Neocarzinostatin (NCS), an antibiotic with a high
molecular weight, showed an inhibittory effect on Rauscher mouse leukemia. In normal mice, no significant changes were found in peri· pheral blood pictures except a tendency of lymphocytopenia, when O. 05mg/kg/day and O.50mg/kg/day of NCS were injected intraperi. toneally to two groups of mice for three days. On the other hand,
peripheral nucleated cells of Rauscher leukemic mice decreased after intraperitoneal administration of NCS in a dose over O.25mg/kg/day for three days. The cells affected by NCS were mainly erythroblasts and smudged cells. Spleens of Rauscher leukemic mice treated with NCS have been reduced in weight, and histological examinations of
livers showed a signicant decrease of infiltrating cells. In three groups treated with 0.25mg/kg/day of NCS for seven days, O.25mg/kg/day for three days and O.50mg/kg/day for three days, the.5()% survival time was longer than in the control group. Particularly, the 50% survival time in Rauscher leukemic mice treated with 0.50 mg/kg/day for three days was over twice that of the control group.</p

Hiraki, Kiyoshi

Irino, Shozo

Kitajima, Koichi

Mikochi, Hiroshi

Moriwaki, Hiroshi

Sakato, Junya

Takahashi, Isao

Okayama University Scientific Achievement Repository

Acta Medica OkayamaVolume 28, Issue 4 1974 Article 5AUGUST 1974Antitumor activity of neocarzinostatin, effecton Rauscher leukemia in miceIsao Takahashi∗ Junya Sakato† Hiroshi Mikochi‡Hiroshi Moriwaki∗∗ Koichi Kitajima††Shozo Irino‡‡ Kiyoshi Hiraki§∗Okayama University,†Okayama University,‡Okayama University,∗∗Okayama University,††Okayama University,‡‡Okayama University,§Okayama University,Copyright c©1999 OKAYAMA UNIVERSITY MEDICAL SCHOOL. All rights reserved.Antitumor activity of neocarzinostatin, effecton Rauscher leukemia in mice∗Isao Takahashi, Junya Sakato, Hiroshi Mikochi, Hiroshi Moriwaki, KoichiKitajima, Shozo Irino, and Kiyoshi HirakiAbstractNeocarzinostatin (NCS), an antibiotic with a high molecular weight, showed an inhibittoryeffect on Rauscher mouse leukemia. In normal mice, no significant changes were found in peri·pheral blood pictures except a tendency of lymphocytopenia, when O. 05mg/kg/day and O.50mg/kg/dayof NCS were injected intraperi. toneally to two groups of mice for three days. On the other hand,peripheral nucleated cells of Rauscher leukemic mice decreased after intraperitoneal administra-tion of NCS in a dose over O.25mg/kg/day for three days. The cells affected by NCS were mainlyerythroblasts and smudged cells. Spleens of Rauscher leukemic mice treated with NCS have beenreduced in weight, and histological examinations of livers showed a signicant decrease of infil-trating cells. In three groups treated with 0.25mg/kg/day of NCS for seven days, O.25mg/kg/dayfor three days and O.50mg/kg/day for three days, the.5()% survival time was longer than in thecontrol group. Particularly, the 50% survival time in Rauscher leukemic mice treated with 0.50mg/kg/day for three days was over twice that of the control group.∗PMID: 4280236 [PubMed - indexed for MEDLINE] Copyright c©OKAYAMA UNIVERSITYMEDICAL SCHOOLActa Med. Okayama 28,271-276 (1974)ANTITUMOR ACTIVITY OF NEOCARZINOSTATIN, EFFECTON RAUSCHER LEUKEMIA IN MICEIsao TAKAHASHI, Junya SAKATO, Hiroshi MIKOCHI, Hiroshi MORIWAKI,Koichi KITAJIMA, Shozo IRINO and Kiyoshi HIRAKIDepartment of Internal Medicine, Okayama University Medical School,Okayama, Japan (Director: Prof K. Hiraki)Received for publication, December 26, 1973Abstract: Neocarzinostatin (NCS), an antibiotic with a highmolecular weight, showed an inhibittory effect on Rauscher mouseleukemia. In normal mice, no significant changes were found in peri·pheral blood pictures except a tendency of lymphocytopenia, whenO. 