- Email: [email protected]
Octreotide steaming ahead
837
concentration, the St Bartholomew’s group achieved a reduction in growth hormone in acromegaly to less than 1 mU/1 in over 55% of their patients. Since plasma concentrations of growth hormone tend to "escape" during the night, it may be necessary to give more octreotide in the evening than in the morning.
EDITORIALS
The
Octreotide
steaming
ahead
Within ten years of the discovery of a hypothalamic inhibitor of growth hormone release, an analogue with a much longer half-life and greater specificity for hormone inhibition was available for clinical testing. The native inhibitor is somatostatin; the analogue is octreotide. The effects of octreotide in acromegaly have been studied in a multicentre world-wide trial that included patients from China.’ Use of the drug has also been explored in gastrointestinal disease and in various other conditions. Clinical impressions of octreotide were reviewed in a Lancet editorial two years ago.2Numerous developments since then were discussed at a symposium in Monte Carlo last October and the proceedings will be published shortly in Metabolism and in Digestive Diseases and Sciences. In some conditions octreotide therapy is now virtually routine. In acromegaly the main indication is after pituitary surgery if the growth hormone concentration remains above 5 mU/1, or if insulin-like growth factor-1(IGF-1) is raised or growth hormone is not suppressed by an oral glucose load. Octreotide is also indicated as first-line therapy in patients unfit for surgery, or preoperatively in those with large pituitary adenomas to induce shrinkage of the tumour and thereby increase the likelihood of surgical cure. The incidence of postoperative hypopituitarism is also less with smaller tumours. Assessment of patients before octreotide therapy is critical. The routine followed at St Bartholomew’s Hospital, London, as outlined at the symposium by Prof M. Besser, is to measure plasma concentrations of growth hormone over several hours. Response to the analogue may vary considerably. Multiple injections act rather like a depot preparation-a higher dose increases the duration of effect but not necessarily the degree of reduction in growth hormone concentrations. By adjusting the dose and frequency of
injections
in relation
to
the fall in hormone
effective dose seems to be 100 g subcutaneously three times daily. Higher doses are needed in about 10% of patients and continuous subcutaneous infusions only exceptionally. Longterm octreotide treatment in acromegaly is associated with surprisingly few side-effects. Prof H. Orskov that blood (Denmark) reported glucose concentrations were unchanged after six years’ therapy. Irrespective of the dose (between 100 and 1500 )J-g/24 hours), glucose tolerance was not impaired whether assessed orally or intravenously, even in those given continuous subcutaneous infusions. Inhibition of growth hormone secretion is not the only hormonal effect of octreotide in acromegaly. The analogue acts peripherally to inhibit secretion of IGF-1, which mediates most of the effects of growth hormone at tissue level and also induces differentiation and proliferation of mesenchymederived cells. A decrease in the concentration of IGF-1 or suppression of its activity might therefore reduce or prevent the mitogenic effects shown in vitro in human fibroblast, breast cancer, and pancreatic cells. Dr S. Melmed and his colleagues at the Cedars Sinai Medical Center, Los Angeles, found that the effect of octreotide on IGF-1 goes beyond simple inhibition of its release. They noted a simultaneous rise in IGF-1 binding protein (IGFBP-1) after octreotide that was independent of any change in insulin or growth hormone concentrations.The analogue could therefore be used to manipulate the growth hormone axis by suppressing both growth hormone and IGF-1 release while simultaneously attenuating or blocking local actions of IGF-1 via stimulation of IGFBP-1release. Such an effect could be especially useful in conditions where growth hormone concentrations are low. Moreover, since IGFBP-1has such a very high affinity for IGF-1 , it may control access of IGF-1 to its receptor and thereby block IGF-1-induced stimulation of DNA and protein synthesis. In the gut, the most obvious action of octreotideinhibition of endocrine and exocrine gastrointestinal secretion-has already found practical application in the treatment of gastroenteropancreatic tumours. Intestinal transport and motility and gallbladder motility are likewise inhibited. The hypomotility of gut and gallbladder can probably be explained by the inhibitory effect of octreotide on the postprandial release of hormones such as cholecystokinin,4as well by a direct action on neuroendocrine mechanisms. The ability of octreotide to inhibit both intestinal motility and secretion of gastrointestinal hormones most
suggested treatment
potential therapeutic application in of complications of gastric surgery and a
838
intestinal
resection--eg, the dumping syndrome and gastrointestinal fistulas.s,6 The analogue reduces fistula output, thereby facilitating skin care and the general condition of the patient, which in turn enhances closure of the fistula itself. The action of octreotide in inhibiting splanchnic blood flow7 has been exploited in the treatment of variceal bleeding, and clinical trials (eg, versus balloon tamponade) are in progress.
