Studies on the treatment of malignant tumors with fibroblast-inhibiting agent III. Effects of chloroquine on human cancers

A fibroblast-inhibiting agent, chloroquine, used in the treatment of animal tumors led to a reasonably good result, and this approach was extended to the treatment of human cancers. Of histologically proven 54 cases, the drug was effective in 38, ineffective in 15, and unknown in one. It proved to be effective in all the patients who were treated for over 2 months with exception of terminal patients. Of the various malignant tumors treated, excellent therapeutic effects were obtained in patients with carcinoma of the lung and bladder. In the cases where the drug was effective there were a decrease of the size of tumors, fall of serum lactic dehydrogenase, increase of necrosis, inhibition of the stroma, as well as improvement of the symptoms and general condition. As to the mechanisms of the drug action, it would be necessary to consider of its anti-inflammatory and humoral effects upon the host in addition to its inhibitory action on the stromal connective tissue of cancers. The present chloroquine treatment appears to have its indication in inoperable cases, and pre- and post-operative cases, and for the prevention of reccurrence of tumors. Studies are currently in progress in our laboratory to discover more potent fibroblastinhibiting agents and on the combined chemotherapy of chloroquine and other anti-turnor agents. We are indebted to the Department of Urology of our University for the generosity to allow us to use the clinical data on patients with cancer of the urinary bladder.</p

Blood vessels and their construction in the cavities of pulmonary tuberculosis

First of all, we investigated the origin, the construction and distribution of the bronchial arteries and veins in adult rabbits, and then observed various changes of the blood vessels in experimental cavities and caseous foci and also studied the effects of streptomycin and isoniazide on the blood vessels of the cavity wall. The summary findings of the present experiments are described in the following. 1) In ten out of the fifteen rabbits emloyed, the bronchial artery originates from the right supreme intercostal artery; in three cases, in addition to this origin, it originates also from the left supreme intercostal artery; and in another case from the intercostal thoracic artery; while in the remaining one from the arc of the aorta. 2) The bronchial veins are divided into the extra-pulmonary and the intra-pulmonary veins. The former arises from the submucous blood vessels located in the proximal part of the third bronchus, and running along with the bronchial artery, finally empties into the superior Vena cava; while the latter, originating from the submucous capillaries in the distal part of the third bronchus, and after anastomosing with one another in the capsule of the bronchus, is communicated with the pulmonary veins. 3) In the caseous foci, although blood vessels are obliterated, capillaries are newly formed around the main trunks of the pulmonary artery and vein as well as around their residual branches. 4) These caseous foci are supplied with arterial blood from the bronchial arteries, the blood vessels in the bronchial wall, and the newlyformed vessels of pulmonary arterial origin. 5) The capillaries in the cavity wall are classified into three types according to their origins; namely, Type I, those regenerating from fine branches of the pulmonary vessels; Type &#8545;, those regenerating from the main trunk of the pulmonary vessels; and Type &#8546;, those regenerating from the bronchial artery situated in the orifice of the drainage bronchus. 6) The tuberculous cavities only in the orifice of the drainage bronchus receive an abundant supply of arterial blood directly from the bronchial artery, but those in other regions receive a scanty blood supply indirectly from the anastomoses between the bronchial artery, its sister vessels and the pulmonary artery. 7) The regeneration of blood vessels in tuberculous foci has been confirmed to occur not only in the bronchial artery and its sister blood vessels but also in the pulmonary artery and vein as well. 8) The constructions of blood vessels in the cavities treated with streptomycin or isoniazide present no significant difference from those of the control. 9) The regeneration of blood vessels and hyperemia in the cavity wall of the cases treated with streptomycin present no significant difference from those observed in the control, but the cases treated with isoniazide show marked hyperemia, newly-formed vessels, and occasional bleedings.</p

Influences of various hormones on the megakaryocyte in bone-marrow tissue culture

