Suppression of Pituitary Tumor Growth and Function by Ergot Alkaloids1' 2

[CANCER RESEARCH 33, 849-855, April 1973] Suppression of Pituitary Tumor Growth and Function by Ergot Alkaloids1' 2

Robert M. MacLeod3 and Joyce E. Lehmeyer

Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, Virginia 22901

SUMMARY mammary tumorigenesis. Among the drugs that are of considerable interest in control of prolactin release are the The in vivo and in vitro effects of ergot derivatives on ergot alkaloids. prolactin and growth hormone biosynthesis in the rat have Nagasawa and Meites (9) and Wuttke et al. ( 14) have shown been studied. Injection with 0.05 or 0.2 mg ergotamine that ergocornine in vivo decreases serum and pituitary tartrate had no effect on in vitro prolactin synthesis by the prolactin levels. When added in vitro, it decreases the release of pituitary gland. Ergocornine and ergocryptine, however, prolactin by the pituitary gland (3). It has also been shown inhibited both synthesis and release of prolactin. Incubation of that both ergocornine and ergocryptine inhibit the growth of glands with 4 or 40 /nM ergotamine greatly decreased prolactin 7,12-dimethylbenzanthracene-induced mammary tumors (1,9) synthesis and release but had no effect on growth hormone. and the growth of spontaneous mammary tumors as well (12). Ergocornine, 10 /Â¿M,and ergocryptine, 10 juM, almost Yanai and Nagasawa (16) demonstrated that ergocornine completely blocked prolactin release and decreased synthesis inhibited the appearance of spontaneous mammary tumors and release of growth hormone as well. and suppressed prolactin secretion in mice. Recently, we Daily administration of 0.05 mg ergotamine for 13 days to reported our finding that ergotamine, ergocryptine, and rats bearing the prolactin- and adrenocorticotropic hormone- ergocornine were all effective in suppressing growth of several secreting pituitary Tumor 7315a dramatically inhibited tumor pituitary tumors (7). Similarly, Quadri et al. (11) found that growth and reversed the adrenal hypertrophy caused by the injection of ergocornine or ergonovine induced regression of tumor adrenocorticotropic hormone. Ergotamine, ergo the growth of the prolactin-secreting pituitary Tumor cryptine, and ergocornine were all effective in suppressing the MtTWIS. growth of pituitary tumors and reversed the spleno- The present study is in agreement with these latter reports hepatomegalia caused by growth hormone-secreting tumors. In on the effects of ergot alkaloids on pituitary tumors. addition, the ergots decreased the high circulating prolactin Additionally, the work presented here demonstrates that the levels found in tumor-bearing animals. Ergotamine alone was primary effect of ergotamine on animals bearing pituitary able to overcome the atrophy of the pituitary glands of tumors is a direct, suppressive effect on the tumor itself, rather tumor-bearing animals and allow gland function to return than on the pituitary gland of the host. toward normal. Ergocryptine and ergocornine tended further to suppress gland function. These data demonstrate that MATERIALS AND METHODS hormone synthesis and release by the pituitary gland and pituitary tumors can be inhibited by derivatives of the ergot Animals. Mature Wistar-Furth rats (obtained from A. R. alkaloids. Schmidt Co., Inc., Madison, Wis.) were inoculated with pituitary Tumors MtTWS, MtTWIS, and SMtTWS as pre viously described (5). Pituitary Tumor 7315a was transplanted INTRODUCTION into mature female Buffalo rats (obtained from Simonsen Laboratories, Gilroy, Calif.). Mature female Sprague-Dawley For the past several years, investigations in this laboratory rats were obtained from Flow Research Animals, Dublin, Va. have been directed toward the mechanisms governing the All rats were routinely housed 4 to 5/cage at 22â€”23Â°and function of the pituitary gland and the function of pituitary allowed water and Purina laboratory chow ad libitum. tumors. More specifically, we have been interested in the Materials. Tissue Culture Medium 199 was obtained from endocrine mechanisms involved in prolactin synthesis and Microbiological Associates, Bethesda, Md. Leucine-4,5-3H, release by the pituitary gland and have been ultimately 29.8 Ci/mmole, was a product of International Chemical and concerned with the role of this hormone in supporting Nuclear Corp., Irvine, Calif. Ergotamine tartrate, ergocryptine, and ergocornine malÃ©atewere gifts from Sandoz Pharmaceuti 1This investigation was supported by USPHS Grant CA-07535 from cals, Hanover, N. J. In some cases, the ergotamine tartrate the National Cancer Institute. injected was Gynergen (Sandoz). The drugs were all injected 'Portions of this work were presented at the Annual Meeting of the s.c. American Association for Cancer Research, 1972. Organ Culture. Incorporation of leucine-4,5-3H into prolac 'Investigation conducted while a recipient of Research Career Development Award CA-07665 from the National Cancer Institute. tin and growth hormone was studied by incubating bisected Received September 5, 1972; accepted January 8, 1973. pituitary glands in 0.5 or 1 ml of Tissue Culture Medium 199