Octreotide may help in the treatment of refractory diarrhoea associated with AIDS. Two multicentre trials discussed at the symposium showed that stool volume and bowel frequency were significantly reduced after a dose of 100 ag eight hourly (doses up to 500 ag eight hourly were needed in some patients).88 Stool volume and frequency of bowel movements were reduced by 50% or more in at least a quarter of the patients studied, and diarrhoea resolved completely in about 15%. Thus, a therapeutic trial of octreotide seems justified in AIDS patients with high-volume diarrhoea if they have not responded to at least a week of conventional antidiarrhoeal measures. Complications of pancreatectomy or of pancreatic transplantation such as fistula formation and acute pancreatitis are likewise reduced by octreotide. A multi centre, double-blind, placebocontrolled trial9 conducted in Germany showed that maximum benefit was achieved in the higher risk patients-ie, those with tumours of the pancreas rather than chronic pancreatitis. The possibility that growth hormone may have a causal role in diabetic angiopathy, its effects being mediated by IGF-1, has opened up another direction in octreotide research. Microalbuminuria regressed or disappeared in diabetic patients with nephropathy who had been treated with octreotide for six months.10 The drug inhibits new vessel growth and endothelial cell replication in in-vitro studies," which would explain why octreotide therapy can be associated with improved visual acuity in patients with preproliferative diabetic retinopathy and macular oedema.l2 Thus, there is now an adequate basis for controlled trials of octreotide in the vascular complications of established diabetes. A limiting factor will be the difficulty of twice or three times daily injections of octreotide in addition to insulin. A depot formulation or an intranasal preparation would therefore be a considerable advance. 13 The action of octreotide in reducing the raised luteinising hormone and androgen concentrations characteristic of patients with polycystic ovaries (as well as the associated hyperinsulinaemia),14 stimulated investigation into its use in infertile women with the syndrome. Initial results of a two-centre trial (Belgrade, Yugoslavia, and the Royal Free Hospital, London) of combined octreotide and gonadotropin stimulant therapy in women with polycystic ovaries, reported by Dr G. M. Prelevic (Belgrade), were encouraging, with better and more orderly follicular growth, a reduced frequency of hyperstimulation, and
increased pregnancy rate with combined octreotide and human menopausal gonadotropin (HMG) than with HMG alone. Improvement in the hormonal milieu after combined octreotide and HMG therapy suggests that the analogue might be useful as an adjunct to gonadotropin stimulation in infertile women, and also encourages speculation about the aetiology of polycystic ovary syndrome itself. Octreotide inhibits growth of implanted pancreatic tumour cells in animals,15 decreasing their RNA and DNA content with very little effect on the growth of normal cells; this observation may have important therapeutic implications. The analogue may act directly and specifically on neoplastic cells or indirectly via peptides or other substances crucial for neoplastic growth. Inhibition of tumour growth by somatostatin analogues has hitherto been attributed to two main mechanisms-inhibition of release of hormones such as growth hormone or IGF-1 that stimulate cellular proliferation, and prevention of new blood vessel formation. Inhibition of angiogenesis results in tumour regression," an effect that seems to be independent of somatostatin receptors. There is also an antiproliferative effect of the analogue on tumour cells mediated via somatostatin receptors; antagonism of the stimulatory effects of epidermal growth factor and of fibroblast growth factor may be an