05mg/kg/day and O.50mg/kg/day of NCS were injected intraperi.toneally to two groups of mice for three days. On the other hand,peripheral nucleated cells of Rauscher leukemic mice decreased afterintraperitoneal administration of NCS in a dose over O.25mg/kg/dayfor three days. The cells affected by NCS were mainly erythroblastsand smudged cells. Spleens of Rauscher leukemic mice treated withNCS have been reduced in weight, and histological examinations oflivers showed a signicant decrease of infiltrating cells. In three groupstreated with 0.25mg/kg/day of NCS for seven days, O.25mg/kg/dayfor three days and O.50mg/kg/day for three days, the.5()% survivaltime was longer than in the control group. Particularly, the 50%survival time in Rauscher leukemic mice treated with 0.50 mg/kg/dayfor three days was over twice that of the control group.Neocarzinostatin (NCS), a new antitumor subutance with a high mole-cular weight, was first isolated from culture filtrates of Streptomyces carzi-nostaticus (1). Studies on the effect of NCS in cultures of Sarcina lutea andHeLa cells revealed specific inhibition of the synthesis of DNA followed byDNA degradation (2). Up to now, the antitumor effect of NCS has beenrecognized in various tumors in mice; sarcoma 180, Ehrlich carcinoma,hepatoma 134 and L-121O (3, 4). However, the effect on virus-inducedleukemic mice has never been reported. The present paper describes a studyon the effect of NCS on Rauscher leukemic mice.MATERIALS AND METHODSMice used were 1. 5-2. O-month old BALB/c male mice weighing 18-20g.Leukemic changes were confirmed through changes in peripheral blood andsplenomegaly at the fourth week after the inoculation of 0.2 ml spleen homo.genates which were obtained from maintaining leukemic mice and suspendedin 20% physiological saline solution. NCS (Lot. 730559 for clinical trial) was2711Takahashi et al.: Antitumor activity of neocarzinostatin, effect on Rauscher leukemProduced by The Berkeley Electronic Press, 1974272 I. TAKAHASHI, J. SAKATO, H. MIKOCHI, H. MORIWAKI, K. KITAjIMA, S.lRIO, K. HIRAKIkindly supplied by the Kayaku Antibiotics Research Laboratory (Tokyo).Fresh solution of NCS was prepared for each experiment and 0.2 ml of thesolution was injected once daily for three or seven days intraperitoneally.Dosage of injected NCS was as follows; O.05mg/kg/day, O.25mg/kg/day,O.50mg/kg/day and l.OOmg/kg/day. Hematological examinations included nuc-leate cell, red blood cell and thrombocyte counts in peripheral blood. Changesin the differentials of peripheral nucleate cells, spleen weights and histologicalfindings of livers were examined in Rauscher leukemic mice treated withO.50mg/kg/day of NCS for three days. The effect of NCS on survival time wasstudied in two groups; one group was treated with each dose of NCS for threedays and another group for seven days.RESULTS AND DISCUSSIONEffects of NCS on normal mice are shown in Fig 1. No significantnucleated cell red blood cell thrombocytee ] "0E E0 §u u UA A A0,100/0Fig. 1. Effect of Neocarzinostatin on peripheral blood in nor-mal BALB/c miceA: 0.05 mg/kg of NCS was injected for 3 days, i. p, B: 0.50 mg/kgof NCS was injected for 3 days, i. p, Cell Count (C. C) after injec-tion of NCS/C. C before injection X 100changes in peripheral nucleated cell, red blood cell and thrombocyte countswere found in normal mice injected with O.05mg/kg/day and O.50mg/kg/dayof NCS for three days. Neither any significant changes in the differentialsof peripheral nucleated cells were recognized, except for a tendency oflymphocytopenia in mice injected with O. 50mg/kg/day of NCS. Effects ofNCS on peripheral nucleate cell counts (NCG) in Rauscher leukemic mice areshown in Fig. 2. In non-treated Rauscher leukemic mice, NCC increased upto 128. 3±27. 7% for tnree days. On the other hand, they decreased signi-ficantly after injection of NCS in a dose more than O.25mg/kg/day for three2Acta Medica Okayama, Vol. 28 [1974], Iss. 4, Art. 5http://escholarship.lib.okayama-u.ac.jp/amo/vol28/iss4/5Antitumor Efects of Neocarzinostatin0,150 /0onotreatmentFig. 2. Effect of Neocarzinostatin on peripheral nucleated cell count inRauscher leukemic miceNCS, injected intraperitoneally for 3 days, • NCC after treat-ment/NCC before treatment X 100%273days. In Rauscher leukemic mice treated with O. 05mgjkgjday of NCS forthree days, NCe were increased slightly although the ratio of the increasetended to be lower than in the non-treated group. Changes in the differen-tials of peripheral nucleated cells are demonstrated in Figs. 3 and 4. It isNO.89 NO. 84 NO. 95 NO. 43~ Erythroblast c:=:=I Granulocyte __ lymphocyte_ OthersFig. 