In our study on the influences of various hormones and various endocrines on the megakaryocyte function by means of bone-marrow tissue culture, we obtained the following. 1. In the repeated administration of ACTH, cortisone, testosterone, progesterone, or thyroxin to guinea pigs, these hormones accelerated the megakaryocyte function, whereas estradiol on the contrary diminished the function. 2. The removal of such endocrines as the pituitary, adrenal, thyroid or testicles will diminish the megakaryocyte function, while removal of the ovaries accelerates it. 3. For the megakaryocytes in the hypophysectomized rats, ACTH acts most effectively to restore their function, followed by cortisone and pulverized thyroid, while testosterone has hardly any effect on the function. 4. ACTH, cortisone, prednisolone, testosterone, progesterone, and pulverized thyroid act directly on megakaryocytes so as to accelerate their function, while estradiol diminishes the megakaryocyte function. 5. For the megakaryocytes in idiopathic thrombocytopenic purpura ACTH is most effective in restoring the function; for the megakaryocytes in hypoplastic anemia cortisone is most effective; and for the megakaryocytes in Banti's disease prednisolone is most effective in restoring the megakaryocyte function.</p

Studies on the treatment of malignant tumors with fibroblast-inhibiting agent IV. Effects of chloroquine on malignant lymphomas

Eleven cases of malignant lymphomas were treated with a fibroblast-inhibiting agent, chloroquine, and of these, one case of lymphosarcoma, two of acute and chronic lymphocytic leukemia, respectively, and two of giant follicle lymphoma showed regression of the enlarged lymph nodes and also of the enlarged spleen in some of the splenomegalic patients. In contrast, the drug proved ineffective in two cases of reticulum cell sarcoma and Hodgkin's disease, respectively. The side effects of the drug were minimal, and three of the 11 cases complained of nausea, anorexia or palpebral ptosis, which disappeared by decreasing the drug dosage or combining ATP preparation. The tissue culture study of biopsied lymph nodes from lymphocytic leukemia showed inhibition of the growth zone in a medium containing chloroquine indicating a possibility of the drug action not only upon the stromal tissue but also upon the parenchymal tumor cell.</p

Study on sideroblasts as a determi­nation method of the erythropoietic function of bone marrow

With the purpose to study sideroblasts as a means of diagnosing blood diseases and to pursue the metabolism of non-hemin iron in erythroblasts we investigated sideroblasts (erythroblasts containing iron granules stainable by Prussian blue) under various erythropoietic conditions in the human and rabbits, and obtained the following results: 1. In blood diseases the proportion of sideroblasts in the case of low erythropoietic condition is higher and in the case with accelerated erythropoietic condition and of iron deficiency it tends to be lower than that in normal persons. Further, obtaining sideroblastogram and sideroblast ratio (S. r.) from the classification of Types I, &#8545;, and &#8546; according to the iron granule content, it has been proven that abnormal conditions can be clearly distinguished from the normal, indicating that sideroblasts are closely associated with erythropoietic function. This is proven to be a far superior method for the diagnosis as well as for the prognosis of blood diseases than the determination of serum iron. 2. In experimental anemic rabbits the relationship of sideroblasts to the condition of erythropoietic function is still more clearly recognized, and it has been found that variations in the sideroblast count is dependent upon the condition of the equilibrium between the iron supply from serum iron and the iron utilization controlled by the erythropoietic function. 3. In addition, in the iron-treated rabbits under various erythropoietic conditions we have been able to confirm that there are a certain mechanism and a limitation to the iron intake by erythroblasts, and that erythroblasts take essentially three steps of metabolic processes, namely, intake, retention, and utilization of iron almost simultaneously, in the latter half of the maturation stage.</p

Studies on esinophils in bone-marrow tissue culture of the human sternum Part 2. Study on the causative factor of eosinophilia in hookworm disease by means of bone-marrow tissue culture with a special reference to the relationship with allergic reaction