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Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1973 American Association for Cancer Research. Robert M. MacLeod and Joyce E. Lehmeyer containing 5 to 10 juCi of leucine-4,5-3H. Flasks were protocol supplied by the Hormone Distribution Program, incubated for 6 to 7 hr at 37Â°in a Dubnoff shaker and were National Institute of Arthritis and Metabolic Diseases. The gassed with 95% O2 -5% C02 . Pituitary glands were homoge prolactin provided was iodinated either with '2 51 or '3 ' I, nized in 0.5 to 1 ml of 50 mM phosphate (pH 7.2) with a glass obtained from New England Nuclear, Boston, Mass. Sheep homogenizer fitted with a Teflon pestle. Homogenates were anti-rabbit y-globulin was obtained from Dr. Ann J. Johanson frozen and thawed 3 times to lyse all granules. Duplicate of the University of Virginia Medical School. aliquots (50 //I) were then subjected to polyacrylamide gel Statistical Analysis of Experimental Data. When appro electrophoresis (4), with the sample, stacking, and separating priate, results are expressed as the mean Â± S.E. The gel system of Jones et al. (2). The incubation medium proteins significance of the difference between the means was were separated on gels as well, but the 50-/J.I aliquots were determined by Student's t test. "top-loaded" according to the system described by Reisfeld et al. (13). The proteins on the gels were stained with Amido RESULTS black and band quantitated by means of a Canalco micro- densitometer with an integrator. The hormone bands on the The effects of ergot alkaloids on pituitary gland function in gels were identified by comparing their mobility with purified normal female rats are illustrated in Chart 1. The open bars in preparations of prolactin and growth hormone. Our results are the chart represent the labeled prolactin or growth hormone found in the incubation medium at the termination of the in excellent agreement with those of Jones et al. (2), who incubation. The open bars, therefore, indicate "release" of eluted these proteins from the polyacrylamide gels and established their identity by bioassay. After the identity of the newly synthesized hormone into the medium during the hormone bands was established, the bands were cut, placed in incubation period. The shaded bars represent the labeled counting vials, and dissolved in 0.5 ml 30% HjC^ at 100Â°. prolactin or growth hormone found in the pituitary tissue at After addition of a Triton-toluene counting solution, the vials termination of incubation. The total height of both the open were placed in a scintillation counter to determine the level of and shaded bars is the sum of the newly synthesized hormone released into the medium and that remaining within the tissue radioactivity. and is termed "total synthesis." Daily injection of 0.05 or 0.2 Prolactin Radioimmunoassay. The immunoassay of sera and incubation media was carried out using the reagents and mg ergotamine tartrate for 7 days had no effect on the release of prolactin by the pituitary gland or on total in vitro

