1) The influence of thyroid secretion upon the induction of leukemia in Dba/2 male mice by methylcholanthrene was investigated. Radiothyroidectomy
significantly reduced the incidence of leukemia in these mice. This reduction in incidence did not occur if radiothyroidectomy was performed after the administration of the carcinogen. 2) Data indicated that hypothyroidism following radiothyroidectomy interfered with the initiation rather than the promotion of methylcholanthrene-
induced-Ieukemogenesis. 3) No correlation between incidence of leukemia and body weights in the mice was noted.</p

Ida, Noriaki

Oda, Nobuo

Okayama University Scientific Achievement Repository

Acta Medica OkayamaVolume 14, Issue 1 1960 Article 2APRIL 1960Influence of thyroid secretion on thein-duction of leukemia in Dba mice bymethylcholanthreneNobuo Oda∗ Noriaki Ida†∗Okayama University,†Anderson Hospital,Copyright c©1999 OKAYAMA UNIVERSITY MEDICAL SCHOOL. All rights reserved.Influence of thyroid secretion on thein-duction of leukemia in Dba mice bymethylcholanthrene∗Nobuo Oda and Noriaki IdaAbstract1) The influence of thyroid secretion upon the induction of leukemia in Dba/2 male mice bymethylcholanthrene was investigated. Radiothyroidectomy significantly reduced the incidence ofleukemia in these mice. This reduction in incidence did not occur if radiothyroidectomy was per-formed after the administration of the carcinogen. 2) Data indicated that hypothyroidism followingradiothyroidectomy interfered with the initiation rather than the promotion of methylcholanthrene-induced-Ieukemogenesis. 3) No correlation between incidence of leukemia and body weights inthe mice was noted.∗Copyright c©OKAYAMA UNIVERSITY MEDICAL SCHOOLActa Med. Okayama 14, 14-21 (1959)INFLUENCE OF THYROID SECRETION ON THEINDUCTION OF LEUKEMIA IN Dba MICE BYMETHYLCHOLANTHRENENobuo ODA* and Noriaki IDAThe University of Texas, M. D. Anderson Hospital and Tumor InstituteTexas, U. S. A. (Director: Dr. A. Kirschbaum)Received for publication, Nov. 10, 1959There has long been speculation regarding a possible relationshipbetween hematopoietic tissues and thyroid function. Lymphocytosis hasoften been noted in patients with hyperthyroidism. Growth of lymphatictissues in thyroxine-treated animals has been demonstrated. Elevation ofmetabolic rates has been observed in patients with leukemia. Blood iodinecan be markedly elevated in the lymphoid leukemia patient. Striking re-mission after thyroidectomy has been reported in a patient with chroniclymphocytic leukemia.GRAD (1955)1.2 investigated the influence of hyper· and hypothyroidismupon the incidence of mouse leukemia. He found that thyroxine decreasedand thiouracil increased the incidence of spontaneous leukemia in AKRmice.In 1953, BIELSCHOWSKy3 reported his studies of tumor induction with2-aminofluorene and its acetyl-derivatives in thyroidectomized rats. In hisexperiment, the incidence of liver tumors was suppressed by thyroidectomyperformed prior to the administration of carcinogen. No suppressive effectwas found when thyroidectomy was done after the administration of car-cinogen.WOLFSON (1956)4 demonstrated that thyroidectomy by radioactiveiodine shortened the interval between the onset of sarcoma and the admi-nistration of methylcholanthrene to rats.Since these results appeared to show some discrepancies, the presentinvestigations were undertaken to evaluate the influence of hypothyroidismupon leukemogenesis in mice.In our experiment, Dba/2 male mice were used as the experimentalanimal, methylcholanthrene as the carcinogen, and radioiodine as the pro-c~dure of thyroidectomy.