therapy with octreotide has generally been reported to be free of major toxicity [1-4]. Nevertheless, a variety of sideeffects have been reported in some patients (Table 4). The majority of complaints are gastrointestinal and consists of abdominal pain, cramping, loose stools, and steatorrhea. These symptoms, however, are usually transient and frequently subside despite continuation of treatment. Glucose intolerance, when present, is mild and clinically insignificant [36-39]. There has been no report of the development of frank diabetes or an increase in glycosylated hemoglobin. Glucose tolerance has actually been shown Table 4. Toxicity reported with the use of somatostatin analog therapy."
Pain at the injection site Transient abdominal pain, cramping and loose stools Transient steatorrhea Glucose intolerance Elevation in serum transaminase concentration Skin rash due to hypersensitivity reaction Water retention and hyponatremia b Cholelithiasis Phamacokinetic interaction with cyclosporine~ "See [1-4] for detailed description of these side effects and additional specific references. b Observed only with i.v. infusion of native somatostatin, not octreotide. A decline in previously stable concentrations of cyclosporine has been observed following institution of octreotide treatment.
This work is supported by a grant from the National Cancer Institute, PO1 CA40011. The author wishes to thank Mrs. Carrie Leitzell for her excellent secretarial assistance.
References 1. Longnecker SM. Somatostatin and octreotide: literature review and description of therapeutic activity in pancreatic neoplasia. Drug lntell Clim Pharm 1988; 2: 99106, 2. Katz MD, Estad BL. Octreotide, a new somatostatin analogue. Clin Pharm 1989; 8: 255-73. 3. Gorden P, Comi RJ, Maton PN, Go VLW. Somatostatin and somatostatin analogue (SMS 201-995) in treatment of hormone-secreting tumors of the pituitary and gastrointestinal tract and non-neoplastic diseases of the gut. Ann Int Med 1989; 110: 35-50. 4. Ho KY, Weissberger A J, Marbach P, Lazarus L. Therapeutic efficacy of the somatostatin analog SMS 201-995 (octreotide) in acromegaly: effects of dose and frequency and long-term safety. Ann Int Med i990; 112: 173-81. 5. Bauer W, Briner U, Doepfner W, Hailer R, Huguenin R, Marbach P, Petcher J, Pless J. SMS 201-995: a very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci 1982; 31: 1133-40. 6. Schally AV, Coy DH, Meyers CA. Hypothalamic regulatory hormones. Annu Rev Biochem 1978; 47: 89-128. 7. Schally AV, Redding TW. Somatostatin analogs as adjuncts to agonists of luteinizing hormone-releasing hormone in the treatment of experimental prostate cancer. Proc Natl Acad Sci USA 1987; 84: 7275-9.
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