PROLACTIN synthesis of prolactin. The injection of ergocornine, however, resulted in a decrease in release of newly synthesized prolactin into the incubation medium (open bar) and a subsequent 10 accumulation of the labeled hormone within the pituitary gland (shaded bar). There was no significant effect on total rii prolactin synthesis. Ergocryptine injection almost completely * blocked prolactin release. Newly synthesized prolactin accu mulated within the tissue (shaded bar), but total synthesis was decreased compared with the control. Injection of 0.2 mg of o the drugs resulted in a slight increase in total growth hormone I synthesis. This increase in growth hormone synthesis may be an example of the reciprocal relationship between prolactin

t^â€¢Iâ€”i-i-Controi1HhÂ»HW1T1M n u Km U N and growth hormone, a preliminary report on which has recently appeared (8). The in vitro effects of the ergots are shown in Chart 2. a Although ergotamine had no effect on in vitro pituitary *â€¢Tj'-I-_!>_-I-ErgotaminÂ« hormone synthesis when injected (Chart 1), incubation of pituitary glands with a 4 Â¿/Mdrug concentration resulted in a greatly decreased release of prolactin into the medium (open bar) and a subsequent accumulation of labeled prolactin within the tissue (shaded bar). Total in vitro synthesis of prolactin was also significantly decreased with respect to the Ergocty0.05 Control ErgotominÂ« Control Ergocor mg doily 0.2 mg daily ninitini0.2 control. At 40 /^M, the effect of ergotamine on release and mg 0.2mgdoily daily total synthesis of prolactin was even more pronounced. No effect on growth hormone production was observed. Ergocor Chart 1. Effect of administration of ergot derivatives on in vitro nine and ergocryptine, 10 juM, almost completely blocked synthesis and release of prolactin and growth hormone. Bisected female rat pituitary glands were incubated with leucine-4,5-3H for 6 to 7 hr. release of prolactin (open bar) and greatly decreased total The prolactin and growth hormone in the incubation medium and in synthesis as well. Growth hormone synthesis and release were the tissue were separated by polyacrylamide gel electrophoresis, and the inhibited to a lesser extent. radioactivity in the hormone bands was measured by scintillation Daily administration of 0.05 mg of ergotamine for 13 days counting techniques. Animals were treated by daily injection s.c. for 7 to animals bearing the prolactin- and ACTH4-secreting days. / bars, mean Â±S.E. of duplicate determinations on 2 to 3 incubation flasks, each containing 4 randomized pituitary gland halves. 4The abbreviation used is: ACTH, adrenocorticotropic hormone.