important. 16,17 One of the most exciting developments discussed at the meeting was the clinical application of the demonstration of somatostatin receptors in various human tumours. One would expect somatostatin receptors to be expressed in neuroendocrine tumours but they are also expressed in malignant lymphoma, meningioma, astrocytoma, and some human breast cancers.18 Somatostatin receptors tend to be expressed in more differentiated tumours—eg, in astrocytoma rather than in gliobastoma. The finding of these receptors may indicate potential antiproliferative effects, which would accord with the observation that somatostatin and its analogues inhibit tumour growth in several animal models and cultured tumour cell lines. Lamberts and his colleagues in Rotterdam, the Netherlands, are already taking advantage of the expression of somatostatin receptors in tumours to guide prognostic and therapeutic decisions.19 Using radiolabelled analogues and in-vivo scintigraphic scanning techniques they found that somatostatin receptors may indicate sensitivity to octreotide therapy in pituitary and gastroenteropancreatic tumours and help in the assessment of tumour spread. Perhaps metastases could even be detected during an operation with a hand-held probe. If the analogue was not only radiolabelled but also capable of delivering radiation, we would have an accurate and specific method of irradiating sensitive tumours without damaging adjacent normal tissue. The most important complications of octreotide treatment are gallstone formation and gastritis.20 Diarrhoea has also been reported but is seldom
839
troublesome. However, the main drawback of octreotide therapy, limiting its clinical application, is the fact that it has to be given several times a day by
injection, occasionally even by continuous infusion. It is also expensive. Currently, the cost of treating a patient with acromegaly needing 300 gg of octreotide daily is over c6000 ($10 000) a year-and this is a life-long commitment. Octreotide has been said to suppress everything except the investigator. Perhaps this dictum will soon apply to its price. 1. Vance ML, Harris AG.
Long term treatment of 189 acromegalic patients with the somatostatin analog octreotide: results of the International Multicenter Acromegaly Study Group. Arch Intern Med 1991; 151: 1573-78. 2. Editorial. All aboard for octreotide. Lancet 1990; 336: 909-11. 3. Ezzat S, Ren SG, Braunstein GD, Melmed S. Octreotide stimulates insulin-like growth factor binding protein-1 (IGFBP-1) levels in acromegaly. J Clin Endocrinol Metab 1991; 73: 441-43. 4. Lembcke B, Creutzfeldt W, Schlesser S, et al. Effect of somatostatin analogue Sandostatin (SMS 201-995) on gastrointestinal, pancreatic and biliary function, and hormone release in normal men. Digestion 1987; 36: 108-24. 5. Geer RJ, Richards WO, O’Dorisio JM, et al. Efficacy of octreotide acetate in treatment of severe postgastrectomy dumping syndrome. Ann Surg 1990; 212: 678-87. 6. Nubiola P, Badia JM, Martinez-Rodenas F, et al. Treatment of 27 postoperative enterocutaneous fistulas with the long half-life somatostatin analogue SMS 201-995. Ann Surg 1989; 210: 56-58. 7. Erikson LS, Brundin T, Soderlund C, et al. Haemodynamic effects of a long-acting somatostatin analogue in patients with liver cirrhosis. Scand J Gastroenterol 1987; 22: 919-25. 8. Cello J, Grendell JH, Basuk P, et al. Effect of octreotide on refractory AIDS-associated diarrhea. Ann Intern Med 1991; 115: 705-10. 9. Buchler M, Freiss H, Klempa I, et al. Role of octreotide in the prevention of postoperative complications following pancreatic resection. Am
J Surgery 1992; 163: 125-31. 10. Chateauneuf C, Babin T, Ducasse MCR, et al. Preliminary results as regards the evolution of microalbuminuria m diabetic patients treated with Sandostatin. Diab Metab 1989; 15: 18 (abstr). 11. Fassler JE, Hughes JH, Titterington L, et al. Somatostatin analog: an inhibitor of angiogenesis? Clin Res 1988; 36: 869. 12. Lee HK, Suh KI, Koh CS, et al. Effects of SMS 201-995 in rapidly progressive diabetic retinopathy. Diab Care 1988; 11: 441-43. 13. Kaal A, Ilum P, Harris AG. A randomised comparison of intranasal and injectable octreotide administration in patients with acromegaly. J Clin Endocrinol Metab (in press). 14. Prelevic GM, Wurzburger MI, Balint-Peric LJ, Nesic JS. Inhibitory effect of sandostatin on secretion of luteinising hormone and ovarian steroids in polycystic ovary syndrome. Lancet 1990; 336: 900-03. 15. Hajri A, Bruns C, Marbach P, Aprahamian M, Longnecker DS, Damge C. Inhibition of the growth of transplanted rat pancreatic acinar carcinoma with octreotide. Eur J Cancer 1991; 27: 1247-53. 