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Experiments with advanced carcinoids
Experiments
with Advanced CYRIL COSTELLO,
M.D.,
From tbe Department of Surgery, Washington University Scboot of Medicine, Saint Louis, Missouri.
St. Louis, Missouri
edema deveIoped in ripheral edema. Progressive the right upper extremity and both lower extremities. Salt privation and digitalization did Iittle in reducing his edema; he died on December 28, 1962, of progressive cardiac failure. At autopsy, thrombosis of the right axiIIary vein was found to account for the edema in the upper extremity. Right pulmonary vaIvuIitis with diIated heart as we11 as generalized metastases through the abdomen and liver from carcinoid disease were confirmed. Because of the patient’s serious cardiac complication, he did not respond weI1 to experimenta-
TUMOR has become an increasingIy popular subject in medica Iiterature since Lubarsch [I] first described the Iesion in 1888, and Oberndorfer [2] further eIaborated its description and designated it “carcinoid.” Gosset and Masson [T] reported the tumor’s peculiar ability to reduce an ammoniaca solution of silver nitrate and stain darkly in 1914. A recent surge of interest dates to 1953 when Lembeck [4] First reported the presence of Iarge amounts of serotonin (5-hydroxytryptamine) in carcinoid tumors. Further information on the nature and function of the carcinoid celIs has been detailed by Sjoerdsma, Weissbach and Udenfriend [5] in 1956 and others [6-91. Interest in the tumor is further manifested by the number of cIinica1 reports encountered in recent medical Iiterature [ 10-191. In 1962 [20] we reported briefly our experience in attempting to combat carcinoid disease in a patient with extensive metastases and are, herewith, presenting more detaiIs on five such patients we have treated utiIizing (I) tryptophan anaIogs, (2) radioactive tryptophan, and (3) radioactive tryptophan anaIogs.
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ARCINOID
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CASE I. A. A. H., a forty-eight year old white to Barnes Hospital on man, was transferred November 2, 1962, through the courtesy of Dr. Edgar J. Poth, who had supervised his care at the John Seeley HospitaI, in Galveston, Texas, where on October 24, 1962, exploration was done for a classic carcinoid syndrome and a carcinoid was found in the distal ileum, 80 cm. from the iIeoceca1 vaIve, with numerous I cm. nodes fiIIing the mesentery and liver. At Barnes Hospital, he was found to have a typica right heart Iesion of carcinoid disease with congestive cardiac failure and peAnnuaI Meeting
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Carcinoids*
excretion by oral administration of tryptozan (aIthough initial and terminaI urinary Ievels were undependabIe because of fauIty collections). GraduaI return to higher levels of indole excretion resuIted when the analog was discontinued. Restarting the analog had less effect-and was enhanced by converting to 5-Auorotryptophan. After discontinuance of the Iatter analog, gradua1 return to higher IeveIs of $-H.I.A.A. excretion resulted. The patient’s clinical symptoms initiaIIy improved as indole excretion was reduced. Subsequentiy, symptoms of severe cardiac decompensation and mental confusion made clinica evaIuation impossible.
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CosteIIo tion with drugs. There were periods in which his mental confusion added to diff&Ity of urinary coIlections even with an indweIIing catheter, and during the terminal week of his iIIness, it was certain that urinary coIIections were incomplete. It was possible, however, to demonstrate that his urinary indole excretion per twenty-four hours could be depressed to near norma levels with zoo mg. every three hours of tryptazan and that this depression persisted for a week before gradually starting to climb after discontinuance of the drug. Smaller doses of tryptazan (zoo mg. every eight hours) did not control the serotonin activity. When 300 mg. of 5-fluorotryptophan were given every six hours, depression of indole excretion was again accomplished with a gradua1 rise to high levels in the week following its discontinuation. (Fig. I.) CASE II. C. B., a forty-six year oId female patient of Dr. Louis F. Aitken, was admitted February 21, 1960, to Barnes HospitaI. She had experienced typical carcinoid syndrome with frequent severe generalized flushes and diarrhea increasingIy for three years. Roentgenographic examination with barium reveaIed partia1 obstruction at the third part of the duodenum and rapid bowel transit time. Urine examination was positive for 5-H.I.A.A. (5-hydroxy-indoIe-acetic acid). SurgicaI exploration on March 24, 1960 (with a diagnosis of smaI1 bowe1 tumor, probably carcinoid) revealed a hard nodular tumor infiltrating the entire smalI bowel mescntery, third part of the duodenum and first part of the jejunum with metastatic nodules, 35 to I cm. in diameter throughout both lobes of the liver. Two quarts of chylous fluid were removed from the peritonea1 cavity. Gastrojejunostomy was performed for the relief of the partial obstruction and bilateral vagotomy was performed to determine what effect, if any, it might have on the rapid transit time of the smaI1 intestine. Biopsies of the metastatic nodules were done and proved to be metastatic carcinoid tumor. On ApriI 15, 1960, the patient was put on a tryptophan-free diet followed by reduction in the number of diarrhea1 stools and flushes. On April zz, 1960, she was given IO mg. of D-L-C-14-tryptophan with specific action of 0.5 mcg. per mm. orally. This was excreted rapidly in the urine. On April 24, 1960, 200 mg. of D-L-tryptophan were administered three times daily. The patient’s cramping and diarrhea promptly increased. On April 26, 1960, the D-L-tryptophan was discontinued and she was given 200 mg. of 6-methyItryptophan three times daily. In the foIlowing twenty-four hours, diarrhea diminished and she gained 136 pounds. No vagotomy effect could be noted. On May 16, 1960, a “second Iook” was taken after three week’s therapy with 6-methyItryptophan, during which time marked abdomina1
ascites had developed. Tumor nodules in the Iiver were found to be one-third to one-half previous dimensions with umbiIication and a tumor of the mesentery was approximateIy 50 per cent of its previous size; 2,500 cc. of chylous fluid were removed. Biopsy specimens, taken at this time, proved no change in ceIIular appearance. After discharge from the hospital, the patient did we11 with less fIushing and diarrhea while continuing 200 mg. of 6-methyltryptophan three times daiIy and gained in weight and strength. On August IO, 1960, paracentesis with remova of 1,500 cc. of chylous fluid was performed; she was given a two week rest period from 6-methyltryptophan. In September 1960, she underwent paracentesis twice and continued to be well except for the recurrent abdominal swelling. Periods of abstinence from 6-methyltryptophan were promptly followed by worsening of flushes and diarrhea. By December, the patient was showing evidences of obstruction in the upper part of the bowel confirmed by barium studies; she was rehospitalized. On December 25, 1960, exploratory operation was again done with removal of 2,000 cc. of chyIous ascitic fluid and with revision of her gastrojejunostomy for relief of an obstructing tumor in the duodenum and jejunum. Th e patient’s condition deteriorated postoperativeIy; she died on January 6, 1961. Autopsy confirmed the cIinica1 findings of extensive metastases from a smaI1 bowel carcinoid throughout the mesentery and liver. The heart did not present the Iesions sometimes associated with the carcinoid syndrome. CASE III. I. R., a fifty-nine year old woman, had experienced malaise, generaIized aching and vomiting for about a year which terminated in her hospitalization and operation in March, 1956, by Dr. 0. W. English, at Lubbock, Texas. At that time, appendectomy and wedge resection of a tumor of the ileum were performed. The tumor was a carcinoid of the ileum. The patient was entirely symptom free until January, 1961, when Aushing developed, usuaIIy following meaIs and often reIieved by lying down. The generalized flushing was synchronous with reddening of her face discernible to others and a bluish-black discoloration of her legs and feet. Shortness of breath usually accompanied these attacks. On March 22, 1961, expIoratory operation was again performed by Dr. EngIish; he resected the distal twenty-eight inches of ileum and right haIf of the colon. The liver contained numerous metastatic lesions, from I to 2 cm. in diameter, and one was excised for biopsy. AI1 tumor tissue proved to be carcinoid. Through the courtesy of Dr. English, this patient was admitted for study at Barnes Hospital, having Iost weight from 138 to 103 pounds since the recur-
538
Adva riced Carcinoids a
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FIG. 2. Patient I. R., a fifty year old woman, demonstrated correlation in improvement of carcinoid symptoms with repeated reductions in 5-H.I.A.A. urinary excretion as produced alternately with: 5-fluorotryptophan in varied doses and schedules, 5_bromotryptophan, and a combination of these analogs with 6-methyItryptophan. The recurrence of symptoms and of elevated 5-1f.I.A.A. excretion was notably gradua1 over a period of seven to ten days after discontinuing the therapy.