850 CANCER RESEARCH VOL. 33

PROLACTIN summarized in Table 1. Injection treatment of normal rats Medium with 0.2 mg ergocryptine or ergocornine for 7 days had no Gland effect on body weight or on the weights of the pituitary gland, the spleen, or the adrenals. Ergocornine slightly but signifi cantly decreased liver weight (Group 1 versus Group 3). 6 rii Injection treatment of normal rats for 7 days with 0.2 mg ergotamine decreased body weight 12% but had no effect on 5 the weight of the pituitary gland, liver, or spleen. Interestingly, the weight of the adrenals was actually increased. 4 Growth hormone-secreting pituitary tumors are known to cause marked splenohepatomegalia (6, 17). Implantation of 3 the SMtTWS tumor resulted in increased body weight and increased liver and spleen weight; the weight of the pituitary Ã®" 2 gland was greatly decreased (Group 4 versus Group 6). When a animals bearing these tumors were given injections of '5 ergotamine (Group 6 versus Group 7), the size of the tumor, E' the liver, and the spleen were all decreased, and the previously o> suppressed pituitary gland returned to almost normal control weight. Ergocornine treatment also reduced tumor, liver, and n GROWTH HORMONE spleen size but did not relieve the suppression of the pituitary O rii gland of the host (Group 8 versus Group 9). Similarly, ergocryptine decreased tumor weight but did not affect E a pituitary gland weight (Group 10 versus Group 11). Treatment of rats bearing the prolactin- and ACTH-secreting pituitary Tumor 731 Sa with 0.05 mg ergotamine for 13 days had no effect on body weight, but tumor size was greatly decreased and the adrenal hypertrophy caused by the tumor ACTH was reversed (Group 12 versus Group 13). The 731 Sa and MtTWS tumors secrete large amounts of prolactin. Consequently, circulating prolactin levels in rats bearing these tumors are 10 to 200 times greater than in non tumorous animals (Chart 4). Injection treatment of normal Control 4xlO-*M Control IO-5M 10-5M female Buffalo rats with ergotamine had no significant effect Etgocor Ergocryp- Ergotamine Tarliate nine tine Chart 2. In vitro effect of ergot alkaloids. Bisected pituitary glands were incubated with the ergot derivatives at the concentrations indicated in the chart. / bars, mean Â±S.E. of duplicate determinations on 2 to 3 incubation flasks, each containing 4 randomized pituitary gland halves. pituitary Tumor 7315a dramatically inhibited tumor growth (Chart 3A), despite the fact that injection of ergotamine produced only minimal endocrine changes in the pituitary glands of nontumorous female rats. While the tumors of the nontreated animals increased 89% in size, the tumors of the injection-treated animals increased only 22%. Rats bearing the SMtTWS and MtTWIS tumors, which secrete both prolactin and growth hormone, were given daily injections of 0.2 mg ergotamine tartrate for 7 days. Again, tumor growth was greatly inhibited (Chart 3, B and C, respectively). DAYS OF INJECTION The efficacy of ergocryptine and ergocornine in retarding Chart 3. Effect of ergot treatment on pituitary tumor growth. Rats tumor growth is illustrated in Chart 3, D and E. Six daily bearing transplanted, hormone-secreting pituitary tumors were given injections of 0.2 mg ergocryptine suppressed growth of the daily s.c. injections of 0.05 mg ergotamine tartrate (A), 0.2 mg ergotamine tartrate (B, C), 0.2 mg ergocryptine (D), and 0.2 mg MtTWS tumor, which secretes both prolactin and growth ergocornine malÃ©ate(Â£").Thetumors studied were 7315a (A), SMtTWS hormone (Chart 3D). Treatment with ergocornine malÃ©atealso (B, E), MtTWIS (O, and MtTWS (D). The number of animals used in inhibited growth of the SMtTWS tumor (Chart 3F). each experiment were 6 untreated, 6 treated (A); 4 untreated, 4 treated The effects of administration of ergot derivatives on organ (B); 3 untreated, 3 treated (C); 5 untreated, 5 treated (D and E). weights of normal and pituitary tumor-bearing rats are Vertical lines, S.E.

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Table 1 Effect of ergot treatment on tissue weights of tumor-bearing rats

Wt/100gbodywt

of wt tumor gland Group12345678910111213GroupControlErgocryptine"Ergocornine0ControlErgotamine0SMtTWSSMtTWSanimals6444444555566Body(g)195 (g)23.8 (mg)4.91 (g)4.50 (g)0.28 (mg)41 Â±186188197175254193 Â±0.324.58 Â±0.094.35 0.020.260.260.310.280.560.320.590.310.010.020.050.010.06e0.01d0.100.01CAdrenalsÂ±237 Â±0.074.39 Â±0.314.05 Â±438 Â±0.164.48 Â±0.18b2.80 Â±226 Â±0.014.54 Â±0.103.00 Â±236Â±2C21 Â±0.362.62 Â±0.045.00 Â±10.4Â±7.1 Â±0.03d4.25 Â±0.37d3.54 Â±lb30 +ergotamine0SMtTWSSMtTWS Â±225 Â±0.04d3.05 Â±0.12d5.32 Â±ld26

Â±186 Â±2.3 Â±0.253.92 +0.134.51 Â±131 +ergocornine"MtTWSMtTWS Â±226 Â±21.4 Â±0.073.29 Â±0.04d4.21 Â±276+

Â±201 Â±8.8 Â±0.313.43 +ergocryptine07315a731Sa Â±236 Â±12.7 +0.273.28 Â±229 Â±1.9 Â±0.123.73 Â±0.153.45 1030Â±2d +ergotamine8No. Â±34253d82d55d135125Pituitary+6.72.61.20.2d6.72.13.40.3dPituitaryÂ±0.27Liver Â±0.02dSpleen