16. Lamberts SWJ, Koper JW, Reubi J-C. Potential role of somatostatin analogues in the treatment of cancer. Eur J Clin Invest 1987; 17: 281-87. 17. Schally AV. Oncological applications of somatostatin analogues. Cancer Res 1988; 48: 6977-85. 18. Reubi J-C, Waser B, Froekens JA, Klijn JGM, Lamberts SWJ, Laissue J. Somatostatin receptor incidence and distribution in breast cancer using receptor autoradiography: relationship to EGF receptors. Int J Cancer 1990; 46: 416-20. 19. Krenning EP, Bakker WH, Breeman WAP, et al. Localisation of endocrine-related tumours with radioiodinated analogues of somatostatin. Lancet 1989; i: 242-44. 20. Plockinger U, Dienemann D, Quabbe H-J, et al. Gastrointestinal side effects of octreotide during long term treatment of acromegaly. J Clin Endocrinol Metab 1990; 71: 1658-62.
AIDS: how can a pussy cat kill? In
his
campaign
to
exculpate
human
immunodeficiency virus (HIV) as the cause of AIDS, Duesberg’ emphasises
that this organism displays only weak cytopathic effects and that the viral load is
much too low to account directly for the remorseless destruction of CD4 lymphocytes characteristic of the disease. His informal classification of HIV as a "pussy cat" has been countered forciblyeg, by Weiss and Jaffe2-but the fact remains that we do not understand how HIV causes the damage it so clearly wreaks. In this issue (p 824), Dalgleish and his colleagues review the evidence that HIV may trigger a selfdestructive immune response, for which appropriate models may be found in graft-versus-host disease (GVHD), certain autoimmune disorders, and some animal viral infections. The central plank of the hypothesis is that some component of HIV causes T cells to behave as if they were encountering non-self tissues (alloantigen). Whereas a conventional viral or bacterial antigen must be processed by antigenpresenting cells and is then recognised by a tiny minority of immunocompetent lymphocytes (those that happen to carry the appropriate antibody or T-cell receptor specificity on their surface), alloantigen can be recognised directly and by a
generally
substantial proportion of the T-cell population. Thus virus that can mimic foreign cells is likely to provoke vigorous and widespread T-cell activation. HIV evidently does so and thereby not only promotes its own replication but also could generate cytotoxic lymphocytes directed against other cells expressing viral antigens on their surface. Since HIV envelope glycoprotein is shed and can bind to the CD4 determinant of uninfected T cells, there may be abundant targets for such cytotoxic action. Another mode of T-cell depletion is suggested by the observation that certain antigenic stimuli evoke a transient proliferative response followed by programmed cell death (apoptosis).3,4 It is not entirely clear what determines this pattern of response. It may be related to the process of clonal selection in the developing thymus, where most antigen encountered is self, so elimination of potentially reactive lymphoid cells is in the interests of the organism.5 Prominent among the antigens found to cause apoptosis in adult T cells are bacterial mitogens known as superantigens. The name refers to their ability (shared with alloantigen) to elicit a response from exceptionally large numbers of lymphocytes. Recognition of either a
superantigen or alloantigen seems not to depend on the specific combining site of the T-cell antigen receptor (TCR) which, like its immunoglobulin counterpart on B cells, is formed from the variable regions of a pair of peptide chains. The genes chains these somatic undergo encoding rearrangement to generate functional products and only one each, from a selection of V, D, and J segments in the genome, is used by any given T cellsThere are twenty V gene segments available within the set specifying the 0 chain of the T-cell receptor, and the products of many of these can be identified as members of individual V (3 gene families. Recognition of alloantigen or superantigen is restricted to cells some
concentration, the St Bartholomew’s group achieved a reduction in growth hormone in acromegaly to less than 1 mU/1 in over 55% of their patients. Since plasma concentrations of growth hormone tend to "escape" during the night, it may be necessary to give more octreotide in the evening than in the morning.
