Cell-mediated immunity was studied in 23 cases of advanced gastrointestinal cancer. The patients received levamisole at 150 mg/day for three consecutive days each week for four weeks. In cases at the terminal stage of gastrointestinal cancer, the blastformation rate of peripheral blood lymphocytes against phytohemagglutinin (PHA) after the administration of levamisole showed a slight increase, but cases with blastformation rates over 40% increased markedly three or four weeks after the initial administration of levamisole. The peripheral blood lymphocyte count showed little change in these cases.</p

Miwa, Hiroaki

Orita, Kunzo

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Reactivating effect of levamisole on cell-mediated immunity in gastrointestinal cancer patients

Okayama University Scientific Achievement Repository

Acta Medica OkayamaVolume 31, Issue 5 1977 Article 5OCTOBER 1977Reactivating effect of levamisole oncell-mediated immunity in gastrointestinalcancer patientsHiroaki Miwa∗ Kunzo Orita†∗Okayama University,†Okayama University,Copyright c©1999 OKAYAMA UNIVERSITY MEDICAL SCHOOL. All rights reserved.Reactivating effect of levamisole oncell-mediated immunity in gastrointestinalcancer patients∗Hiroaki Miwa and Kunzo OritaAbstractCell-mediated immunity was studied in 23 cases of advanced gastrointestinal cancer. The pa-tients received levamisole at 150 mg/day for three consecutive days each week for four weeks. Incases at the terminal stage of gastrointestinal cancer, the blastformation rate of peripheral bloodlymphocytes against phytohemagglutinin (PHA) after the administration of levamisole showed aslight increase, but cases with blastformation rates over 40% increased markedly three or fourweeks after the initial administration of levamisole. The peripheral blood lymphocyte countshowed little change in these cases.∗PMID: 146404 [PubMed - indexed for MEDLINE] Copyright c©OKAYAMA UNIVERSITYMEDICAL SCHOOLActa Med. Okayama 31, 325-329 (1977)REACTIVATING EFFECT OF LEVAMISOLE ON CELL~MEDIATED IMMUNITY IN GASTROINTESTINALCANCER PATIENTSHiroaki MIWA and Kunzo ORITADepartment oj Surgery, Okayama University Medical School,Okayama 700, Japan (Director: Prof. S. Tanaka)Received April 14, 1977Abstract. Cell-mediated immunity was studied in 23 cases of ad-vanced gastrointestinal cancer. The patients received levamisole atl50mgjday for three consecutive days each week for four weeks. Incases at the terminal stage of gastrointestinal cancer, the blastforma-tion rate of peripheral blood lymphocytes against phytohemagglutinin(PHA) after the administration of levamisole showed a slight increase,but cases with blastformation rates over 40% increased markedly threeor four weeks after the initial administration of levamisole. The pe-ripheral blood lymphocyte count showed little change in these cases.Recently, the progress and prognosis of carcinoma in cancer patients havebeen investigated immunologically (1, 2). We have previously reported that cell-mediated immunity in gastrointestinal cancer patients reflected cancer progress,and that it was helpful in assessing the possibility of curative tumor resection andthe prognosis (3-5).Mathe et at. (6) used bacille Calmette Guerin (BCG) and demonstrated theefficiency of active immunotherapy of acute lymphoblastic leukemia in man forthe first time. Bast et at. (7) reported the effectiveness of BCG immunotherapyfor melanoma.Various kinds of immunostimulants have been investigated for the purposeof cancer immunotherapy.In the present study, we used levamisole, a kind of immunostimulant, forgastrointestinal cancer patients and found that levamisole was somewhat effec-tive in activating cell-mediated immunity in cases of terminal stage of cancerpatients.MATERIALS AND METHODSThe study comprised 23 cases of advanced gastrointestinal cancer (threecases with curative resection, three of noncurative resection, and 17 of non-resectable and recurrent cases) who received levamisole for its antitumor effectand for the treatment of leukopenia following anticancer therapy.Levamisole was administered orally in a dosage of l50mgjday for threeconsecutive days a week for four weeks.3251Miwa and Orita: Reactivating effect of levamisole on cell-mediated immunity inProduced by The Berkeley Electronic Press, 1977326 H. MIWA and K. ORITAAs a parameter of cell-mediated immunity, the blastformation rate wasdetermined each week after levamisole administration. Peripheral lymphocytecounts were also performed.The blastformation rate of peripheral blood lymphocytes against PHA wasdetermined by the morphological procedure described previously (3-5).RESULTSIn 23 cases given levamisole