0 Animals received 0.2 mg ergot daily for 6 to 7 days. b p < 0.05; Groups 1 vs. 3,4 vs. 6. cp< 0.025 Â¡Groups4 vs. 5,4 vs. 6, 8 vs. 9. d p < 0.01; Groups 4 vs. 5,4 vs. 6, 6 vs. 7,8 vs. 9, 12 vs. 13. e Animals received 0.05 mg ergot daily for 13 days. on circulating prolactin levels. The control Buffalo rats had circulating prolactin levels in excess of 3000 ng/ml. Treatment prolactin levels of 120.4 Â±17-5 ng/ml while the injection- with ergotamine reduced the level to 1200 ng/ml. Similarly, treated rats had levels of 149.5 Â±31.8 ng/ml. We have injection treatment of animals bearing the MtTWS tumor with consistently found the circulating levels of prolactin in the ergocryptine reduced serum prolactin levels from in excess of Buffalo strain to be much higher than in other strains of rats. 3000 ng/ml to 960 ng/ml. The normal Wistar-Furth female rats Immunoassay of serum from Sprague-Dawley female rats gave used for controls had serum prolactin levels of 15.4 Â±0.8 prolactin values of 29.6 Â±2.2 ng/ml. The meaning of this is ng/ml. not now clear. The animals bearing the 7315a tumors had We have previously reported that pituitary gland function is greatly reduced in rats bearing hormone-producing pituitary

20000 r- tumors (4). The in vitro synthesis of prolactin by glands of normal animals and animals bearing the 7315a tumor is illustrated in Chart 5. Again, ergotamine treatment had no ef 15000 fect on the in vitro release of prolactin (open bars) or on total synthesis by glands of normal animals. The glands of rats bearing the 7315a tumor synthesize and release much less -t 5000 prolactin than do glands of normal animals. This situation n presumably occurs via an autofeedback mechanism due to the -5 1000 greatly elevated circulating levels of prolactin (Chart 4). 55 Ergotamine treatment of animals bearing this tumor sup I 800 pressed tumor growth (Chart 3/1), thus decreasing the serum -I prolactin level (Chart 4). Consequently, the in vitro release and 600 synthesis of prolactin by the glands of these animals rebounded toward normal (Chart 5). The radioimmunoassay 400 on the incubation media also shows that ergotamine treatment had no effect on the in vitro release of prolactin by normal 200 glands. The glands of the tumor animals release much less n n prolactin than do normal glands, but suppression of tumor Non-tumor Non-tumor 7315o 7315o MtTWS MtTWS growth by injection of ergotamine allowed in vitro prolactin + + + Ergotamine Ergotamine Ergocryptine release to increase. Chart 4. Effect of ergot treatment on serum prolactin. Serum Similar experiments with animals bearing other pituitary prolactin levels in normal female rats and in rats bearing pituitary tumors are summarized in Table 2. As was seen earlier, tumors were measured by radioimmunoassay. Serum samples from 3 to ergotamine treatment had no effect on total in vitro prolactin 6 animals/group were assayed in duplicate. synthesis or release by the glands of control animals

852 CANCER RESEARCH VOL. 33

5 e I

0_ o> E

CONTROL CONTROL 7315o 7315o CONTROL CONTROL 7315a 7315o ERGOTAMINE ERGOTAMINE ERGOTAMINE ERGOTAMINE Chart 5. Effect of administration of ergotamine on in vitro prolactin synthesis. Six normal female rats and 6 female rats bearing the prolactin- and ACTH-secreting pituitary Tumor 7315a were given daily injections of 0.05 mg ergotamine tartrate for 7 (normal rats) or 13 (tumor rats) days. The pituitary glands were incubated as described in Chart 1. Left, in vitro synthesis and release of prolactin. T-bars, mean Â±S.E. of duplicate determinations on 3 incubation flasks, each containing 4 randomized pituitary gland halves. Right, results of a prolactin radioimmunoassay on the incubation media. T-bars, mean Â±S.E. of triplicate determinations on each of the 3 incubation flasks in each group.