EDITORIALS
The
Octreotide
steaming
ahead
Within ten years of the discovery of a hypothalamic inhibitor of growth hormone release, an analogue with a much longer half-life and greater specificity for hormone inhibition was available for clinical testing. The native inhibitor is somatostatin; the analogue is octreotide. The effects of octreotide in acromegaly have been studied in a multicentre world-wide trial that included patients from China.’ Use of the drug has also been explored in gastrointestinal disease and in various other conditions. Clinical impressions of octreotide were reviewed in a Lancet editorial two years ago.2Numerous developments since then were discussed at a symposium in Monte Carlo last October and the proceedings will be published shortly in Metabolism and in Digestive Diseases and Sciences. In some conditions octreotide therapy is now virtually routine. In acromegaly the main indication is after pituitary surgery if the growth hormone concentration remains above 5 mU/1, or if insulin-like growth factor-1(IGF-1) is raised or growth hormone is not suppressed by an oral glucose load. Octreotide is also indicated as first-line therapy in patients unfit for surgery, or preoperatively in those with large pituitary adenomas to induce shrinkage of the tumour and thereby increase the likelihood of surgical cure. The incidence of postoperative hypopituitarism is also less with smaller tumours. Assessment of patients before octreotide therapy is critical. The routine followed at St Bartholomew’s Hospital, London, as outlined at the symposium by Prof M. Besser, is to measure plasma concentrations of growth hormone over several hours. Response to the analogue may vary considerably. Multiple injections act rather like a depot preparation-a higher dose increases the duration of effect but not necessarily the degree of reduction in growth hormone concentrations. By adjusting the dose and frequency of
injections
in relation
to
the fall in hormone
effective dose seems to be 100 g subcutaneously three times daily. Higher doses are needed in about 10% of patients and continuous subcutaneous infusions only exceptionally. Longterm octreotide treatment in acromegaly is associated with surprisingly few side-effects. Prof H. Orskov that blood (Denmark) reported glucose concentrations were unchanged after six years’ therapy. Irrespective of the dose (between 100 and 1500 )J-g/24 hours), glucose tolerance was not impaired whether assessed orally or intravenously, even in those given continuous subcutaneous infusions. Inhibition of growth hormone secretion is not the only hormonal effect of octreotide in acromegaly. The analogue acts peripherally to inhibit secretion of IGF-1, which mediates most of the effects of growth hormone at tissue level and also induces differentiation and proliferation of mesenchymederived cells. A decrease in the concentration of IGF-1 or suppression of its activity might therefore reduce or prevent the mitogenic effects shown in vitro in human fibroblast, breast cancer, and pancreatic cells. Dr S. Melmed and his colleagues at the Cedars Sinai Medical Center, Los Angeles, found that the effect of octreotide on IGF-1 goes beyond simple inhibition of its release. They noted a simultaneous rise in IGF-1 binding protein (IGFBP-1) after octreotide that was independent of any change in insulin or growth hormone concentrations.The analogue could therefore be used to manipulate the growth hormone axis by suppressing both growth hormone and IGF-1 release while simultaneously attenuating or blocking local actions of IGF-1 via stimulation of IGFBP-1release. Such an effect could be especially useful in conditions where growth hormone concentrations are low. Moreover, since IGFBP-1has such a very high affinity for IGF-1 , it may control access of IGF-1 to its receptor and thereby block IGF-1-induced stimulation of DNA and protein synthesis. In the gut, the most obvious action of octreotideinhibition of endocrine and exocrine gastrointestinal secretion-has already found practical application in the treatment of gastroenteropancreatic tumours. Intestinal transport and motility and gallbladder motility are likewise inhibited. The hypomotility of gut and gallbladder can probably be explained by the inhibitory effect of octreotide on the postprandial release of hormones such as cholecystokinin,4as well by a direct action on neuroendocrine mechanisms. The ability of octreotide to inhibit both intestinal motility and secretion of gastrointestinal hormones most
suggested treatment
potential therapeutic application in of complications of gastric surgery and a
838
intestinal
resection--eg, the dumping syndrome and gastrointestinal fistulas.s,6 The analogue reduces fistula output, thereby facilitating skin care and the general condition of the patient, which in turn enhances closure of the fistula itself. The action of octreotide in inhibiting splanchnic blood flow7 has been exploited in the treatment of variceal bleeding, and clinical trials (eg, versus balloon tamponade) are in progress.