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FIG. 3. Patient J. C., a sixty-one year old man, demonstrated concomitant improvement in carcinoid symptoms and reduction in 5-H.I.A.A. urinary excretion on variabIe doses of 54Iuorotryptophan with the characteristic recurrence of symptoms and elevated indoIe excretion over a period of seven to ten days after discontinuance of the drugs. His response to tryptazan was inconcIusive during the brief period this anaIog was administered.
rencc of her symptoms and second operation. Appetite, however, was good, ahhough diarrhea, Uushes, shortness of breath and changes in the color of her lees and feet had a11 oersisted with diarrhea being the most prominent part of her problem and described as yeIIow water gushing out of the rectum intermittentIy throughout the day and night and most marked during the morning hours. She had discovered that use of three Lomoti1” tablets in the morning could reduce her loose stools to two or three daily. The physica findings were those of characteristic carcinoid syndrome with moderate emaciation, a right heart murmur and nink to red flushina of the face and extremit.ies repeatedly during the day and night. This patient was subjected to variables in her
vear oId man. was CASE IV. J. C.. a sixtv-one admitted to Barnes Ho&a1 on October 14, 1962, through the courtesy of Dr. Edward Bud& of SpringtieId, IIIinois, who performed a liver biopsy demonstrating metastatic in September, 1962, carcinoid tumor. This patient had a tumor of the cecum removed with termina1 iIeum and ascending colon in November, 1957, with the microscopic diagnosis of carcinoid tumor. He had maintained a good state of nutrition despite three to four diarrhea1 stools dailv., for a oeriod of vears and increasing episodes of Bushing three to four times daiIy which were not severe and which the patient associated with periods of becoming tense or nervous. He was foIlowed on genera1 diet with daiIy urinary indoIe quantitative determinations and on two occasions had indole excretion reduced markedly by ora administration of 5&orotryptophan in the amount of 200 mg. every eight hours. Each time after discontinuing the drug, his indoIe excretion graduaIIy increased over a ten to eIeven day period. A brief tria1 with tryptazan, 200 mg. every six hours, was inconclusive. While the indoIe excretion was at low Ievels, the patient had formed stools, although he continued having three or four daily. The flushing was of such little consequence to this patient that it was impossibIe to evaIuate the effect of the drug on it. (Fig. 3.) The patient was given intravenous radioactive 5-iodotryptophan tracer dosage on December 21, Y
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diet and in tryptophan anaIog therapy while undergoing daiIy physical observations in the hospita1 and daily 5-H.I.A.A. quantitative urinary determinations. (Fig. 2.) She was discharged from Barnes Hospital in December, 1962, and is reported to have died in her sleep at home on January 4, 1963. Throughout her hospital course and upon discharge, she continued to uresent a lame nodular liver. She remained weak, aIthough she was ambulatory, and in October, 1962, anasarca deveIoped, which was uninfluenced by salt restriction and by digitaIization but which did cIear compIeteIy with massive intravenous doses of human serum albumin. She was given a tracer dose of radioactive tryptophan oraIly on December 12, 1962, followed by externa1 body scanning. 539
Costello tion of body protein and niacin [5]. It was the purpose of our cIinica1 experiment to determine in patients with far-advanced carcinoid disease the turnover rate of radioactive tryptophan and to determine if specific carcinoid ceIIuIar damage might resuIt from administration of radioactive tryptophan. Moyer [20] further suggested the possibiIity of destroying or incapacitating the carcinoid ceIIs by feeding tryptophan anaIogs. We have procured and administered: (I) D-L-C-Iq-tryptophan, (2) 6_methyItryptophan, (3) g-ffuorotryptophan, (4) q-iodotryptophan, (5) tryptazan, and (6) radioactive 5-iodotryptophan. In addition, we have attempted to evaIuate the effect of dietary tryptophan by feeding Iow-tryptophan diet, general diet, high protein diet and D-L-tryptophan enriched diet. Effect of Diet. Two patients (C. B. and I. R.) were evaIuated cIinicaIIy whiIe receiving a low tryptophan diet. The immediate response was one of improvement which, however, was short lived. C. B. was kept on this diet for two weeks, at the end of which time the carcinoid syndrome had recurred. The effect on I. R. was even Iess marked. In both patients, the diet was considered reIativeIy unpaIatabIe, and the fear of creating serious systemic disorders with such a deficient diet posed a contraindication to pursuing it Ionger [zr-231. D-L-tryptophan (200 mg. three times daily) was given to C. B. with aggravation of symptoms of carcinoid syndrome. When pIaced on genera1 diet and on high protein diet, both without medication and with medication, no discernibIe difference couId be determined in I. R. over a period of many months. It couId, therefore, be concIuded from the experiences with these two patients that Iow-tryptophan, high protein and genera1 diet produced essentiaIIy no effect on the clinica course of the carcinoid syndrome, although high tryptophan feedings aggravated the symptoms. E$ect of Radioactive D-L-Tryptopban. C. B. was given a tracer dose of carbon-14-D-Ltryptophan oraIIy, whiIe urine was coIIected hourIy and assayed for radioactive content. The materia1 passed rapidIy in the urine and within four hours practicaIIy a11 was so colIected. It was concIuded that so rapid a turnover rate of the materia1 and such a Iow radioactive yieId made it unIikeIy that carcinoid ceIIuIar destruction couId be effectiveIy accomplished with this materia1.
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Patient M. S., a fifty-three year old man, was known to have extensive carcinoid residual in the mesentery of the smaI1 intestine without gross evidence at operation of Iiver metastases. He had no symptoms of carcinoid syndrome and had no significant eIcvation of urinary indoIe excretion. He exhibited increased activity over his Iiver folIowing intravenous administration of radioactive 5-iodotryptophan as determined bv external scanning. The sirmificance of this observatron is presentIy indeterminate.
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1962, and was examined by externa1 scanning. He was discharged on December 21, 1962, and is being observed while on therapy with +ffuorotryptophan at home.