(Experiment 1). The glands of rats bearing the SMtTWS tumor or release of labeled growth hormone. Implantation in male synthesized and released significantly less prolactin than did rats of the growth hormone-secreting pituitary Tumor MtTWl 5 control glands. Treatment of animals bearing this tumor with decreased in vitro growth hormone synthesis by the glands of ergotamine tartrate suppressed tumor growth (Chart 35) and the hosts by 55% (Group 122 versus Group 14). Release of allowed the in vitro synthesis and release of prolactin by the labeled hormone into the medium was reduced 51%. Treat glands of the treated animals to increase significantly. Total ment of animals bearing this tumor suppressed growth of the synthesis of labeled prolactin increased 104% and release tumor (Chart 3C) and tended to relieve the suppression of the increased 87% (Group 3 versus Group 4). The radioimmuno host glands. Release of growth hormone was significantly assay of the incubation media suggested a small although greater when compared to release by glands of untreated nonsignificant increase in release of total prolactin (i.e., tumor-bearing animals (Group 14 versus Group 15). pre-formed as well as newly synthesized). In Chart 1 it was shown that injection of ergocornine, DISCUSSION unlike ergotamine, had a direct, suppressive effect on prolactin synthesis by the gland. When animals bearing the SMtTWS The present report verifies the previous finding (3, 7,9,14, tumor were treated with ergocornine, tumor growth was 15) that the administration of ergocornine and ergocryptine to retarded (Chart 3E). The synthesis and release of labeled normal female rats suppresses release and, to a lesser extent, prolactin by the pituitary glands of the hosts were decreased, synthesis of prolactin. Ergocryptine and ergocornine in vitro, although the effect was not statistically significant. (Table 2, however, not only blocked prolactin release and, subsequently, Experiment 2). The radioimmunoassay also strongly suggested synthesis, but they inhibited release and synthesis of growth a decrease in release of prolactin into the incubation medium hormone as well. The injection of ergotamine was without although, again, the difference was not statistically significant. effect on in vitro prolactin production. Nicoli et al. (10) were Experiment 3 illustrates the direct, suppressive effect of able to demonstrate that ergotamine tartrate injected at 5 ergocryptine injection on in vitro prolactin synthesis and times the amount used in the current experiments caused a release. The 98% decrease in release of labeled prolactin was 40% decrease in prolactin secretion in vitro. Ergotamine in accompanied by an accumulation of the hormone within the vitro was partially effective in reducing prolactin production gland. Total synthesis was decreased 85%. The decrease in but had no effect on growth hormone. Consequently, it is release as measured by radioimmunoassay was highly signifi unclear whether the administered ergots exert their effects by cant. acting directly on the gland or by indirect means. Wuttke et al. Implantation of the MtTW5 tumor resulted in decreased in (14) have recently proposed that ergocornine acts via the vitro synthesis and release of prolactin by the pituitary glands hypothalamus to decrease pituitary function although a direct of the host animals (Experiment 4). When animals bearing this action of the drug was not excluded. tumor were treated with ergocryptine tumor growth was It has been clearly demonstrated (1, 9, 12, 15, 16) that inhibited (Chart 3D), synthesis and release of labeled prolactin ergot treatment can inhibit growth of mammary tumors. A by the glands of the host were even further suppressed. recent report showed that ergocornine and ergonovine could The effect of ergotamine in the in vitro synthesis of growth suppress growth of a prolactin-secreting pituitary tumor (11). hormone is shown in Experiment 5. Injection treatment of We have found (7) that the administration of ergotamine male rats with the drug had no significant effect on synthesis tartrate, as well as ergocryptine and ergocornine, causes

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Table 2 Effect of ergot treatment on in vitro prolactin and growth hormone synthesis Rats were treated by s.c. injection of 0.2 mg ergot daily for 6 to 7 days. Pituitary glands were incubated, and newly synthesized, labeled hormone was measured as described in Chart 1. Prolactin concentration in the media was measured by radioimmunoassay. The values presented are the means Â±S.E. of duplicate determinations on 2 to 3 incubation flasks, each containing 3 to 5 randomized pituitary gland halves, except in Experiment 4, in which single glands were incubated individually.