Octreotide may help in the treatment of refractory diarrhoea associated with AIDS. Two multicentre trials discussed at the symposium showed that stool volume and bowel frequency were significantly reduced after a dose of 100 ag eight hourly (doses up to 500 ag eight hourly were needed in some patients).88 Stool volume and frequency of bowel movements were reduced by 50% or more in at least a quarter of the patients studied, and diarrhoea resolved completely in about 15%. Thus, a therapeutic trial of octreotide seems justified in AIDS patients with high-volume diarrhoea if they have not responded to at least a week of conventional antidiarrhoeal measures. Complications of pancreatectomy or of pancreatic transplantation such as fistula formation and acute pancreatitis are likewise reduced by octreotide. A multi centre, double-blind, placebocontrolled trial9 conducted in Germany showed that maximum benefit was achieved in the higher risk patients-ie, those with tumours of the pancreas rather than chronic pancreatitis. The possibility that growth hormone may have a causal role in diabetic angiopathy, its effects being mediated by IGF-1, has opened up another direction in octreotide research. Microalbuminuria regressed or disappeared in diabetic patients with nephropathy who had been treated with octreotide for six months.10 The drug inhibits new vessel growth and endothelial cell replication in in-vitro studies," which would explain why octreotide therapy can be associated with improved visual acuity in patients with preproliferative diabetic retinopathy and macular oedema.l2 Thus, there is now an adequate basis for controlled trials of octreotide in the vascular complications of established diabetes. A limiting factor will be the difficulty of twice or three times daily injections of octreotide in addition to insulin. A depot formulation or an intranasal preparation would therefore be a considerable advance. 13 The action of octreotide in reducing the raised luteinising hormone and androgen concentrations characteristic of patients with polycystic ovaries (as well as the associated hyperinsulinaemia),14 stimulated investigation into its use in infertile women with the syndrome. Initial results of a two-centre trial (Belgrade, Yugoslavia, and the Royal Free Hospital, London) of combined octreotide and gonadotropin stimulant therapy in women with polycystic ovaries, reported by Dr G. M. Prelevic (Belgrade), were encouraging, with better and more orderly follicular growth, a reduced frequency of hyperstimulation, and
increased pregnancy rate with combined octreotide and human menopausal gonadotropin (HMG) than with HMG alone. Improvement in the hormonal milieu after combined octreotide and HMG therapy suggests that the analogue might be useful as an adjunct to gonadotropin stimulation in infertile women, and also encourages speculation about the aetiology of polycystic ovary syndrome itself. Octreotide inhibits growth of implanted pancreatic tumour cells in animals,15 decreasing their RNA and DNA content with very little effect on the growth of normal cells; this observation may have important therapeutic implications. The analogue may act directly and specifically on neoplastic cells or indirectly via peptides or other substances crucial for neoplastic growth. Inhibition of tumour growth by somatostatin analogues has hitherto been attributed to two main mechanisms-inhibition of release of hormones such as growth hormone or IGF-1 that stimulate cellular proliferation, and prevention of new blood vessel formation. Inhibition of angiogenesis results in tumour regression," an effect that seems to be independent of somatostatin receptors. There is also an antiproliferative effect of the analogue on tumour cells mediated via somatostatin receptors; antagonism of the stimulatory effects of epidermal growth factor and of fibroblast growth factor may be an