CASE v. M. S., a fifty-three year old man, was admitted for study to Barnes HospitaI on December II, 1962, through the courtesy of Dr. W. S. Lorimer, Jr., of Fort Worth, Texas, with a history of carcinoid tumor of the mid-iIeum metastatic to nodes in the mesentery for which segmenta resection was performed in 1956. In November 1962, adhesiolisis and remova of hard nodes from the iIea1 mesentery were performed because of intestina obstruction. The tissue was carcinoid and recovery was uneventfu1. He had no symptoms of carcinoid syndrome and no signs of a heart Iesion. His twenty-four hour urine specimens contained no significant eIevations of g-H.I.A.A. during his hospita1 stay. (Fig. 4.) Radioactive 5-iodotryptophan administered intravenously on December 23, 1962, was foIIowed by externa1 scanning and was found to show increased activity over the liver as compared to a norma contro1. COMMENTS Tracer studies cent of dietary 5-hydroxy indoIe disease, whiIe the is presumed to be
have indicated that 60 per tryptophan is converted to in some cases of carcinoid remaining dietary tryptophan utiIized in the normal produc540
Advanced
Carcinoids
Use of Tryptopban Analogs. While there are numerous drugs presently being utilized and tested for their antiserotonin effect [9,24], the reports have indicated that as promptly as such serotonin antagonists are discontinued, symptoms of carcinoid syndrome reappear. We, therefore, sought to discover a tryptophan analog which wouId react with enzymes and enter into carcinoid cehular -metabolism, blocking growth within the cell and possibly ending growth and hormone production, or destroying the cell through faulty metabolism. The reactivity of analogs with pancreatic, tryptophanactivating enzyme was reported in 1957 by Sharon and Lipmann [25]. Their studies indicated that various tryptophan analogs could be roughly divided into two groups. One group reacts like tryptophan with hydroxylamine to form the corresponding hydroxamic acid and also catalyzes the enzymic pyrophosphate exchange with adenosine triphosphate (ATP). The other group is not reactive but does inhibit the activation of tryptophan in either test. In the first group, they reported that the tryptophan analogs 7-azatryptophan, tryptazan, G-fluorotryptophan and S-fluorotryptophan are activated by the tryptophan-activating enzyme of pancreas in the hydroxamate test as well as for amino acid dependent ATP pyrophosphate exchange. In the other group of analogs (inhibitory for tryptophan activation but not showing any activation effects) were included 5- and 6-methyltryptophan. A comparison of the analogs with regard to their activation by enzyme and their growth effects shows that only the enzyme-activated anaIogs appear to be first incorporated into protein and then bIock growth, presumably by erroneous protein synthesis. Other analogs, such as methyltryptophan, are not enzymatically activated but compete with tryptophan for enzyme activation. These appear to inhibit growth immediateIy and are not incorporated into protein. Therefore, on the basis of these studies performed on the growth of Escherichia coli, we could anticipate that administration of 6-methyltryptophan to the patient with advanced carcinoid might exert an effect by inhibition of tryptophan activation without being itself enzyme-activated and incorporated into the carcinoid cell. E$ect of 5-Fluorotryptopban. The anaIog
54uorotryptophan has not been tested for incorporation into protein but has demonstrated on E. coli culture that it is activated by the enzyme and that it does inhibit growth [25]. The analog was administered in varying dosages to three patients of this series (A. A. H., J. C. and I. R.). (Figs. 1-4.) It was also administered in combination with other analogs to I. R. and its effect was studied with relation to various diets. The effect of the drug was determined by clinical observations on flushing and diarrhea as well as by quantitative daily determinations of urinary excretion of g-H.I.A.A. Flushing and diarrhea were controlled and re-precipitated at will by administering and withhording this drug to J. C. and I. R. Patient, A. A. H., had a less spectacular response, probably because of difficulties in evaluating his clinical course which was complicated by extreme edema, cardiac failure and mental confusion. The serotonin activity (as assayed by urinary excretion of s-H.I.A.A. daiIy) could likewise be Iowered at will by administering this analog and paralleled the reduction in IIushes and diarrhea. When +fluorotryptophan was decreased in each case (repeatedly in two cases and once in the other), there followed periods of seven to ten days before the 5-H.I.A.A. and the symptoms returned to higher activity. This, we consider to be sign&cant since it has not occurred with 6-methyltryptophan and has been reported not to have occurred with the numerous serotonin antagonists tried for the control of carcinoid syndrome. It suggests that S-II uorotryptophan exerts its effect on serotonin, not by extra ceIIuIar blocking or neutralizing, but by its incorporation into the carcinoid cell and there interfering with serotonin production for seven to ten days afterwards. is an analog E$ect qf Tryptazan. Tryptazan of tryptophan which has been demonstrated tryptophan-activating enwith pancreatic, zyme to be incorporated into protein on a cuIture of E. coli, to be activated by the enzyme, and to inhibit growth of the organism [25]. It seemed desirable, therefore, to attempt use of this analog on carcinoid patients. It was used briefly on J. C. and its effect was inconclusive. (Fig. 3.) The patient was returned to therapy with 5-fl uorotryptophan which had already demonstrated its effectiveness in controlling his carcinoid syndrome. Further experiments with this anaIog will be performed. 541
Costello E$ect of 5-Bromotryptopban. Since 5-fluorotryptophan had proved so effective, it was believed advisable to further explore the effectiveness of other haIogenated anaIogs. The next one obtained by synthesis was It was found to produce bromotryptophan. simiIar effects on the carcinoid syndrome in simiIar doses when administered to I. R. (Fig. 2.) When given in combination with Auorotryptophan and methyItryptophan, the most effective cIinica1 and urinary results were obtained. E$ect of 5-Zodotryptopban. The analog most intriguing (and most tedious in synthesizing) has been iodotryptophan, since it offers a maximum of theoretic excellence in both incorporation and radiation factors. The material has been radioactivated by bombarding it with I131. As such, it was given to I. R. and foIlowed by body surface scanning. It pooIed in the bIadder region and showed no evidence of being picked up in the Iiver region where extensive metastases were palpabIe. Given to another patient (J. C.), it pooIed in the intestine. It was then prepared for intravenous administration and given in tracer dosage to a norma contro1 (a forty-seven year oId woman, T. H.), and to two of the patients, J. C. and M. S. ExternaI scanning intermittentIy for twenty-four hours revealed no Iiver concentration in the contro1 patient and for reasons undetermined, one of the carcinoid patients had concentration over the Iiver region in thirty minutes, while the other had none. EDEMA