pituitary)Medium(cpm/mg

ofanimalsProlactin (Mg/mgpituitary in Group GroupNo. Gland TotalProlactin medium) Experiment I

1 Control 4 4838 Â±241 1230Â±124 6068 + 117 16.0 Â±0.5 2 Ergo lamine 4 5311 Â±376 1013Â± 70 6324 Â±306 16.0 Â±1.5 3 SMtTWS 4 1720 Â±23Â° 131 Â±47Â° 1851 Â±24b 13.0 Â±1.0 4 SMtTWS + 4 3223Â±210Â° 551Â±104 3774 Â±106b 14.5 Â±0.5 ergotamine Experiment 2

SMtTWS 2566 Â±393 182Â± 18 2748 Â±376 2.9 Â±0.9 SMtTWS + 1648 Â±213 326Â±182 1974 Â± 31 0.9 Â±0.0 ergocornine Experiment 3

Control 3437Â±189 44 Â± 8 3481 Â±196 5.2 Â±1.7 ergocryptine 84 Â±176 423Â± 48b 507 Â±37& 0.7 Â±O.lb

Experiment 4

9 Â±385 Â±72 Â±440 10 MtTWS 553022 1006 Â±104b 268 Â± 15b 1274Â±109b 11ControlMtTW5+ergocryptine4 301 Â±67bMedium922IIIeTotalExperiment540 Â±91CGrowth 841 +

hormone(cpm/mg pituitary)Gland3944

.512131415ControlErgotamine

Â±1001419 Â±1002726 +2804145 Â±28 Â± 6 Â± 37 MtTWISMITW15 331273 625 Â±8C934+ 1428 Â±112Â°1769 2053 Â±166Â°2703+ +ergotamine33 47a3251 Â±1354524 53

" p< 0.025; Groups 1 vs. 3, 3 vs. 4, 12 vs. 14, 14 vs. 15. 6 p < 0.005; Groups 1 vs. 3, 3 vs. 4, 7 vs. 8, 9 vs. 10, 10 vs. 11. c p< 0.05; Groups 10 vs. 11, 12 vs. 14. inhibition of growth or even actual regression of several contains an ergotamine-sensitive receptor site which is not hormone-producing pituitary tumors. Suppression of tumor found in the gland. This specificity for the tumor suggests that growth is accompanied by a decrease in serum prolactin levels ergotamine might be of clinical importance in the treatment of and a reversal of the tumor hormone-induced organ hypertro pituitary tumors. phy. Of the 3 alkaloids, only ergotamine showed a specificity The fact that ergot derivatives decrease serum prolactin and for the tumor. The glands of the host animals were not further leutinizing hormone (14) suggests that the drugs have a general suppressed by treatment with the alkaloid. After the expected suppressive effect on pituitary function rather than a specific decrease in circulating prolactin following tumor suppression, effect on selected pituitary cell receptors. Additionally, the the glands of these animals synthesized increased amounts of drugs presumably decrease ACTH secretion by the pituitary prolactin. When tumor-bearing animals were given ergo tumors since the ergots cause atrophy of the adrenal glands. cryptine or ergocornine, the glands of the host animals were Because ergot alkaloids have a vasoconstrictive effect, there is even further suppressed, in spite of a reduction in serum a strong possibility that the decreased pituitary gland and prolactin levels. tumor function may result from this action. It would be of interest to learn whether the pituitary tumor