* Present address: Department of Pediatrics, Okayama University Medical school,Okayama, Japan141Oda and Ida: Influence of thyroid secretion on the in-duction of leukemia inProduced by The Berkeley Electronic Press, 1960Thyroid Secretion and Leukemia 15MATERIAL AND METHODSDda/2 male mice were divided into the following six groups:1. Methylcholanthrene only.2. p:n + Methylcholanthrene.3. p31 + Isograft of thyroid + Methylcholanthrene.4. Methylcholanthrene + I 1:n•5. Methylcholanthrene + F:1 + Isograft of thyroid.6. P;:J only.Beginning at the age 6-10 weeks, generally at 8 weeks, Dba/2 malemice were given eighteen skin paintings (three times weekly for 6 weeks)of 0.2596 solution of methylcholanthrene in benzene. A number 6 camel'shair brush was used to apply the carcinogen at a dfferent site for each suc-cessive skin painting.To determine more clearly whether hypothyroidism interferes with"initiation" of carcinogenesis by methylcholanthrene or with the "pro-motion" of methylcholanthrene-induced carcinogenesis, radioactive iodinewas administered either before or after painting with methylcholanthrene.Male mice of the same age and strain were given three hundred micro-curies of radioactive iodine, intraperitoneally, and skin painted 2 weekslater with methylcholanthrene.Thyroid replacement therapy consisted of the subcutaneous implan-tation, in the axillary region, of both lobes of the thyroid glands of youngadult mice of the same strain.Thyroid isograft was made 2 weeks after radioactive iodine administ-ration; this was followed in one week by methylcholanthrene painting.RESULTSAs shown in Fig. 1, 34 mice out of 49 painted with methylcholanthrenedeveloped leukemia. This represented an incidence of leukemia of 69 96at 400 days of age (Exp. I).Male mice given 300 llC of radioactive iodine, intraperitoneally, andskin painted 2 weeks later with methylcholanthrene showed a reduction inthe incidence of leukemia to 1296. Only 9 out of 74 mice developed leukemiaby 400 days of age (Exp. 2).In 52 control mice receiving radioactive iodine alone, no leukemia de-veloped (Exp. 6). Of the mice, which received isografts of thyroid'tissueafter radiothyroidectomy, 16 out of 30 mice (53 96) developed leukemiaafter methylcholanthrene painting (Exp. 3).2Acta Medica Okayama, Vol. 14 [1960], Iss. 1, Art. 2http://escholarship.lib.okayama-u.ac.jp/amo/vol14/iss1/216 N. ODA and N. IDA80 "4604020200 300 400OAYSFig. 1. Suppression of methylcholanthrene leukemogenesisin mice by radio-thyroidectomyThis suggests that the effect of radioactive iodine on methylcholan-threne leukemogenesis is related to its thyroidectomy effect, rather than toother pharmacological or radiological effects.If radioactive iodine was not administered until 2 weeks after the lastpainting with methylcholanthrene, its suppressive effect on methylcholan-threne leukemogenesis was largely eliminated. Under these conditions, 16out of 28 mice (57 %) developed leukemia (Exp. 4).In animals which were painted with methylcholanthrene first and sub-sequently underwent radiothyroidectomy and isograft, the incidence ofleukemia was 54 % out of 26 mice developing leukemia (Exp. 5).BODY WEIGHTSBody weights were routinely measured. No significant differences inbody weights were found among the various experimental groups of animalsuntil after 100 days of treatment. After this time the body weight databecame distorted by the development of leukemia and the death of experi-mental animals (Fig. 2).These data therefore appeared to indicate that in order to suppressmethylcholanthrene leukemogenesis, the hypothyroid state must be presentduring the period of "initiation" of leukemogenesis; further, this effect isnot dependent upon body weight changes.3Oda and Ida: Influence of thyroid secretion on the in-duction of leukemia inProduced by The Berkeley Electronic Press, 1960sw(SM)52124Z2201116Thyroid Secretion and LeukemiaI"~GRAFT.MCA10ll,MCA.....