IN ADVANCED
CARCINOID
DISEASE
PeripheraI and body edema has been observed and recorded as a frequent compIication in advanced carcinoid disease and its cause has not been eIucidated. CertainIy the incidence appears to be greater than that encountered in other patients dying with far-advanced maIignant disease. The surface of primary Iesions in the intestina1 tract is generaIIy smaI1 or absent (by surgica1 remova1) so as to discount the expIanatory theory of protein-Iosing enteropathy. The fluid accumuIations in our three patients with far-advanced carcinoids, who died, began in the abdomen and proceeded to invoIve the Iower extremities and ultimateIy the entire body. In C. B., the abdomina1 sweIIing was most marked and was found by repeated tappings to resuIt from Iymphatic
obstruction. The edema of the trunk and extremities in A. A. H. was accountabIe on the basis of cardiac decompensation, aIthough the edema in the uniIatera1 upper extremity which was most troublesome during his termina1 three weeks, was found at autopsy to have been the resuIt of axiIIary vein thrombosis. The anasarca which graduaIIy deveIoped in I. R. could not be controIIed by saIt restriction or by digitaIization. She manifested, over a period of months, gradua1 reduction in serum protein vaIues and uItimateIy responded with compIete reIief of edema when massive amounts of human serum albumin were given in divided doses over a period of three days. Thus, there was found to be nothing in common about the ffuid accumuIation which these patients exhibited, since they appeared to be the resuIt, respectively, of protein deficiency, cardiac faiIure, axiIIary vein thrombosis and Iymph obstruction. FUTURE
PROJECTION
These preIiminary findings with advanced carcinoid disease suggest that some progress has been made in obtaining an anaIog which may be activated by tryptophan-activating enzyme and thus incorporated into carcinoid ceIIs. There is suggestive evidence that intravenous radioactivated iodotryptophan may be picked up simiIarIy by carcinoid ceIIs. We are pursuing studies on the basis of these findings and are pIanning to repeat the use of 5-fIuorotryptophan, tryptazan and other anaIogs by intravenous administrations, as previously done oraIIy. Radioactive iodotryptophan wiI1 be administered to such patients intravenousIy and studied by externa1 body scanning and by direct autoradiography of biopsy tissue to determine its vaIue as a diagnostic and therapeutic agent. Acknowledgment: I am grateful to Dr. Louis F. Aitken for cardiac and medica supervision of these patients during hospitaIization at Barnes HospitaI; to Doctors M. Terpagossian and M. Friedenberg, Depasrtment of RadioIogy, MaIIinckrodt Institute, Barnes HospitaI, for advice and heIp in the radiophysica1 aspects of the problem; to Dr. L. P. Gebhardt, Department of BacterioIogy, University of Utah, CoIIege of Medicine, SaIt Lake City, Utah, for
542
Carcinoids
Advanced supplying ~methyltryptophan; and to Captain Fred Conrad, U.S.A.F., M.C., Chief, HemaHospitaI LackIand, tology Service, U.S.A.F. Aerospace MedicaI Division, LackIand Air Force Base, San Antonio, Texas, for assistance with S-H.I.A.A. determinations. ClinicaI studies on some of these patients were made in the Washington University Barnard HospitaI CIinicaI Research Center under support of Grant 8-MOI-FR-36-03, Division of Genera1 Medical Services, NationaI Institutes of HeaIth, and supported in part by grants from the McBride Foundation and William McBride Love Trust Fund. REFERENCES I.
t.
3. 4. 5.
6.
7.
8.
9.
LUBAKSCW,0. Ueber den primaren Krebs des IIeum nebst Bemerkungen tiber das gieichzeitge Vorkommen van Krebs und Tuberculose. Virebows Arc-b. patb. Anat., I I I : 280, 1888. OBERNDORFER,HEKR. Faber die kIeinen Dunndormcarcinome. Verbandl. deutscb. patb. Gesekcb., 11: 113, 1907. GOSSET, A. and MASSON, P. Tumeurs endocrines de I’appendice. Presse mkd., 22: 237, 1914. LEMBECK, F. Five hydroxytryptamine in a carcinoid tumor. Nature, London, 172: 910, 1953. SJOERDSMA, A., WEISSBACH, H. and UDENFRIEND, S. A clinical, physioIogic and biochemical study of patients with maIignant carcinoid (argentafiinoma). Am. J. Med., 20: 520, 1956. DAVIDS~X, J., SJOERDSILIA, A., LOOWIS, L. N. and UDENFRIEND, S. Studies with the serotonin precursor, ~-hydro~ytryptophan, in experimentaf animals and man. J. CZin. Invest., 36: 1594, 1957. STONE, H. II. and NEMIR, P., JR. Study of the roie of ~-hydrox‘ytryptamine (~roton~n) and histamine in the pathogenesis of puImonary emboIism in man. Ann. Surg., 152: 890, 1960. UDENFRIEXD, S., TITUS, E. and WEISSBACH, H. The identification of 5-hydroxy-3-indoleacetic acid in normal urine and method for its assay. J. Biol. Cbem., 216: 499, 1955. URELES, A., MURRAY, M. and WOLF, R. ResuIts of pharmacologic treatment in the malignant car-
543
cinoid syndrome. New England J. Med., 267: 435, 1962. IO. BO~YER, &I. F. Manifestations of smaII bowel tumors. Tex. J. Med., 54: 480, 1958. II. WILLIAMS, R. Carcinoid tumor. hit. M. J., I: 28, 1960. 12. LAIRD, G. J. Carcinoid of the duodenum. J. A. M. A., 174: 1743, 1960. 13. COSTELLO, C. and AITKEN, L. F. Carcinoid of the duodenum. Missouri Med., 57: 1252, 1960. 14. MOERTEL, C. G., SA~IER, W. G., DOCKERTY, M. B. and BAGGENSTOSS,A. H. Carcinoid tumors of the small intestine. Cancer, 14: 901, 1961. W. J. 15. KANTOR, S., CRANE, R. D. and GILLESBY, Carcinoids of the gastrointestinal tract. Am. Surgeon, 27: 448, 1961. 16. WARNER, R. R. P., KIRSCHNER, P. A. and WARNER, G. M. Serotonin production by bronchial adenomas without the careinoid syndrome. J. A. M. A., 178: 1175, 1961. W. H., B..XRTLETT,R. M., BISHOP, H. M., 17. STEWART, CA~~PBELL,D. A. GOLDSMITH, I?. A., MACLEAN, K., MIDDLETON, E. A., MCSSELM.~X, M., RANNICK, G. and TAPPAN, W. Carcinoid tumors presenting with acute abdominal signs. Ann. Surg., Suppl. 154: 112, 1961. 18. LECHNER, G. W. and CHAMBLIK, S. A., JK. Carcinoid tumors of Meckel’s divcrticula. Am. J. Surg., 103: 266, 1962. H., STORER, E. H. and SrAn, F. J. Car19. WILSON, cinoid tumors. Am. J. Surg., 103: 35, 1963. 20. COSTELLO, C. Specific chemocidal therapy. Missouri Med., 59: 418, 1962. 21. ADAMSTONE, F. B. and SPECTOR, H. Tryptophan deficiency in the rat. Histologic change induced by forced feeding of a acid hydrolyzed casein diet. Arch. Patb., 49: 173, 1950. 22. COLE, A. S. and SCOTT, P. P. Tissue changes in an aduft trypt(~phan-de~cient rat. Brit. J. ~~~~~~~on, 8: 125, 1954. 23. HARPER, A. E. Nutritional fatty Iivers in rats. Am. J. Clin. Nutrition, 6: 242, rgg8. 24. BROWS, R. E., HILL, S. R., JR., BERRY, K. W. and BING, R. J. Studies in several antiserotonin compounds in the functioning carcinoid syndrome. Clin. Res., 8: 61, 1960. 25. SHARON, N. and LIPMANN, F. Reactivity of anaIogs with pancreatic tryptophan-activating enzyme. Arch. Biocbem., 24: 227, 1957.
with Advanced CYRIL COSTELLO,
M.D.,
From tbe Department of Surgery, Washington University Scboot of Medicine, Saint Louis, Missouri.
