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

Large-n Limit of N=2 Supersymmetric Q^n Model in Two Dimensions

We investigate non-perturbative structures of the two-dimensional N=2 supersymmetric nonlinear sigma model on the quadric surface Q^{n-2}(C) = SO(n)/SO(n-2)xU(1), which is a Hermitian symmetric space, and therefore Kahler, by using the auxiliary field and large-n methods. This model contains two kinds of non-perturbatively stable vacua; one of them is the same vacuum as that of supersymmetric CP^{n-1} model, and the other is a new kind of vacuum, which has not yet been known to exist in two-dimensional nonlinear sigma models, the Higgs phase. We show that both of these vacua are asymptotically free. Although symmetries are broken in these vacua, there appear no massless Nambu-Goldstone bosons, in agreement with Coleman's theorem, due to the existence of two different mechanisms in these vacua, the Schwinger and the Higgs mechanisms.Comment: LaTeX, 28 pages, 22 figures, published versio

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 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

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 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

スミス マーゲニス ショウコウグン ノ ニホンジン カンジャ ニオケル センショクタイ 17p11.2 ケッシツ リョウイキ ニオケル ブンシ イデンガクテキ カイセキ

Smith-Magenis syndrome (SMS) is a contiguous gene syndrome caused by an interstitial deletion of chromosome 17p11.2. The clinical SMS spectrums include short stature, brachydactyly, developmental delay, dysmorphic features, mental retardation, hyperactivity, self-injury, seizures, and sleep abnormalities (especially, reduced REM sleep). Here we attempted to define the minimum common deletion at 17p11.2 in 8 Japanese patients with SMS using molecular cytogenetic approaches, including a prophase fluorescence in situ hybridization (FISH) ordering system and a stretched DNA fiber FISH. Our precise deletion mapping constructed by FISH revealed that one patient with SMS showed a much smaller deletion at 17p11.2 as compared with the other 7 patients with SMS. LLGL1 and FLII, previously mapped within the SMS critical deletion, were mutually nested, and retained on both chromosomes 17 in two patients. ZNF179, a RING finger protein family gene, on the SMS critical region was deleted on one of the two homologues 17p11.2 in 6 out of 8 patients with SMS in the present study. ZNF179 is a neuronal gene mapped on the SMS critical deletion and seems to be one of the candidates most likely to be affected with an impairment of the CNS in SMS patients. However, ZNF179 was retained on both 17p11.2 in two SMS patients exhibiting clinical findings characteristic of SMS, suggesting that ZNF179 might not be associated with the neurobehavioral impairments in SMS. Furthermore, DNA fragments from the region at 17p11.2 contained highly repetitive sequences, probably including the low-copy repeats (LCRs) associated with the deletion/duplication mechanism through non-allelic homologous recombination in the patients with SMS.　Key words : Smith-Magenis syndrome, 17p11.2, deletion map, LLGL1, FLII, ZNF17

Two Distinct Pathways to Development of Squamous Cell Carcinoma of the Vulva

Squamous cell carcinoma (SCC) accounts for approximately 95% of the malignant tumors of the vaginal vulva and is mostly found in elderly women. The future numbers of patients with vulvar SCC is expected to rise, mainly because of the proportional increase in the average age of the general population. Two different pathways for vulvar SCC have been put forth. The first pathway is triggered by infection with a high-risk-type Human Papillomavirus (HPV). Integration of the HPV DNA into the host genome leads to the development of a typical vulvar intraepithelial neoplasia (VIN), accompanied with overexpression of p14ARF and p16INK4A. This lesion subsequently forms a warty- or basaloid-type SCC. The HPV vaccine is a promising new tool for prevention of this HPV related SCC of the vulva. The second pathway is HPV-independent. Keratinizing SCC develops within a background of lichen sclerosus (LS) through a differentiated VIN. It has a different set of genetic alterations than those in the first pathway, including p53 mutations, allelic imbalances (AI), and microsatellite instability (MSI). Further clinical and basic research is still required to understand and prevent vulvar SCC. Capsule. Two pathway for pathogenesis of squamous cell carcinoma of the value are reviewed