-:.MCA,I'a.1714 'tTREATMENT EXPERIMENTAL DAY500.Fig. 2. Body weight of Dba/2 male treated with pi andmethylcholanthreneDISCUSSIONAccording to our data, hypothyroidism showed a significant suppres-sive effect upon the induction of leukemia by methylcholanthrene.As far back as 1909, STUART-Low 5 reported that cancer was rarelyfound among patients with myxedema. Surgical thyroidectomy was asso-ciated with regression in the size of tumors in his patients. According toHOHNENBURG, BULLOCK and ]OHNSTON(1911)6, the removal of certain glands(L e., thyroid, thymus and testes) appeared to decrease the susceptibilityof rats to Flexner-]obling sarcoma. MUROHARA (1930) 7 demonstrated thatthyroidectomy as well as the injection of large doses of thyroxine inhibitedthe growth rate of transplanted sarcoma in the rabbit. These data wereconfirmed by NISHIDA (1935) B, and KOSUGI (1937) 9, LEVINE and KUGEL(1933)'°, MC]UNKIN, TEMPLETON and KRAVEC (1936)11), and DARGENT,VIALLIER and GUINET (1951)12 also reported the suppressive effect of hypo-thyroidism upon implanted ~ 180 mouse tumor, uterine spindle cell sarcomain albino rats and inoculated tumor ~ 8 of Guerin (uterine adenocarcinoma).As cited earlier, BIELSCHOWSKY (1953) 3 found that thyroidectomyresultej in the suppression of the induced liver tumor in rats by 2-amino-fluorene. In our experiment in which radiothyroidectomy significantlylowered the incidence of methylcholanthrene-induced leukemia in Dba/2mice, the magnitude of the suppression was equivalent to that observed for4Acta Medica Okayama, Vol. 14 [1960], Iss. 1, Art. 2http://escholarship.lib.okayama-u.ac.jp/amo/vol14/iss1/218 N. ODA and N. IDAhepatic tumorigenesis in thyroidectomized rats fed acetylaminofluorene(KIRSCHBAUM, 1957)13.WOLFSON (1956)4 noticed that sarcoma in rats was induced by 3-me-thylcholanthrene and that the onset of the disease was delayed when radio-active iodine was injected into the animals. According to MORRIS, WOLFand UPTON(1957)14, average survival time of rats and mice with trans-planted lymphoma was prolonged if hypothyroidism was induced by eitherpropylthiouracil or surgical thyroidectomy. These data cited above seemedto be quite similar to the results obtained in our experiment.GRAD (1957) 2, however, reported that AKR mice rendered hypothyroidby thiouracil developed spontaneous leukemia at a significantly higher ratethan AKR mice rendered hyperthyroid by the administration of thyroxine.KAPLAN (1954)15 has pointed out that although these contrasting data weresignificantly different from each other, neither result differed significantlyfrom the incidence in untreated controls. GRAD2 further concluded thatthe influence of hyper- or hypothyroidism on the incidence of spontaneouslymphatic leukemia of AKR mice depends on what effect these states hadon the body weight of the animals.In our experiment, no significant difference in body weight was notedbetween the radioiodine-treated mice and non-radioiodine-treated mice.Therefore, body weight may not be the important factor in the inductionof leukemia in mice.In 1942, SMITH, WELLS and D'AMOUR16 reported that thyroidectomydid not influence the induction of tumor by methylcholanthrene in rats.However, in their study, methylcholanthrene administration precededthyroidectomy. BIELSCHOWSKY and HALL (1953)3 investigated tumor induc-tion by 2-aminofluorene and its acetylderivatives in thyroidectomized rats.In their experiment, thyroidectomy prior to the administration of the car-cinogens prevented the development of neoplasms of the liver; thyroidec-tomy performed after the administration of the carcinogens did not modifycarcinogenesis. These data, as well as ours, suggest that the time ofthyroidectomy was the critical factor in the induction of neoplasms bycarcinogens.In our experiment, a dose of 300 fJ.C of 11;:1 was used to destroy