The Journal of Kansai Medical University

Sensitivity Test for Anti-Cancer Drugs by Tumor Cell Cultivation on the Chorio-allantoic Membrane of Embryonated Chicken Eggs and its Clinical Application in the Treatment of Leukemia

Part I. Yoshida Sarcoma Cell Cultivation on the Chorioallantoic Membrane of Embryonated Chicken Eggs and its Influence on the Tumor Cells

Terutoshi KOKAWA

1971 Volume 23 Issue 2 Pages 177-194
Published: June 20, 1971
Released on J-STAGE: February 19, 2013

DOIhttps://doi.org/10.5361/jkmu1956.23.2_177

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A series of experiments were designed in order to estimate the validity of cultivation methods for evaluating the effectiveness of anti-cancer drugs aginst human malignant tumor diseases involving the leukemias.
In this experiment, Yoshi da Sarcoma (YS) cells inoculated on the chorio-allantoic membrane (CAM) were examined for cultivation influence, especially as to growth rate by using the radio-autographic method.
Results:
1) Macr oscopical tumors were obtained in all cases when 7.5x 10⁵ or more cells had been inoculated in each 10 days old egg. The mean weight of the tumors was 1224.5±269.3mg.
2) Up to the third generation of the serial passage, no remarkable differences were recognized in tumor histology, growth rate, reaction to anti-cancer drugs, or the rate of successful reinoculation to rats; but after the fifth generation, the reinoculation rate was slightly depressed.
3) The labeling index by tritium thymidine (³H-TdR) of YS cells cultivated 48 hours on the CAM of the embryonated chicken eggs was 45.0%, which was similar to that of YS cells cultivated in the peritoneal cavity of rats.
4) The average silver grain number of YS cells labeled with ³H-TdR after cultivation on the CAM of embryonated eggs decreased in 48 hours at almost the same rate as that of YS cells cultivated in the peritoneal cavity of rats.
5) In conclusion: Since the properties of tumor cells cultivated on the CAM hardly undergo any change for at least three generations, the worth of in ovo cultivation merits recognition in the evaluation of anti-cancer drugs.

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Sensitivity Test for Anti-Cancer Drugs by Tumor Cell Cultivation on the Chorio-allantoic Membrane of Embryonated Chicken Eggs and its Clinical Application in the Treatment of Leukemia

Part II. Growth Inhibition of Yoshida Sarcoma Cells by Anti-Cancer Drugs Injected into the Yolk Sack

Terutoshi HOKAWA

1971 Volume 23 Issue 2 Pages 195-215
Published: June 20, 1971
Released on J-STAGE: February 19, 2013

DOIhttps://doi.org/10.5361/jkmu1956.23.2_195

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In this experiment, observations were made on the effect of anti-cancer drugs on the growth of chicken embryos as well as on the proliferation of tumor cells cultivated on the CAM.
Re sults:
1) No re markable deviations were found in the weights of the chicken embryos or in those of the cultivated tumors in eggs whose weight range was from 50.0 to 64.9g.
2) As to the anti-cancer drugs examined (5-fluorouracil, cyclophosphamide, cytosine arabinoside, bleomycin, daunomycin, chromomycin A₃, and mitomycin C), their maximum toleration doses for 13-14 days old non-tumor eggs were commonly about 1-2 per cent of those usually given to human adults.
3) Embryos of 13-14 days inc ubation were found to be able to activate cyclophosphamide and to inactivate chromomycin A3 as effectively as other experimetal animals.
4) yolk sack injection of the above mentioned anticancer drugs could inhibit the growth of the YS cells cultivated on the CAM, thus yielding results similar to those obtained by the author using the ip (intraperitoneal) - ip system in rats and to those previously reported by other authors.
5) The toxicity of β-methasone to chicken embryos was so remarkable that an evaluation of its anti-cancer effect was impossible to obtain.
6) The above mentioned results testify to the aptitud e of the in ovo sensitivity test for anti-cancer drugs as an adequate in vivo test system.