St. Louis, Missouri
edema deveIoped in ripheral edema. Progressive the right upper extremity and both lower extremities. Salt privation and digitalization did Iittle in reducing his edema; he died on December 28, 1962, of progressive cardiac failure. At autopsy, thrombosis of the right axiIIary vein was found to account for the edema in the upper extremity. Right pulmonary vaIvuIitis with diIated heart as we11 as generalized metastases through the abdomen and liver from carcinoid disease were confirmed. Because of the patient’s serious cardiac complication, he did not respond weI1 to experimenta-
TUMOR has become an increasingIy popular subject in medica Iiterature since Lubarsch [I] first described the Iesion in 1888, and Oberndorfer [2] further eIaborated its description and designated it “carcinoid.” Gosset and Masson [T] reported the tumor’s peculiar ability to reduce an ammoniaca solution of silver nitrate and stain darkly in 1914. A recent surge of interest dates to 1953 when Lembeck [4] First reported the presence of Iarge amounts of serotonin (5-hydroxytryptamine) in carcinoid tumors. Further information on the nature and function of the carcinoid celIs has been detailed by Sjoerdsma, Weissbach and Udenfriend [5] in 1956 and others [6-91. Interest in the tumor is further manifested by the number of cIinica1 reports encountered in recent medical Iiterature [ 10-191. In 1962 [20] we reported briefly our experience in attempting to combat carcinoid disease in a patient with extensive metastases and are, herewith, presenting more detaiIs on five such patients we have treated utiIizing (I) tryptophan anaIogs, (2) radioactive tryptophan, and (3) radioactive tryptophan anaIogs.
C
ARCINOID
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FIG. I. In patient A. A. H., daily quantities of $H.I.A.A. indicate that it was possible to depress indole
CASE I. A. A. H., a forty-eight year old white to Barnes Hospital on man, was transferred November 2, 1962, through the courtesy of Dr. Edgar J. Poth, who had supervised his care at the John Seeley HospitaI, in Galveston, Texas, where on October 24, 1962, exploration was done for a classic carcinoid syndrome and a carcinoid was found in the distal ileum, 80 cm. from the iIeoceca1 vaIve, with numerous I cm. nodes fiIIing the mesentery and liver. At Barnes Hospital, he was found to have a typica right heart Iesion of carcinoid disease with congestive cardiac failure and peAnnuaI Meeting
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CASE REPORTS
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* Presented
Carcinoids*
excretion by oral administration of tryptozan (aIthough initial and terminaI urinary Ievels were undependabIe because of fauIty collections). GraduaI return to higher levels of indole excretion resuIted when the analog was discontinued. Restarting the analog had less effect-and was enhanced by converting to 5-Auorotryptophan. After discontinuance of the Iatter analog, gradua1 return to higher IeveIs of $-H.I.A.A. excretion resulted. The patient’s clinical symptoms initiaIIy improved as indole excretion was reduced. Subsequentiy, symptoms of severe cardiac decompensation and mental confusion made clinica evaIuation impossible.
of the Southwestern 19%.
537
Surgical
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American Journal of Surgery.
D. F., ApriI 22-25, Volume
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CosteIIo tion with drugs. There were periods in which his mental confusion added to diff&Ity of urinary coIlections even with an indweIIing catheter, and during the terminal week of his iIIness, it was certain that urinary coIIections were incomplete. It was possible, however, to demonstrate that his urinary indole excretion per twenty-four hours could be depressed to near norma levels with zoo mg. every three hours of tryptazan and that this depression persisted for a week before gradually starting to climb after discontinuance of the drug. Smaller doses of tryptazan (zoo mg. every eight hours) did not control the serotonin activity. When 300 mg. of 5-fluorotryptophan were given every six hours, depression of indole excretion was again accomplished with a gradua1 rise to high levels in the week following its discontinuation. (Fig. I.) CASE II. C. B., a forty-six year oId female patient of Dr. Louis F. Aitken, was admitted February 21, 1960, to Barnes HospitaI. She had experienced typical carcinoid syndrome with frequent severe generalized flushes and diarrhea increasingIy for three years. Roentgenographic examination with barium reveaIed partia1 obstruction at the third part of the duodenum and rapid bowel transit time. Urine examination was positive for 5-H.I.A.A. (5-hydroxy-indoIe-acetic acid). SurgicaI exploration on March 24, 1960 (with a diagnosis of smaI1 bowe1 tumor, probably carcinoid) revealed a hard nodular tumor infiltrating the entire smalI bowel mescntery, third part of the duodenum and first part of the jejunum with metastatic nodules, 35 to I cm. in diameter throughout both lobes of the liver. Two quarts of chylous fluid were removed from the peritonea1 cavity. Gastrojejunostomy was performed for the relief of the partial obstruction and bilateral vagotomy was performed to determine what effect, if any, it might have on the rapid transit time of the smaI1 intestine. Biopsies of the metastatic nodules were done and proved to be metastatic carcinoid tumor. On ApriI 15, 1960, the patient was put on a tryptophan-free diet followed by reduction in the number of diarrhea1 stools and flushes. On April zz, 1960, she was given IO mg. of D-L-C-14-tryptophan with specific action of 0.5 mcg. per mm. orally. This was excreted rapidly in the urine. On April 24, 1960, 200 mg. of D-L-tryptophan were administered three times daily. The patient’s cramping and diarrhea promptly increased. On April 26, 1960, the D-L-tryptophan was discontinued and she was given 200 mg. of 6-methyItryptophan three times daily. In the foIlowing twenty-four hours, diarrhea diminished and she gained 136 pounds. No vagotomy effect could be noted. On May 16, 1960, a “second Iook” was taken after three week’s therapy with 6-methyItryptophan, during which time marked abdomina1
ascites had developed. Tumor nodules in the Iiver were found to be one-third to one-half previous dimensions with umbiIication and a tumor of the mesentery was approximateIy 50 per cent of its previous size; 2,500 cc. of chylous fluid were removed. Biopsy specimens, taken at this time, proved no change in ceIIular appearance. After discharge from the hospital, the patient did we11 with less fIushing and diarrhea while continuing 200 mg. of 6-methyltryptophan three times daiIy and gained in weight and strength. On August IO, 1960, paracentesis with remova of 1,500 cc. of chylous fluid was performed; she was given a two week rest period from 6-methyltryptophan. In September 1960, she underwent paracentesis twice and continued to be well except for the recurrent abdominal swelling. Periods of abstinence from 6-methyltryptophan were promptly followed by worsening of flushes and diarrhea. By December, the patient was showing evidences of obstruction in the upper part of the bowel confirmed by barium studies; she was rehospitalized. On December 25, 1960, exploratory operation was again done with removal of 2,000 cc. of chyIous ascitic fluid and with revision of her gastrojejunostomy for relief of an obstructing tumor in the duodenum and jejunum. Th e patient’s condition deteriorated postoperativeIy; she died on January 6, 1961. Autopsy confirmed the cIinica1 findings of extensive metastases from a smaI1 bowel carcinoid throughout the mesentery and liver. The heart did not present the Iesions sometimes associated with the carcinoid syndrome. CASE III. I. R., a fifty-nine year old woman, had experienced malaise, generaIized aching and vomiting for about a year which terminated in her hospitalization and operation in March, 1956, by Dr. 0. W. English, at Lubbock, Texas. At that time, appendectomy and wedge resection of a tumor of the ileum were performed. The tumor was a carcinoid of the ileum. The patient was entirely symptom free until January, 1961, when Aushing developed, usuaIIy following meaIs and often reIieved by lying down. The generalized flushing was synchronous with reddening of her face discernible to others and a bluish-black discoloration of her legs and feet. Shortness of breath usually accompanied these attacks. On March 22, 1961, expIoratory operation was again performed by Dr. EngIish; he resected the distal twenty-eight inches of ileum and right haIf of the colon. The liver contained numerous metastatic lesions, from I to 2 cm. in diameter, and one was excised for biopsy. AI1 tumor tissue proved to be carcinoid. Through the courtesy of Dr. English, this patient was admitted for study at Barnes Hospital, having Iost weight from 138 to 103 pounds since the recur-
538
Adva riced Carcinoids a
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FIG. 2. Patient I. R., a fifty year old woman, demonstrated correlation in improvement of carcinoid symptoms with repeated reductions in 5-H.I.A.A. urinary excretion as produced alternately with: 5-fluorotryptophan in varied doses and schedules, 5_bromotryptophan, and a combination of these analogs with 6-methyItryptophan. The recurrence of symptoms and of elevated 5-1f.I.A.A. excretion was notably gradua1 over a period of seven to ten days after discontinuing the therapy.