for four consecutive weeks, the blastformationrate was 48.8± 17.0% in the third week compared with 39.2± 18.2% beforelevamisoleadministration (p=O.I) and 47.4± 14.4% in the fourth week (0.1<p<0.5). This indicated a slight rise in the latter half of the month after levami-sole administration (Fig. 1). Cases with blastformation rates over 40% comprised47.6% of the entire group before levamisole administration, and increased to80% of the group by four weeks after levamisole administration (Table 1). Theperipheral blood lymphocyte count showed little variation throughout the courseof levamisole administration (Fig. 1).7060 M@30 E~ M.....Q) 50 10..... ~colo.40 ~"2t: ::J0 015 U..... 30 16co 22E Q)20 .....lo. >-0 20 U'+- n=21 o 1.....en .c: 22 18co 0- n;:22 20 17EOJ 10 >--I2 3 4 2 3 4Weeks after levamisoleadministrationFig. 1. Blastformation rate and lymphocyte count after administration of levami-sole. Twenty-three cases received levamisole, p.o., 150 mg/day three consecutive daysin a week for four weeks. Data indicate mean ± S. D.2Acta Medica Okayama, Vol. 31 [1977], Iss. 5, Art. 5http://escholarship.lib.okayama-u.ac.jp/amo/vol31/iss5/5Effect of Levamisole on Gastrointestinal CancerTABLE 1. PERCENT OF CASES OVER 40% IN BLASTFORMATION RATE AFTERADMINISTRATION OF LEVAMISOLE 4 CONSECUTIVE WEEKS327Weeks after levamisoleadministrationo1234Number ofcases10/21*19/228/2011/1612/15Percent ofcases47.663.640.068.880.0* Number of cases over 40% in blastformation rate/number of cases examined.A comparison of the results before levamisole administration with thoseafter levamisole administration showed that the blastformation rate rose slightlyin the first and the third weeks but dropped in the second and the fourth weeksafter levamisole administration (Table 2).TABLE 2. PERCENT OF CASES SHOWING HIGHER VALUES AFTER LEVAMISOLEADMINISTRATION THAN VALUES BEFORE THE ADMINISTRATIONWeeks after levamiso1e administrationExamination2 3 4------- --------Blastformation rate (12/20)* 60.0 ( 6/18) 33.3 ( 9/16) 56. 3 (7/15) 46.7%Lymphocyte count (12/21) 57.1 (11/19) 57.9 (14/17) 82.4 (6/16) 37.5%----------_ ..._---* Number of cases showing higher values after 1evamiso1e administration than valuesbefore the administration/number of cases examined.Peripheral blood lymphocyte counts after the start of levamisole administra-tion in each individual rose until, and mostly during, the third week, but de-creased in the fourth week (Table 2).DISCUSSIONThe interest around the world in nonspecific and specific immunotherapy asan adjunct to cancer therapy has been focused on using BGG. Recently, levami-sole has also been used for its activation of cell-mediated immunity and for itsantitumor effect.Renoux and Renoux (8) showed that levamisole activates cell-mediated im-munity in vivo. Since then, there have been several reports of the in vitro or in vivoactivation of cell-mediated immunity by, and the antitumor effect of, levamisole(9-13).Levamisole, chemically L-2, 3, 5, 6,-tetrahydro-6-phenyl-imidazo (2, I-b)thiazole hydrochloride, is an isomer of tetramisole. Levamisole acts as a stimu-3Miwa and Orita: Reactivating effect of levamisole on cell-mediated immunity inProduced by The Berkeley Electronic Press, 1977328 H. MIWA and K. ORITAlant in those patients who have decreased cell-mediated immunity. This im-munostimulation consists of four processes: 1. increase of the peripheral bloodlymphocyte count, 2. stimulation of T lymphocytes, 3. increase of reactivity todinitrochlorobenzene (DNCB) or purifed protein derivatives (PPD) 4. anti-tumoreffect resulting from the above I. to 3. processes. Contradictory reports haveappeared of the effect of levamisole on the peripheral lymphocyte count. Chanet al. reported a definite increase in the peripheral lymphocyte count due to levam-isole (14), while Levo et al. contended that it did not increase the lymphocytecount but increased the percentage of active T lymphocytes (10). The effect oflevamisole on the stimulation of T lymphocytes was an increased blastformationrate when lymphocytes were cultured with mitogen or antigen in vitro (II).Various workers have shown that, when peripheral blood lymphocytes werecultured with both levam:sole and PHA, Pockeed mitogen (PWM), or the lym-phocytes of another person, the blastformat;on rate increased (11,12). However,this only occurred with certain concentrations of levam;sole (11) and did notoccur without mitogen. In our results, the peak effect of levamisole (increasedblastformation rate against PHA) was in the third week after levamisole admin-istration. The value, however, was only significant at the p = 0.1 level.The administration of levamisole was associated