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Sensitivity Test for Anti-Cancer Drugs by Tumor Cell Cultivation on the Chorio-allantoic Membrane of Embryonated Chiken Eggs and its Clinical Application in the Treatment of Leukemia

Part III. The Effect of Anti-Cancer Drugs on the Incorporation of Tritiated Thymidine and Tritiated Uridine by Yoshida

Terutoshi KOKAWA

1971 Volume 23 Issue 2 Pages 216-238
Published: June 20, 1971
Released on J-STAGE: February 19, 2013

DOIhttps://doi.org/10.5361/jkmu1956.23.2_216

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Experiments were designed in order to study autoradiographically the effects of anticancer drugs on DNA and RNA synthesis in YS cells cultivated on the CAM of embryonated eggs. On the other hand, the blood levels of anti-cancer drugs in the chicken embryos were estimated by utilizing their anti-microbial activities (“Band culture method”, OKUBO).
Results
1) Cyclophosphamide inhibited markedly and mitomycin C moderately the thymidine incorporation by YS cells, while cytosine arabinoside did not affect it. As to the uridine incorporation by YS cells, daunomycin and 5-fluorouracil showed marked inhibition, while β -methasone and chromomycin A₃ showed no effect.
2) The peak levels of each anti-cancer drug in the serum of 13-14 days old chicken embryos after yolk sack injection of 100mcg mitomycin C,5mg 5-fluorouracil,800mcg bleomycin, or 1mg daunomycin were 0.8mcg/ml,160mcg/ml,11 mcg/ml, and 0.45mcg/ml respectively; while the administration of 50mcg chromomycin A₃ yielded no detectable serum level (< 0.1mcg/ml). The kinetics of these anti-cancer drugs in the chicken embryos was discussed.

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Sensitivity Test for Anti-Cancer Drugs by Tumor Cell Cultivation on the Chorio-allantoic Membrane of Embryonated Chicken Eggs and its Clinical Application in the Treatment of Leukemia

Part IV. The Cultivation of Human Leukemia Cells on the Chorio-allantoic Membrane of Embryonated Eggs and a Sensitivity Test

Terutoshi KOKAWA

1971 Volume 23 Issue 2 Pages 239-257
Published: June 20, 1971
Released on J-STAGE: February 19, 2013

DOIhttps://doi.org/10.5361/jkmu1956.23.2_239

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Five million to forty million leucocytes taken from the Peripheral blood of leukemia patients were inoculated on to the CAM of 7 to 13 days old eggs. More than 60% of the eggs inoculated with 20×10⁶ leucocytes showed tumor formation six days after inoculation, but most of these tumors were necrotized nine to twelve days after inoculation. Inoculation of leukemia cells previously labeled with tritiated thymid ine on to the CAM and labeling of the inocuated cells on the CAM by yolk sack injection of tritiated thymidine revealed that the inoculated leukemia cells survived and proliferated on the CAM for at least 48 to 72 hours.
Tests to detect leukemia cell sensitivity to anti-cancer drugs were designed and carried out by applying the inhibitory effects of these drugs on tritiated thymidine and uridine incorporation of the leukemia cells in ovo as well as in vitro.
Satisfactory correlations were observed between these test res ults and the therapeutic effects observed in patients. Several case reports were presented.

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Ultrastructure, and Localization of Electronmicroscopic Histochemical Activity of Alkaline Phosphatase on Various Mammary Tumors

Haruaki Izumi

1971 Volume 23 Issue 2 Pages 258-290
Published: June 20, 1971
Released on J-STAGE: February 19, 2013

DOIhttps://doi.org/10.5361/jkmu1956.23.2_258

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On biopsy materials from 101 cases of various mammary tumors (carcinoma, fibroadenoma and mastopathy), the ultrastructure of those which were fixed in Karnovsky's fixative was observed under an electron microscope in contrast with the resting or lactating mammary gland of adult women. The localization and the intensity of the histochemical activity of nonspecific alkaline phosphatase (alk-P) on the same materials as above-mentioned were investigated electron-microscopically by means of Ogawa et al's lead citrate method, in comparison of light-microscopic histochemical activities of alk-P, detected by Burstone azo dye method, on the same materials.