854 CANCER RESEARCH VOL. 33

ACKNOWLEDGMENTS of the Fourth International Congress of Endocrinology, Washing ton, D.C., June 18-24, 1972, p. 250. Amsterdam: Excerpta We would like to thank Mr. Ronald C. Pace for his excellent Medica, 1972. technical assistance. 9. Nagasawa, H., and Meites, J. Suppression by Ergocornine and Iproniazid of Carcinogen-Induced Mammary Tumors in Rats; REFERENCES Effects on Serum and Pituitary Prolactin Levels. Proc. Soc. Exptl. 1. Cassell, E. E., Meites, J., and Welsch, C. W. Effects of Ergocornine Biol. Med., 135: 469-472, 1970. and Ergocryptine on Growth of 7,12-Dimethylbenzanthracene- 10. Nicoli, C. S., Yaron, Z., Nutt, N., and Daniels, E. Effects of induced Mammary Tumors in Rats. Cancer Res., 31: 1051-1053, Ergotamine Tartrate on Prolactin and Growth Hormone Secretion 1971. by Rat Adenohypophysis in Vitro. Biol. Reprod., 5: 59-66, 1970. 2. Jones, A. E., Fisher, J. N., Lewis, U. J., and VanderLaan, W. P. 11. Quadri, S. K., Lu, K. H., and Meites, J. Ergot-Induced Inhibition of Electrophoretic Comparison of Pituitary Glands from Male and Pituitary Tumor Growth in Rats. Science, 176: 417 -418, 1972. Female Rats. Endocrinology, 76: 578-583, 1965. 12. Quadri, S. K., and Meites, J. Regression of Spontaneous Mammary 3. Lu, K. H., Koch, Y., and Meites, J. Direct Inhibition by Tumors in Rats by Ergot Drugs. Proc. Soc. Exptl. Biol. Med., 138: Ergocornine of Pituitary Prolactin Release. Endocrinology, 89: 999-1001,1971. 229-233,1971. 13. Reisfeld, R. A. Lewis, U. J., and Williams, D. E. Disk 4. MacLeod, R. M., and Abad, A. On the Control of Prolactin and Electrophoresis of Basic Proteins and Peptides on Polyacrylamide Growth Hormone Synthesis in Rat Pituitary Glands. Endo Gels. Nature, 195: 281-283, 1965. crinology, 83: 799-806, 1968. 14. Wuttke, W., Cassell, E., and Meites, J. Effects of Ergocornine on 5. MacLeod, R. M., Abad, A., and Eidson, L. L. In Vivo Effect of Sex Serum Prolactin and LH, and on Hypothalamic Content of PIP and Hormones on the in Vitro Synthesis of Prolactin and Growth LRF. Endrocrinology. 88: 737-741, 1971. Hormone in Normal and Pituitary Tumor-Bearing Rats. Endo- 15. Yanai, R., and Nagasawa, H. Suppression of Mammary Hyper- crinology, 84: 1475-1483, 1969. plastic Nodule Formation and Pituitary Prolactin Secretion in Mice 6. MacLeod, R. M., Allen, M. S., and Hollander, V. P. Hormonal Induced by Ergocornine or 2-Bromo-a-Ergocryptine. J. Nati. Requirements for the Growth of Mammary Adenocarcinoma Cancer Inst., 45: 1105-1112, 1970. (MTW9) in Rats. Endocrinology, 75: 249-258, 1964. 16. Yanai, R., and Nagasawa, H. Inhibition by Ergocornine and 7. MacLeod, R. M., and Lehmeyer, J. E. Regulation of the Synthesis 2-Br-a-Ergocryptine of Spontaneous Mammary Tumor Appearance and Release of Prolactin. In: G. E. W. Wolstenholme and J. Knight in Mice. Experientia, 27: 934, 1971. (eds.), Ciba Foundation Symposium on Lactogenic Hormones 17. Yokoro, K., Furth, J., and Haran-Ghera, N. Induction of 1971, pp. 53-82. London: Churchill Livingstone, 1972. Mammotropic Pituitary Tumors by X-rays in Rats and Mice: The 8. MacLeod, R. M., and Lehmeyer, J. E. Reciprocal Relationship Role of Mammotropes in Development of Mammary Tumors. between Prolactin and Growth Hormone Production. In: Abstracts Cancer Res., 21: 178-186,1961.

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Robert M. MacLeod and Joyce E. Lehmeyer

Cancer Res 1973;33:849-855.

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