with an increase in delayedhypersensitivity in cancer patients. Levo et al. (15) reported that the admin:stra-tion of levamisole to patients with Hodgkin's disease resulted in the convers'on oftheir skin tests from negative to positive. Rojas et al. (16) also reported thatwhen the skin reactions to DNCB and PPD were compared in two groups ofbefore levamisole treatment and after 20 months of follow-up, levamisole treat-ment was associated with an increase in positive DNCB tests, candida tests andPPD tests compared with pretreatment in the same group. Similar results havebeen reported by Tripodi et al. (13) and Verhaegen et al. (9).In animal tumors, as well as in some human neoplasms, levamisole maylead to antitumor effects (16, 17).The administration of levamisole clinically is not uniform, but many au-thors use the drug in a dose of 150 mg/day for three consecutive days a week,continued every other week. There is as yet no report giving levamisole 150mg/day for three consecutive days a week for four weeks.There is no major toxicity attributable to levamisole. In our study, twopatients complained of urticaria and one patient complained of nausea. Theseside effects disappeared soon after withdrawal of levamisole.Acknowledgment. The authors wish to express their profound thanks to Professor SanaeTanaka for his painstaking proof reading and kind guidance throughout this work.4Acta Medica Okayama, Vol. 31 [1977], Iss. 5, Art. 5http://escholarship.lib.okayama-u.ac.jp/amo/vol31/iss5/5Effect of Levamisole on Gastrointestinal CancerREFERENCE3291. Mekori, T., Sher, S. and Robinson, E.: Supression of the mitogenic response to phyto-hemagglutinin in malignant neoplasia. j. Nat!. Cancer lnst. 52, 9-12, 1974.2. Bolton, P. M., Mander, A. M., Davidson, J. M., james, S. L., Newcombe, R. G. andHughes, L. E.: Cellular immunity in cancer. Br. Med. j. 3, 18-20, 1975.3. Miwa, H., Fukuda, H., Ogawa, K., Orita, K. and Tanaka, S.: Blastformation rate oflymphocytes, tuberculin and DNCB test and cancer progress. Geka 36, 477-482, 1974 (injapanese).4. Orita, K., Miwa, H., Fukuda, H., Yumura, M., Uchida, Y., Mannami, T., Konaga, E. andTanaka, S.: Preoperative cell-mediated immune status of gastric cancer patients. C'l'lCer38, 2343-2348, 1976.5. Miwa, H., Or ita, K. and Tanaka, S.: B1astformation rate of peripheral blood lympho-cytes before and after recurrence of cancer. Ada Med. Okayarna 30, 379-383, 1976.6. Mathe, G., Amiel, J. L., Schwarzenberg, L., Schneider, M., Cattan, A., Sch1umberger,J. R., Hayat, M. and Vassal, F.: Active immunotherapy for acute lymphoblastic leuke-mia. Lrzncet 1, 697-699, 1969.7. Bast, R. c., Zbar, B., Borsos, T. and Rapp, H. J.: BCG and cancer. N. Eng'.,T. Med.290, 1458-1469, 1974.8. Renoux, G. and Renoux, M.: Restoration par Ie phenylimidothiazole de 1a responseimmuno10gique des souris agees. C. R. Acad. Sc. Paris 274, 3034-3035, 1972.9. Verhaegen, H., Cree, J. DE., Cock, W. DE. and Verbruggen, F.: Levamisole and immuneresponse. N. Engl.]. Med. 22, 1148, 1973.10. Ramot, B., Biniaminov, M., Sheham, CH. and Rosenthal, B.: Effect of 1evamiso1e onE-rosette-forming cells in vivo and in vitro in Hodgkin's disease. N. Eng!.]. Med. 294,809-811, 1976.11. Sampson, D. and Lui, A.: The effect of 1evamisole on cell-mediated immunity andsupressor cell function. Cancer Res. 36, 952-955, 1976.12. Copeland, D., Stewart, T. and Harris, j.: Effect of 1evamiso1e (NSC-177023) on in vitrohuman lymphocyte transformation. Cancer Chemotherapy Rep. 58, 167-170, 1974.13. Tripodi, D., Leon, PH. D., Parks, C. and Brugmans, jo.: Drug-induced restoration ofcutaneous delayed hypersensitivity in anergic patients with cancer. N. Engl. j. Med.289,354-357, 1973.14. Chan, S. H., Lee. S. K. and Simons, M. J.: Levamiso1e augumentation of lymphocytehyporesponsiveness to phytohemagglutinin in patients with pulmonary tuberculosis.Proc. Soc. Exp. Bioi. Med. 151, 716-719, 1976.15. Levo, Y., Rotter, V. and Ramot, B.: Restoration of cellular immune response by leva-misole in patients with Hodgkin's disease. Biomedicine 23, 198-200, 1975.16. Rojas. A. F., Mickiewicz, E., Feierstein, j. N., Glait, H. and Olivali, A. J.: Levamisolein advanced human breast cancer. Lancet 1, 211-215, 1976.17. Study group for bronchogenic carcinoma: Immunopotentiation with levamisole in re-sectable bronchogenic carcinoma.: A double-blind controlled trial. Br. Med. j. 23, 461-468, 1975.5Miwa and Orita: Reactivating effect of levamisole on cell-mediated immunity inProduced by The Berkeley Electronic Press, 1977

Reactivating effect of levamisole on cell-mediated immunity in gastrointestinal cancer patients

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