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A Study on Microcirculatory Disturbances and Morphological Changes in both Hypothalamus and Hypophysis Induced by Increased Intracranial Pressure

Takayuki Nakajima

1971 Volume 23 Issue 2 Pages 291-302
Published: June 20, 1971
Released on J-STAGE: February 19, 2013

DOIhttps://doi.org/10.5361/jkmu1956.23.2_291

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Functional distubarnces of the hypothalamo-pituitary system have been reported in cases of various intracranial disorders, especially in those of craniocerebral injury. It is important that increased intracranial pressure with such functional disturbances should affect the prognosis of the patient, since disturbances of the hypothalamo-hypophysial system cause dysfunction of the target endocrine organs and metabolic disorders.
Pituitary necrosis in increased intracranial pressure has been described by E. J. Kraus (1933) and L. WoIman (1956), but no experimental investigation has been carried out on the mechanism of pituitary necrosis.

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A case of Thrombocytopenic Purpura Due to Hypersensitivity to Quinidine Sulfate

Terutoshi KOKAWA, Yuruko OKAMOTO, Takako MIZUNO

1971 Volume 23 Issue 2 Pages 303-311
Published: June 20, 1971
Released on J-STAGE: February 19, 2013

DOIhttps://doi.org/10.5361/jkmu1956.23.2_303

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An 82 year old man suffering from myocardial infarction and complete A-V block showed remarkable hemorragic signs during treatment with quinidine sulfate.
The patient's history, clinical course, and laboratory data (especiall y those revealed by serorogical examination, i. e. clot retraction and platelet agglutination) gave evidence corroborating diagnosis as thrombocytopenic purpura due to hypersensitivity to quinidine sulfate.
Although the purpura was successfully combatted with ACTH and corticosteroid after discontinuance of the responsible drug, the patient subsequently died of broncopneumonia probably brought on by his original heart disease.

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Two Cases of Myelofibrosis

Yuruko Okamoto, Teratoshi Kokawa, Takeshi Iba, Hiroshi Yutaka

1971 Volume 23 Issue 2 Pages 312-323
Published: June 20, 1971
Released on J-STAGE: February 19, 2013

DOIhttps://doi.org/10.5361/jkmu1956.23.2_312

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Case I
The 44 -year-old housewife was admitted in Jan.1967, with high fever and coma.
Early history: Since Oct.1965, the patient has had fatigue, palpitation and dizziness. Since Oct.1966, she has had cold sweat, nausea and vomiting. In November 1966, she was treated with Hormin (a rocambole preparation) and Kamara, and discharged diphyllobothrium latum.
On admission th e most remarkable findings of the patient were hepatosplenomegaly and anemia with thrombocytopenia and slight leuko-erythroblastosis. Repeated bone marrow aspirations were unsu ccesfull, while needle biopsy revealed bone marrow fibrosis.
After h er general condition was improved, the patient was discharged to be observed at our ambulatory clinic.
In Dec.1967, she was again admitted to our hospital because of fever, bleeding and increasing anemia.
She died in July 1968, i. e. about three years after the onset of the desease.
Autopsy findings: Hepatosplenomegaly with extramedullary hematopoie sis accompanied by leukemic cell infiltration.
Bone marrow sh owed extensive proliferation of collagen fibril's partially infiltrated by leukemic cells.
Case II
The 63 -year-old male was admitted in Feb.1970, with hepatosplenomegaly, anemia and leukopenia.
Ea ry history: Since May 1969, the patient has been complaining of abdominal distension, and treated for ascites and hepatosplenomegaly at a clinic since Sep.1969.
On admission to our clinic, general findings and laboratory data were similar to those of the case I. (Bone marrow fibrosis was confirmed by needle biopsy. )
He died in Feb.1971 because of hemorrhage from digestive o rgans. Autopsy was not allowed.
Discussions were made on the relationship between the myelofibrosis and the myeloproliferative disorders.
As for the course of the disease in the case I, proliferation of collagen fibril's in the bone marrow was assumed to have been the first process followed by reactive leukemic proliferation of the hematopoietic cells.