thyroidfunction. GORBMAN (1947)17 has shown that 100.'lc in normal adult miceproduced almost complete and 200.'lC complete thyroidal destruction. Inaddition, he (1949)18 reported that following doses of radioactive iodinesufficient to cause destruction of most or all of the thyroid, tumorous en-largements were found in the pituitary gland of mice. In our experiment,pituitary gland tumors were noticed in 6 out of 52 mice given radioiodine5Oda and Ida: Influence of thyroid secretion on the in-duction of leukemia inProduced by The Berkeley Electronic Press, 1960Mhyroid Secretion and Leukemia 19only and in 4 out of 74 mice given radioiodine plus methykholanthrene.GOLDBERG and CHAIKOFF (1949)19 have shown that thyroidectomywithout parathyroidectomy can be achieved with intraperitoneal radioactiveiodine, when newborn rats are injected with p31, in a dose of 80 to 150/.lc,or adult rats in a dose ranging from 300 to 875 /.lC (GOLDBERG and CHAI-KOFF 1950)20. In view of these data, it could be assumed that parathyroidfunction in our animals was not significantly influenced by the dose of 300pc.No significant influence of hypothyroidism upon neoplasm was reportedby MORIMOTO (1932)21 BISCHOFF and MAXWELL (1932)22 and VAZQUEZ-LOPEZ (1949)23, using rabbits, rats and R III strain of mice respectively.Since the animal used in these experiments and the treatment which causedhypothyroidism were different from those in our experiment, differentresults might be expected.SOLVITER (1951)24 was among the first to study the effect of radio-thyroidectomy on the survival of tumor bearing mice. No noticeable effectwas found in his experiment. However, his experiment differed from oursin that he used implanted, rather than chemically induced tumors.Recently, NAGAREDA and KAPLAN (1959)25 studied the effect of radio-thyroidectomy and thyroid grafts on the incidence of lymphomas in thethymic implants in thymectomized irradiated C 57BL mice. Hypothyroi-dism significantly inhibited thymic implant tumor development in females;a similar reduction of lymphoma incidence in hypothyroid males was notstatistically significant. In our experiment, only Dba/2 male mice wereused in order to avoid the complication of mammary cancer in evaluationof the incidence of leukemia.SUMMARY1) The influence of thyroid secretion upon the induction of leukemiain Dba/2 male mice by methylcholanthrene was investigated. Radiothyroi-dectomy significantly reduced the incidence of leukemia in these mice.This reduction in incidence did not occur if radiothyroidectomy was per-formed after the administration of the carcinogen.2) Data indicated that hypothyroidism following radiothyroidectomyinterfered with the initiation rather than the promotion of methylcholan-threne-induced-Ieukemogenesis.3) No correlation between incidence of leukemia and body weights inthe mice was noted.ACKNOWLEDGMENTSThe authors gratefully acknowledge the guidance of the late Dr. ArthurKIRSCHBAUM and Dr. Grant TAYLoR.6Acta Medica Okayama, Vol. 14 [1960], Iss. 1, Art. 2http://escholarship.lib.okayama-u.ac.jp/amo/vol14/iss1/220 N. ODA and N. lDABIBLIOGRAPHY1. GRAD, B., BERENSON, J. & CAPLAN, L.: The influence of hyper- and hypothyroi-dism on the incidence of lymphogenous leukemia in AKR mice. Proc. Amer. Ass.Cancer Res. 2, 20, 19552. GRAD, B.: The influence of hyper- and hypothyroidism on the incidence of lym-phatic leukemia of AKR mice. Cancer Res. 17, 226-271, 19573. BIELSCHOWSKY, F. & HALL, W. H.: Carcinogenesis in the thyroidectomized rat.British Journal of Cancer 7, 358-366, 19534. WOLFSON, S. L., DRAKE, J. & BASS, A. D.: Effect of athyreosis on the inductionof rat sarcoma with 3-methylcholanthrene. Growth, 20, 19-28, 19565. STUART-Low, W.: Thyroidectomy and a theory of cancer causation. Lance, 177,Part 2, 1138-1140, 19096. HOHNENBURG, G. L., BULLOCK, F. D., and JOHNSTON, P. J.: The effects of certaininternal secretions on malignant tumors. Arch. lnt. Med. 7, 491-499, 19117. MURoHARA, N.: The relation between the thyroid gland and the growth of thetumor. Trans. Ja. Path. Soc. 20, 658-659, 19308. NISHIDA, S.: An experimental study of the effect of thyroid function to the gro-wth of malignant tumors. Jap. J. of Obst. and Gynec. 