3. Effect of Neocarzinostatin on differentials of peri-pheral blood in Rauscher leukemic mice NCS, 0.50 mg/kg/dayx3 days, i. p3Takahashi et al.: Antitumor activity of neocarzinostatin, effect on Rauscher leukemProduced by The Berkeley Electronic Press, 1974274 1. TAKAHASHI, J. SAKATO, H. MIKOCHI, H. MORIWAKI, K. KITAJIMA, S.IRINo, K. HIRAKIsmudgedcell !nucleated cellNCS: 0.50",g' kg, i. p tor 3 days••SpleenW ight.mgNCS; 0.50mg 'kg 'day, for 3 day. i.p96500,__--'20001000•non treatedRlMtreatedRlMFig. 4. Smudged cell in peripheral blood Fig. 5. Effect of Neocarzinostatin onspleen weight in Rauscher leuke-mic micepostulated that affected cells with NOS are mainly composed of erythroblastsand smudged cells. We have already reported hematological findings inRauscher leukemic mice (5). In BALB/c mice inoculated with Rauscherleukemic virus (RLV), erythroblasts begin to appear in the peripheral bloodat around the second or third week and erythroblasts and smudged cells aregradually increased in quantity as spleen becomes larger. Histologically,there are marked splenomegaly infiltration, and proliferation of erythro-blasts in hematopoietic organs. In Rauscher leukemic mice treated withO. 5mg/kg/day of NOS for three days, the significant decrease in the spleenweight with a decrease in number of peripheral nucleated cells was recog-nized (Fig. 5). Infiltrating cells were also decreased in the liver of this group(Figs. 6, 7).Effects of NOS on survival time are shown in Fig. 8. Each group wascomposed of five Rauscher leukemic mice. When O. 25mg/kg/day, 0.50mg/kg/day and 1. OOmg/kg/day of NOS was given to three groups for seven days,a slight prolongation of 50% survival time was recognized only in the grouptreated with O. 25mg/kg/day of NOS. In the group treated with 1. OOmg/kg/day of NOS, Rauscher leukemic mice began to die at day 2 after treatmentand all mice have died during treatment. On the other hand, when 0.25mg/kg/day or 0.50mg/kg/day of NOS was given for three days, the 50%4Acta Medica Okayama, Vol. 28 [1974], Iss. 4, Art. 5http://escholarship.lib.okayama-u.ac.jp/amo/vol28/iss4/5Antitumor Efects of NeocarzinostatinNCS, i,P for 7 days_~,-k9 _275~ 5 10~ ~1.00m9/kg;;; I I control'~ ~Q.50mg/kgtil~0.25mg/kg~ooII> NCS,i,p for 3 days15 days10! [------- _"1 :comrol;;; ~,;.O.05m9/1(g'5~~O,25mg'kg~~0.50m9'kg°0II>Fig. 8. Effect of Neocarzinostatin on survivaltime in Rauscher leukemic micesurvival times were longer than in the control. Particularly, the 50%survival time of Rauscher leukemic mice treated with O. 50mgjkg/day ofNCS was over twice that of the control. From these results, it can be saidthat NCS has also an influence on Rauscher leukemic mice. However, thequestion whether or not NCS acts on RLV remains to be solved. Furtherstudies of antitumor effects of NCS on Rauscher leukemic mice are necessary.REFERENCES1. ISHIDA, N., KUMAGAI, K., MIYAZAKI, K. and ITo, M.: Carzinostatin, a new anti-tumc,rsubstance. Gann, 51 (Supple), 56, 19602. ONO, Y., WATANABE, T. and ISHIDA, N.: Mode of action of neocarzinostatin; Inhibitionof DNA synthesis and degradation of DNA in Sarcina lutea. Biophys. Biocpem. Acta. 119,46, 19663. KUMAGAI, K.: Antitumor activity of carzinostatin. ]. Antbiotics. Ser. A. 15, 53, 19624. BRADNER, W. T. and D. J. HUTCHINSON: Neocarzinostatin (NCS·69856): Antitumor anti-biotic effective against ascitic leukemia L 1210 in mice. Cancer Chemoth. Rep. SO, 79, 19665. SEZAKI, T., TAKAHASHI, I., NAGAO, T., KlTAJIMA, K., IRINO, S. and HIRAKI, K.: Initialpictures, particularly changes in erythroid series, in mice in mice inoculated withRauscher leukemic virus. Acta Hemat. lap. 34, 296, 1971 (in Japanese)5Takahashi et al.: Antitumor activity of neocarzinostatin, effect on Rauscher leukemProduced by The Berkeley Electronic Press, 1974276 1. TAKAHASHI,]. SAKATO, H. MIKOCHI, H. MORIWAKI, K. KITA.JIMA, S. IRINO, K. HIRAKIFig. 6. Liver of Rauscher leukemic mouseFfg. 7. Liver of Rauscher leukemic mouse Ireated with O.50mg/kg/day of Neocarzino-stalin for 3 days Ii. pi6Acta Medica Okayama, Vol. 28 [1974], Iss. 4, Art. 5http://escholarship.lib.okayama-u.ac.jp/amo/vol28/iss4/5

Antitumor activity of neocarzinostatin, effect on Rauscher leukemia in mice

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Antitumor activity of neocarzinostatin, effect on Rauscher leukemia in mice

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