0
-------_ -_--- ------_----_ October ’ November ’ December
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FIG. 3. Patient J. C., a sixty-one year old man, demonstrated concomitant improvement in carcinoid symptoms and reduction in 5-H.I.A.A. urinary excretion on variabIe doses of 54Iuorotryptophan with the characteristic recurrence of symptoms and elevated indoIe excretion over a period of seven to ten days after discontinuance of the drugs. His response to tryptazan was inconcIusive during the brief period this anaIog was administered.
rencc of her symptoms and second operation. Appetite, however, was good, ahhough diarrhea, Uushes, shortness of breath and changes in the color of her lees and feet had a11 oersisted with diarrhea being the most prominent part of her problem and described as yeIIow water gushing out of the rectum intermittentIy throughout the day and night and most marked during the morning hours. She had discovered that use of three Lomoti1” tablets in the morning could reduce her loose stools to two or three daily. The physica findings were those of characteristic carcinoid syndrome with moderate emaciation, a right heart murmur and nink to red flushina of the face and extremit.ies repeatedly during the day and night. This patient was subjected to variables in her
vear oId man. was CASE IV. J. C.. a sixtv-one admitted to Barnes Ho&a1 on October 14, 1962, through the courtesy of Dr. Edward Bud& of SpringtieId, IIIinois, who performed a liver biopsy demonstrating metastatic in September, 1962, carcinoid tumor. This patient had a tumor of the cecum removed with termina1 iIeum and ascending colon in November, 1957, with the microscopic diagnosis of carcinoid tumor. He had maintained a good state of nutrition despite three to four diarrhea1 stools dailv., for a oeriod of vears and increasing episodes of Bushing three to four times daiIy which were not severe and which the patient associated with periods of becoming tense or nervous. He was foIlowed on genera1 diet with daiIy urinary indoIe quantitative determinations and on two occasions had indole excretion reduced markedly by ora administration of 5&orotryptophan in the amount of 200 mg. every eight hours. Each time after discontinuing the drug, his indoIe excretion graduaIIy increased over a ten to eIeven day period. A brief tria1 with tryptazan, 200 mg. every six hours, was inconclusive. While the indoIe excretion was at low Ievels, the patient had formed stools, although he continued having three or four daily. The flushing was of such little consequence to this patient that it was impossibIe to evaIuate the effect of the drug on it. (Fig. 3.) The patient was given intravenous radioactive 5-iodotryptophan tracer dosage on December 21, Y
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diet and in tryptophan anaIog therapy while undergoing daiIy physical observations in the hospita1 and daily 5-H.I.A.A. quantitative urinary determinations. (Fig. 2.) She was discharged from Barnes Hospital in December, 1962, and is reported to have died in her sleep at home on January 4, 1963. Throughout her hospital course and upon discharge, she continued to uresent a lame nodular liver. She remained weak, aIthough she was ambulatory, and in October, 1962, anasarca deveIoped, which was uninfluenced by salt restriction and by digitaIization but which did cIear compIeteIy with massive intravenous doses of human serum albumin. She was given a tracer dose of radioactive tryptophan oraIly on December 12, 1962, followed by externa1 body scanning. 539
Costello tion of body protein and niacin [5]. It was the purpose of our cIinica1 experiment to determine in patients with far-advanced carcinoid disease the turnover rate of radioactive tryptophan and to determine if specific carcinoid ceIIuIar damage might resuIt from administration of radioactive tryptophan. Moyer [20] further suggested the possibiIity of destroying or incapacitating the carcinoid ceIIs by feeding tryptophan anaIogs. We have procured and administered: (I) D-L-C-Iq-tryptophan, (2) 6_methyItryptophan, (3) g-ffuorotryptophan, (4) q-iodotryptophan, (5) tryptazan, and (6) radioactive 5-iodotryptophan. In addition, we have attempted to evaIuate the effect of dietary tryptophan by feeding Iow-tryptophan diet, general diet, high protein diet and D-L-tryptophan enriched diet. Effect of Diet. Two patients (C. B. and I. R.) were evaIuated cIinicaIIy whiIe receiving a low tryptophan diet. The immediate response was one of improvement which, however, was short lived. C. B. was kept on this diet for two weeks, at the end of which time the carcinoid syndrome had recurred. The effect on I. R. was even Iess marked. In both patients, the diet was considered reIativeIy unpaIatabIe, and the fear of creating serious systemic disorders with such a deficient diet posed a contraindication to pursuing it Ionger [zr-231. D-L-tryptophan (200 mg. three times daily) was given to C. B. with aggravation of symptoms of carcinoid syndrome. When pIaced on genera1 diet and on high protein diet, both without medication and with medication, no discernibIe difference couId be determined in I. R. over a period of many months. It couId, therefore, be concIuded from the experiences with these two patients that Iow-tryptophan, high protein and genera1 diet produced essentiaIIy no effect on the clinica course of the carcinoid syndrome, although high tryptophan feedings aggravated the symptoms. E$ect of Radioactive D-L-Tryptopban. C. B. was given a tracer dose of carbon-14-D-Ltryptophan oraIIy, whiIe urine was coIIected hourIy and assayed for radioactive content. The materia1 passed rapidIy in the urine and within four hours practicaIIy a11 was so colIected. It was concIuded that so rapid a turnover rate of the materia1 and such a Iow radioactive yieId made it unIikeIy that carcinoid ceIIuIar destruction couId be effectiveIy accomplished with this materia1.
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Patient M. S., a fifty-three year old man, was known to have extensive carcinoid residual in the mesentery of the smaI1 intestine without gross evidence at operation of Iiver metastases. He had no symptoms of carcinoid syndrome and had no significant eIcvation of urinary indoIe excretion. He exhibited increased activity over his Iiver folIowing intravenous administration of radioactive 5-iodotryptophan as determined bv external scanning. The sirmificance of this observatron is presentIy indeterminate.
FIG.
4.