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Two Autopsy Cases of Acute Death.

Michiko Ogawa, Noboru Yamaguchi, Yoshichica Aosaki, Hiroshi Okubo, Ich ...

1971 Volume 23 Issue 2 Pages 324-334
Published: June 20, 1971
Released on J-STAGE: February 19, 2013

DOIhttps://doi.org/10.5361/jkmu1956.23.2_324

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Michiko Ogawa, Noboru Yamaguchi, Yoshichica Aosaki, and Hiroshi Okubo First Department of Internal Medicine, Kansai Medical school, Moriguchi, Osaka, Japan Ichiro Yamagata, Ichiro Kuwabara and Sotokichi Morii Department of Pathologx, Kansai Medical School Case 1.40 years old male:
When he was walking, sudd enly attacked by shock syndrome. Clinical diagnosis was myocardial infarction, but autopsy revealed no remarkable infarction in the myocatd. Main pathological changes were severe sclerosis of coronary arteries, atherosclerosis of aorta, nephrosclerosis, atrophy of adrenal glands, hypoplasia of bone marrow and adhesion of pleura.
C ase 2.40 years old male:
Clinical picture was that of waterhouse-Friederichsen synndrome. As the lesion which directly caused the death, a large hemorrhage was found in the ventricular septum of the heart, which compressed the conduction system.
Autopsy revealed atrophy of adrenal glands, although bleeding was not detected there. The other Pathological findings were hypoplasia of spleen, small softening in parietal lobe of the brain and chronic hepatitis.
Discussions were made on the mechanism of shock including the role of adrenal glands, and on the nessecity of precise examinations in such cases.

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[in Japanese], [in Japanese], [in Japanese]

1971 Volume 23 Issue 2 Pages 335-337
Published: June 20, 1971
Released on J-STAGE: February 19, 2013

DOIhttps://doi.org/10.5361/jkmu1956.23.2_335

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[title in Japanese]

[in Japanese], [in Japanese], [in Japanese]

1971 Volume 23 Issue 2 Pages 338-340
Published: June 20, 1971
Released on J-STAGE: February 19, 2013

DOIhttps://doi.org/10.5361/jkmu1956.23.2_338

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[title in Japanese]

[in Japanese], [in Japanese], [in Japanese]

1971 Volume 23 Issue 2 Pages 341-343
Published: June 20, 1971
Released on J-STAGE: February 19, 2013

DOIhttps://doi.org/10.5361/jkmu1956.23.2_341

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[title in Japanese]

[in Japanese], [in Japanese]

1971 Volume 23 Issue 2 Pages 344-345
Published: June 20, 1971
Released on J-STAGE: February 19, 2013

DOIhttps://doi.org/10.5361/jkmu1956.23.2_344

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[title in Japanese]

[in Japanese], [in Japanese], [in Japanese]

1971 Volume 23 Issue 2 Pages 346-348
Published: June 20, 1971
Released on J-STAGE: February 19, 2013

DOIhttps://doi.org/10.5361/jkmu1956.23.2_346

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[title in Japanese]

1971 Volume 23 Issue 2 Pages 349-351
Published: June 20, 1971
Released on J-STAGE: February 19, 2013

DOIhttps://doi.org/10.5361/jkmu1956.23.2_349

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[title in Japanese]

1971 Volume 23 Issue 2 Pages e1-
Published: 1971
Released on J-STAGE: February 19, 2013

DOIhttps://doi.org/10.5361/jkmu1956.23.2_e1

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