important. 16,17 One of the most exciting developments discussed at the meeting was the clinical application of the demonstration of somatostatin receptors in various human tumours. One would expect somatostatin receptors to be expressed in neuroendocrine tumours but they are also expressed in malignant lymphoma, meningioma, astrocytoma, and some human breast cancers.18 Somatostatin receptors tend to be expressed in more differentiated tumours—eg, in astrocytoma rather than in gliobastoma. The finding of these receptors may indicate potential antiproliferative effects, which would accord with the observation that somatostatin and its analogues inhibit tumour growth in several animal models and cultured tumour cell lines. Lamberts and his colleagues in Rotterdam, the Netherlands, are already taking advantage of the expression of somatostatin receptors in tumours to guide prognostic and therapeutic decisions.19 Using radiolabelled analogues and in-vivo scintigraphic scanning techniques they found that somatostatin receptors may indicate sensitivity to octreotide therapy in pituitary and gastroenteropancreatic tumours and help in the assessment of tumour spread. Perhaps metastases could even be detected during an operation with a hand-held probe. If the analogue was not only radiolabelled but also capable of delivering radiation, we would have an accurate and specific method of irradiating sensitive tumours without damaging adjacent normal tissue. The most important complications of octreotide treatment are gallstone formation and gastritis.20 Diarrhoea has also been reported but is seldom
839
troublesome. However, the main drawback of octreotide therapy, limiting its clinical application, is the fact that it has to be given several times a day by
injection, occasionally even by continuous infusion. It is also expensive. Currently, the cost of treating a patient with acromegaly needing 300 gg of octreotide daily is over c6000 ($10 000) a year-and this is a life-long commitment. Octreotide has been said to suppress everything except the investigator. Perhaps this dictum will soon apply to its price. 1. Vance ML, Harris AG.
Long term treatment of 189 acromegalic patients with the somatostatin analog octreotide: results of the International Multicenter Acromegaly Study Group. Arch Intern Med 1991; 151: 1573-78. 2. Editorial. All aboard for octreotide. Lancet 1990; 336: 909-11. 3. Ezzat S, Ren SG, Braunstein GD, Melmed S. Octreotide stimulates insulin-like growth factor binding protein-1 (IGFBP-1) levels in acromegaly. J Clin Endocrinol Metab 1991; 73: 441-43. 4. Lembcke B, Creutzfeldt W, Schlesser S, et al. Effect of somatostatin analogue Sandostatin (SMS 201-995) on gastrointestinal, pancreatic and biliary function, and hormone release in normal men. Digestion 1987; 36: 108-24. 5. Geer RJ, Richards WO, O’Dorisio JM, et al. Efficacy of octreotide acetate in treatment of severe postgastrectomy dumping syndrome. Ann Surg 1990; 212: 678-87. 6. Nubiola P, Badia JM, Martinez-Rodenas F, et al. Treatment of 27 postoperative enterocutaneous fistulas with the long half-life somatostatin analogue SMS 201-995. Ann Surg 1989; 210: 56-58. 7. Erikson LS, Brundin T, Soderlund C, et al. Haemodynamic effects of a long-acting somatostatin analogue in patients with liver cirrhosis. Scand J Gastroenterol 1987; 22: 919-25. 8. Cello J, Grendell JH, Basuk P, et al. Effect of octreotide on refractory AIDS-associated diarrhea. Ann Intern Med 1991; 115: 705-10. 9. Buchler M, Freiss H, Klempa I, et al. Role of octreotide in the prevention of postoperative complications following pancreatic resection. Am
J Surgery 1992; 163: 125-31. 10. Chateauneuf C, Babin T, Ducasse MCR, et al. Preliminary results as regards the evolution of microalbuminuria m diabetic patients treated with Sandostatin. Diab Metab 1989; 15: 18 (abstr). 11. Fassler JE, Hughes JH, Titterington L, et al. Somatostatin analog: an inhibitor of angiogenesis? Clin Res 1988; 36: 869. 12. Lee HK, Suh KI, Koh CS, et al. Effects of SMS 201-995 in rapidly progressive diabetic retinopathy. Diab Care 1988; 11: 441-43. 13. Kaal A, Ilum P, Harris AG. A randomised comparison of intranasal and injectable octreotide administration in patients with acromegaly. J Clin Endocrinol Metab (in press). 14. Prelevic GM, Wurzburger MI, Balint-Peric LJ, Nesic JS. Inhibitory effect of sandostatin on secretion of luteinising hormone and ovarian steroids in polycystic ovary syndrome. Lancet 1990; 336: 900-03. 