1962, and was examined by externa1 scanning. He was discharged on December 21, 1962, and is being observed while on therapy with +ffuorotryptophan at home.
CASE v. M. S., a fifty-three year old man, was admitted for study to Barnes HospitaI on December II, 1962, through the courtesy of Dr. W. S. Lorimer, Jr., of Fort Worth, Texas, with a history of carcinoid tumor of the mid-iIeum metastatic to nodes in the mesentery for which segmenta resection was performed in 1956. In November 1962, adhesiolisis and remova of hard nodes from the iIea1 mesentery were performed because of intestina obstruction. The tissue was carcinoid and recovery was uneventfu1. He had no symptoms of carcinoid syndrome and no signs of a heart Iesion. His twenty-four hour urine specimens contained no significant eIevations of g-H.I.A.A. during his hospita1 stay. (Fig. 4.) Radioactive 5-iodotryptophan administered intravenously on December 23, 1962, was foIIowed by externa1 scanning and was found to show increased activity over the liver as compared to a norma contro1. COMMENTS Tracer studies cent of dietary 5-hydroxy indoIe disease, whiIe the is presumed to be
have indicated that 60 per tryptophan is converted to in some cases of carcinoid remaining dietary tryptophan utiIized in the normal produc540
Advanced
Carcinoids
Use of Tryptopban Analogs. While there are numerous drugs presently being utilized and tested for their antiserotonin effect [9,24], the reports have indicated that as promptly as such serotonin antagonists are discontinued, symptoms of carcinoid syndrome reappear. We, therefore, sought to discover a tryptophan analog which wouId react with enzymes and enter into carcinoid cehular -metabolism, blocking growth within the cell and possibly ending growth and hormone production, or destroying the cell through faulty metabolism. The reactivity of analogs with pancreatic, tryptophanactivating enzyme was reported in 1957 by Sharon and Lipmann [25]. Their studies indicated that various tryptophan analogs could be roughly divided into two groups. One group reacts like tryptophan with hydroxylamine to form the corresponding hydroxamic acid and also catalyzes the enzymic pyrophosphate exchange with adenosine triphosphate (ATP). The other group is not reactive but does inhibit the activation of tryptophan in either test. In the first group, they reported that the tryptophan analogs 7-azatryptophan, tryptazan, G-fluorotryptophan and S-fluorotryptophan are activated by the tryptophan-activating enzyme of pancreas in the hydroxamate test as well as for amino acid dependent ATP pyrophosphate exchange. In the other group of analogs (inhibitory for tryptophan activation but not showing any activation effects) were included 5- and 6-methyltryptophan. A comparison of the analogs with regard to their activation by enzyme and their growth effects shows that only the enzyme-activated anaIogs appear to be first incorporated into protein and then bIock growth, presumably by erroneous protein synthesis. Other analogs, such as methyltryptophan, are not enzymatically activated but compete with tryptophan for enzyme activation. These appear to inhibit growth immediateIy and are not incorporated into protein. Therefore, on the basis of these studies performed on the growth of Escherichia coli, we could anticipate that administration of 6-methyltryptophan to the patient with advanced carcinoid might exert an effect by inhibition of tryptophan activation without being itself enzyme-activated and incorporated into the carcinoid cell. E$ect of 5-Fluorotryptopban. The anaIog
54uorotryptophan has not been tested for incorporation into protein but has demonstrated on E. coli culture that it is activated by the enzyme and that it does inhibit growth [25]. The analog was administered in varying dosages to three patients of this series (A. A. H., J. C. and I. R.). (Figs. 1-4.) It was also administered in combination with other analogs to I. R. and its effect was studied with relation to various diets. The effect of the drug was determined by clinical observations on flushing and diarrhea as well as by quantitative daily determinations of urinary excretion of g-H.I.A.A. Flushing and diarrhea were controlled and re-precipitated at will by administering and withhording this drug to J. C. and I. R. Patient, A. A. H., had a less spectacular response, probably because of difficulties in evaluating his clinical course which was complicated by extreme edema, cardiac failure and mental confusion. The serotonin activity (as assayed by urinary excretion of s-H.I.A.A. daiIy) could likewise be Iowered at will by administering this analog and paralleled the reduction in IIushes and diarrhea. When +fluorotryptophan was decreased in each case (repeatedly in two cases and once in the other), there followed periods of seven to ten days before the 5-H.I.A.A. and the symptoms returned to higher activity. This, we consider to be sign&cant since it has not occurred with 6-methyltryptophan and has been reported not to have occurred with the numerous serotonin antagonists tried for the control of carcinoid syndrome. It suggests that S-II uorotryptophan exerts its effect on serotonin, not by extra ceIIuIar blocking or neutralizing, but by its incorporation into the carcinoid cell and there interfering with serotonin production for seven to ten days afterwards. is an analog E$ect qf Tryptazan. Tryptazan of tryptophan which has been demonstrated tryptophan-activating enwith pancreatic, zyme to be incorporated into protein on a cuIture of E. coli, to be activated by the enzyme, and to inhibit growth of the organism [25]. It seemed desirable, therefore, to attempt use of this analog on carcinoid patients. It was used briefly on J. C. and its effect was inconclusive. (Fig. 3.) The patient was returned to therapy with 5-fl uorotryptophan which had already demonstrated its effectiveness in controlling his carcinoid syndrome. Further experiments with this anaIog will be performed. 541
Costello E$ect of 5-Bromotryptopban. Since 5-fluorotryptophan had proved so effective, it was believed advisable to further explore the effectiveness of other haIogenated anaIogs. The next one obtained by synthesis was It was found to produce bromotryptophan. simiIar effects on the carcinoid syndrome in simiIar doses when administered to I. R. (Fig. 2.) When given in combination with Auorotryptophan and methyItryptophan, the most effective cIinica1 and urinary results were obtained. E$ect of 5-Zodotryptopban. The analog most intriguing (and most tedious in synthesizing) has been iodotryptophan, since it offers a maximum of theoretic excellence in both incorporation and radiation factors. The material has been radioactivated by bombarding it with I131. As such, it was given to I. R. and foIlowed by body surface scanning. It pooIed in the bIadder region and showed no evidence of being picked up in the Iiver region where extensive metastases were palpabIe. Given to another patient (J. C.), it pooIed in the intestine. It was then prepared for intravenous administration and given in tracer dosage to a norma contro1 (a forty-seven year oId woman, T. H.), and to two of the patients, J. C. and M. S. ExternaI scanning intermittentIy for twenty-four hours revealed no Iiver concentration in the contro1 patient and for reasons undetermined, one of the carcinoid patients had concentration over the Iiver region in thirty minutes, while the other had none. EDEMA