18, 195-232, 19359. KOSUGI, T. & KIM, Y. S.: Zur Pathohistologie der Glatze der Kopfhaut und desErgrauens der Kopfhaare. Trans. Jap. Path. Soc. 27, 651-653, 193710. LEVINE, M. & KUGEL, V. H. : Disturbance of the thyroid mechanism and its effectson tumor growth in mice. Am. J. Cancer, 19, 817-828, 193311. Mc JUNKIN, F. A., TEMPUToN, R. D., and KRAVEC, F. G.: Resistance of thyroidec-tomized rats to growth of a spindle-cell sarcoma. Proc. Soc. Exp. BioI. and Med.34, 801-804, 193612. DARGENT, M., VIALLIER, J. and GUINET, E. : lnfuence de la secretion thyroidiennedur la croissance des tumeurs. Ann. Inst. Pasteur, 81, 357-361, 1951 (fromWOLFSON'S paper)13. KIRSCHBAUM, A. The role of hormones in cancer: Laboratory animals (sympo-sium; Role of hormones in the origin and control of abnormal and neoplasticgrowth). Cancer Res. 17, 432-457, 195714. MORRIS, D. M., WOLFF, E. F. & UPTON, A. C.: The influence of the thyroid glandon the survival of rats and mice bearing transplanted lymphoid leukemia. CancerRes. 17, 325-328, 195715. KAPLAN, H. S., NAGAREDA, C. S. & BROWN, M. B.: Endocrine factors and radia-tion-induced lymphoid tumors of mice. Recent Progress in Hormone Research, 10,293-338, 195416. SMITH, D. L., WELLS, J. A. and D'AMouR, F. E. : The relationship of the endocrinesystem to carcinogenesis. Cancer Res. 2, 40-44, 194217. GORBMAN, A.: Effect of radiotoxic dosages of p:JJ upon thyroid and contiguoustissue in mice. Proc. Soc. Exp. BioI. and Med. 66, 212, 194718. GORBMAN, A.: Tumorous growth in the pituitary and trachea following radiotoxicdosages of 11::]. Proc. Soc. Exp. BioI. and Med. 71, 237-240, 194919. GOLDBERG, R. C. and CHAIKOFF, I. L.: A simplified procedure for thyroidectomyof the new-born rat without concomitant parathyroidectomy. Endocrinology, 45,64, 194920. GOLDBERG, R. C. & CHAIKOFF, K. L. : Histopathological changes induced in thenormal thyroid and other tissues of the rat by internal radiation with various dosesof radioactive iodine. Endocrinology, 46, 72-90, 19507Oda and Ida: Influence of thyroid secretion on the in-duction of leukemia inProduced by The Berkeley Electronic Press, 1960Thyroid Secretion and Leukemia 2121. MORIMOTO, S.: Influence of thyroidectomy on tar-epithelioma. Acta Dermat. 19,185-186, 193222. BlscHOFF, F. & MAXWELL, L. c.: The effect of glandular extirpation upon thegrowth of transplantable tumors. J. Pharmacol. and Exper. Therapy. 46, 51-62,193223. VAZQUEZ-LOPEZ, E. : The effects of thiourea on the development of spontaneoustumors on mice. British Journal of Cancer. 3, 401-414, 194924. SOLVITER, H. A.: The effect of complete ablation of thyroid tissue by radioactiveiodine on the survival of tumor-bearing mice. Cancer Res. 11, 447-449, 195125. NAGAREDA, C. S. & KAPLAN, H. S.: Effect of hypothyroidism and thyroid graftson lymphoid tumor development in irradiated C 57 BL mice. Cancer Res. 19, 292-296, 19598Acta Medica Okayama, Vol. 14 [1960], Iss. 1, Art. 2http://escholarship.lib.okayama-u.ac.jp/amo/vol14/iss1/2

Influence of thyroid secretion on the induction of leukemia in Dba mice by methylcholanthrene

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Influence of thyroid secretion on the in­duction of leukemia in Dba mice by methylcholanthrene

Abstract

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Influence of thyroid secretion on the induction of leukemia in Dba mice by methylcholanthrene