From these results it is but natural to assume that the antigen-antibody reaction is involved in the phenomenon, eosinophilia. The antigen in this instance is the filtrate of hookworm emulsion, and the serum of hookworm disease as well as the bone marrow can be thought to contain the antibody. In any case, so long as the medium contains the serum or bone marrow or both of them obtained from the patient of hookworm disease, eosinophilia and the acceleration in the motility of eosinophils are brought about in the growth zone by addition of the filtrate of hookworm emulsion. Therfore, as for the mechanism inducing hookworm eosinophilia, it may by interpreted that the patient of hookworm disese is repeatedly sensitized by the antigen arising all probability from the metabolic products of hookworms or from the dead bodies of the worms; and producing the antibody in tissues and blood, thus the antigen-antibody reaction is elicited in vivo as long as hookworms live in the human body so that the increase in the mitosis and the acceration in the motility of eosinophils in the bone marrow are brought about with the resultant continuous discharge of a large quantity of eosinophils from the bone marrow parenchma into the sinusoids, there by inducing eosinophilia in the peripheral blood.</p

Studies on the treatment of malignant tumors with fibroblast-inhibiting agent. I. Fibroblast-inhibiting action of chloroquine

The effects of chloroquine on the growth and morphology of fibroblasts in tissue culture, and in vivo granulomas were investigated. As the result, the drug was shown to have a potent action to inhibit fibroblast growth, which has led to a possibility of its clinical use to patients with malignant tumors.</p

Studies on eosinophils in bone-marrow tissue culture of the human sternum Part 1. Observations on the behaviors of eosinophils in bone-marrow tissue culture of the sternum in patients with various eosinophilia

Of eosinophilias that we often encounter clinically, we selected two of the most representative ones, namely, hookworm diseae and bronchial astma, for our present sternal bone-marrow tissue culture, and studied the movement patterns and wandering capacity of eosinophils. As the results, even in those eosinophils that show no significant change other than the increase in number in ordinary stained-smear specimens of peripheral blood or bone marrow, it has been clarified that, when observed under living condition, they reveal a picture specific to individualistic behaviors according to diseases. Therefore, it can be assumed that in the pathologic condition what is known as eosinopilia not only eosinophils increase in number but also qualitative changes of eosinophlils specific to each disease are brought about, and consequently these specific changes are reflected on the movement patterns of the eosinophil.</p

Causal Therapy of Alkylphosphate Poisoning

We have designed to apply 2-pyridine aldoxime methiodide(PAM), considered to be a cholinesterase reactivator in vitro, both to the laboratory rabbits poisoned by parathion and to the patients of parathion poisoning, and obtained the following results: 1. With administration of PAM, a prompt and complete dispersion of symptoms of the poisoning can be realized. 2. Cholinesterase activity of red blood cell has instantly and completely recovered, and that of serum transiently. 3. The amount of serum mucoprotein and the activity of active protein-SH-radical of serum varied in direct proportion to the activity of serum cholinesterase. 4. Generally, an intravenous injection of 1g. PAM is sufficient even in the severe case and it may be increased when necessary. 5. The ill effect has not been encountered in the PAM administration. 6. PAM exerts no influence on the cholinesterase activity of normal blood. 7. PAM is expected to play an important role as a prophylactic agent of alkylphosphate poisoning. From these results it seems clear that PAM is a specific and effective antidote against alkylphosphate intoxication.</p

Studies on the treatment of malignant tumors with fibroblast-inhibiting agent. II. Effects of chloro­quine on animal tumors

Based on our original concept, a fibroblast-inhibiting agent, chloroquine, was used against various animal tumors. Among transplanted animal tumors, the drug was most effective on relatively connective tissue-rich Bashford and Brown-Pearce tumors, as reflected by prolongation of life span, inhibition of tumor growth, inhibition of lowering of liver catalase activity, improvement of iron metabolism, increase of tumor necrosis, inhibition of connective tissue formation, and decrease of acid mucopolysaccharide. On the other hand, it was of little advantage in Ehrlich, Yoshida and MH134 tumors which contain little connective tissue, except for a decrease of the amount of ascites and ascites tumor cells in the former two tumors. These results indicate that chloroquine suppress the growth of the tumors relatively rich in connective tissue. This effect of chloroquine appears to be due to the primary attack of the stromal connective tissue of tumors being followed by the degeneration of tumor cells, though its probable anti-tumor activity by the indirect effects through its anti-inflammatory and systemic humoral activities should be taken into consideration.</p