IN ADVANCED
CARCINOID
DISEASE
PeripheraI and body edema has been observed and recorded as a frequent compIication in advanced carcinoid disease and its cause has not been eIucidated. CertainIy the incidence appears to be greater than that encountered in other patients dying with far-advanced maIignant disease. The surface of primary Iesions in the intestina1 tract is generaIIy smaI1 or absent (by surgica1 remova1) so as to discount the expIanatory theory of protein-Iosing enteropathy. The fluid accumuIations in our three patients with far-advanced carcinoids, who died, began in the abdomen and proceeded to invoIve the Iower extremities and ultimateIy the entire body. In C. B., the abdomina1 sweIIing was most marked and was found by repeated tappings to resuIt from Iymphatic
obstruction. The edema of the trunk and extremities in A. A. H. was accountabIe on the basis of cardiac decompensation, aIthough the edema in the uniIatera1 upper extremity which was most troublesome during his termina1 three weeks, was found at autopsy to have been the resuIt of axiIIary vein thrombosis. The anasarca which graduaIIy deveIoped in I. R. could not be controIIed by saIt restriction or by digitaIization. She manifested, over a period of months, gradua1 reduction in serum protein vaIues and uItimateIy responded with compIete reIief of edema when massive amounts of human serum albumin were given in divided doses over a period of three days. Thus, there was found to be nothing in common about the ffuid accumuIation which these patients exhibited, since they appeared to be the resuIt, respectively, of protein deficiency, cardiac faiIure, axiIIary vein thrombosis and Iymph obstruction. FUTURE
PROJECTION
These preIiminary findings with advanced carcinoid disease suggest that some progress has been made in obtaining an anaIog which may be activated by tryptophan-activating enzyme and thus incorporated into carcinoid ceIIs. There is suggestive evidence that intravenous radioactivated iodotryptophan may be picked up simiIarIy by carcinoid ceIIs. We are pursuing studies on the basis of these findings and are pIanning to repeat the use of 5-fIuorotryptophan, tryptazan and other anaIogs by intravenous administrations, as previously done oraIIy. Radioactive iodotryptophan wiI1 be administered to such patients intravenousIy and studied by externa1 body scanning and by direct autoradiography of biopsy tissue to determine its vaIue as a diagnostic and therapeutic agent. Acknowledgment: I am grateful to Dr. Louis F. Aitken for cardiac and medica supervision of these patients during hospitaIization at Barnes HospitaI; to Doctors M. Terpagossian and M. Friedenberg, Depasrtment of RadioIogy, MaIIinckrodt Institute, Barnes HospitaI, for advice and heIp in the radiophysica1 aspects of the problem; to Dr. L. P. Gebhardt, Department of BacterioIogy, University of Utah, CoIIege of Medicine, SaIt Lake City, Utah, for
542
Carcinoids
Advanced supplying ~methyltryptophan; and to Captain Fred Conrad, U.S.A.F., M.C., Chief, HemaHospitaI LackIand, tology Service, U.S.A.F. Aerospace MedicaI Division, LackIand Air Force Base, San Antonio, Texas, for assistance with S-H.I.A.A. determinations. ClinicaI studies on some of these patients were made in the Washington University Barnard HospitaI CIinicaI Research Center under support of Grant 8-MOI-FR-36-03, Division of Genera1 Medical Services, NationaI Institutes of HeaIth, and supported in part by grants from the McBride Foundation and William McBride Love Trust Fund. REFERENCES I.
t.
3. 4. 5.
6.
7.
8.
9.
LUBAKSCW,0. Ueber den primaren Krebs des IIeum nebst Bemerkungen tiber das gieichzeitge Vorkommen van Krebs und Tuberculose. Virebows Arc-b. patb. Anat., I I I : 280, 1888. OBERNDORFER,HEKR. Faber die kIeinen Dunndormcarcinome. Verbandl. deutscb. patb. Gesekcb., 11: 113, 1907. GOSSET, A. and MASSON, P. Tumeurs endocrines de I’appendice. Presse mkd., 22: 237, 1914. LEMBECK, F. Five hydroxytryptamine in a carcinoid tumor. Nature, London, 172: 910, 1953. SJOERDSMA, A., WEISSBACH, H. and UDENFRIEND, S. A clinical, physioIogic and biochemical study of patients with maIignant carcinoid (argentafiinoma). Am. J. Med., 20: 520, 1956. DAVIDS~X, J., SJOERDSILIA, A., LOOWIS, L. N. and UDENFRIEND, S. Studies with the serotonin precursor, ~-hydro~ytryptophan, in experimentaf animals and man. J. CZin. Invest., 36: 1594, 1957. STONE, H. II. and NEMIR, P., JR. Study of the roie of ~-hydrox‘ytryptamine (~roton~n) and histamine in the pathogenesis of puImonary emboIism in man. Ann. Surg., 152: 890, 1960. UDENFRIEXD, S., TITUS, E. and WEISSBACH, H. The identification of 5-hydroxy-3-indoleacetic acid in normal urine and method for its assay. J. Biol. Cbem., 216: 499, 1955. URELES, A., MURRAY, M. and WOLF, R. ResuIts of pharmacologic treatment in the malignant car-
543
cinoid syndrome. New England J. Med., 267: 435, 1962. IO. BO~YER, &I. F. Manifestations of smaII bowel tumors. Tex. J. Med., 54: 480, 1958. II. WILLIAMS, R. Carcinoid tumor. hit. M. J., I: 28, 1960. 12. LAIRD, G. J. Carcinoid of the duodenum. J. A. M. A., 174: 1743, 1960. 13. COSTELLO, C. and AITKEN, L. F. Carcinoid of the duodenum. Missouri Med., 57: 1252, 1960. 14. MOERTEL, C. G., SA~IER, W. G., DOCKERTY, M. B. and BAGGENSTOSS,A. H. Carcinoid tumors of the small intestine. Cancer, 14: 901, 1961. W. J. 15. KANTOR, S., CRANE, R. D. and GILLESBY, Carcinoids of the gastrointestinal tract. Am. Surgeon, 27: 448, 1961. 16. WARNER, R. R. P., KIRSCHNER, P. A. and WARNER, G. M. Serotonin production by bronchial adenomas without the careinoid syndrome. J. A. M. A., 178: 1175, 1961. W. H., B..XRTLETT,R. M., BISHOP, H. M., 17. STEWART, CA~~PBELL,D. A. GOLDSMITH, I?. A., MACLEAN, K., MIDDLETON, E. A., MCSSELM.~X, M., RANNICK, G. and TAPPAN, W. Carcinoid tumors presenting with acute abdominal signs. Ann. Surg., Suppl. 154: 112, 1961. 18. LECHNER, G. W. and CHAMBLIK, S. A., JK. Carcinoid tumors of Meckel’s divcrticula. Am. J. Surg., 103: 266, 1962. H., STORER, E. H. and SrAn, F. J. Car19. WILSON, cinoid tumors. Am. J. Surg., 103: 35, 1963. 20. COSTELLO, C. Specific chemocidal therapy. Missouri Med., 59: 418, 1962. 21. ADAMSTONE, F. B. and SPECTOR, H. Tryptophan deficiency in the rat. Histologic change induced by forced feeding of a acid hydrolyzed casein diet. Arch. Patb., 49: 173, 1950. 22. COLE, A. S. and SCOTT, P. P. Tissue changes in an aduft trypt(~phan-de~cient rat. Brit. J. ~~~~~~~on, 8: 125, 1954. 23. HARPER, A. E. Nutritional fatty Iivers in rats. Am. J. Clin. Nutrition, 6: 242, rgg8. 24. BROWS, R. E., HILL, S. R., JR., BERRY, K. W. and BING, R. J. Studies in several antiserotonin compounds in the functioning carcinoid syndrome. Clin. Res., 8: 61, 1960. 25. SHARON, N. and LIPMANN, F. Reactivity of anaIogs with pancreatic tryptophan-activating enzyme. Arch. Biocbem., 24: 227, 1957.