15. Hajri A, Bruns C, Marbach P, Aprahamian M, Longnecker DS, Damge C. Inhibition of the growth of transplanted rat pancreatic acinar carcinoma with octreotide. Eur J Cancer 1991; 27: 1247-53. 16. Lamberts SWJ, Koper JW, Reubi J-C. Potential role of somatostatin analogues in the treatment of cancer. Eur J Clin Invest 1987; 17: 281-87. 17. Schally AV. Oncological applications of somatostatin analogues. Cancer Res 1988; 48: 6977-85. 18. Reubi J-C, Waser B, Froekens JA, Klijn JGM, Lamberts SWJ, Laissue J. Somatostatin receptor incidence and distribution in breast cancer using receptor autoradiography: relationship to EGF receptors. Int J Cancer 1990; 46: 416-20. 19. Krenning EP, Bakker WH, Breeman WAP, et al. Localisation of endocrine-related tumours with radioiodinated analogues of somatostatin. Lancet 1989; i: 242-44. 20. Plockinger U, Dienemann D, Quabbe H-J, et al. Gastrointestinal side effects of octreotide during long term treatment of acromegaly. J Clin Endocrinol Metab 1990; 71: 1658-62.
AIDS: how can a pussy cat kill? In
his
campaign
to
exculpate
human
immunodeficiency virus (HIV) as the cause of AIDS, Duesberg’ emphasises
that this organism displays only weak cytopathic effects and that the viral load is
much too low to account directly for the remorseless destruction of CD4 lymphocytes characteristic of the disease. His informal classification of HIV as a "pussy cat" has been countered forciblyeg, by Weiss and Jaffe2-but the fact remains that we do not understand how HIV causes the damage it so clearly wreaks. In this issue (p 824), Dalgleish and his colleagues review the evidence that HIV may trigger a selfdestructive immune response, for which appropriate models may be found in graft-versus-host disease (GVHD), certain autoimmune disorders, and some animal viral infections. The central plank of the hypothesis is that some component of HIV causes T cells to behave as if they were encountering non-self tissues (alloantigen). Whereas a conventional viral or bacterial antigen must be processed by antigenpresenting cells and is then recognised by a tiny minority of immunocompetent lymphocytes (those that happen to carry the appropriate antibody or T-cell receptor specificity on their surface), alloantigen can be recognised directly and by a
generally
substantial proportion of the T-cell population. Thus virus that can mimic foreign cells is likely to provoke vigorous and widespread T-cell activation. HIV evidently does so and thereby not only promotes its own replication but also could generate cytotoxic lymphocytes directed against other cells expressing viral antigens on their surface. Since HIV envelope glycoprotein is shed and can bind to the CD4 determinant of uninfected T cells, there may be abundant targets for such cytotoxic action. Another mode of T-cell depletion is suggested by the observation that certain antigenic stimuli evoke a transient proliferative response followed by programmed cell death (apoptosis).3,4 It is not entirely clear what determines this pattern of response. It may be related to the process of clonal selection in the developing thymus, where most antigen encountered is self, so elimination of potentially reactive lymphoid cells is in the interests of the organism.5 Prominent among the antigens found to cause apoptosis in adult T cells are bacterial mitogens known as superantigens. The name refers to their ability (shared with alloantigen) to elicit a response from exceptionally large numbers of lymphocytes. Recognition of either a
superantigen or alloantigen seems not to depend on the specific combining site of the T-cell antigen receptor (TCR) which, like its immunoglobulin counterpart on B cells, is formed from the variable regions of a pair of peptide chains. The genes chains these somatic undergo encoding rearrangement to generate functional products and only one each, from a selection of V, D, and J segments in the genome, is used by any given T cellsThere are twenty V gene segments available within the set specifying the 0 chain of the T-cell receptor, and the products of many of these can be identified as members of individual V (3 gene families. Recognition of alloantigen or superantigen is restricted to cells some