Cyclosporins: immunosuppressive agents with antitumor activity

Initial screening of the 2 recently developed immunosuppressive agents, cyclosporin A and cyclosporin C, in 11 murine transplantable neoplasms revealed significant increase of lifespan with long-term survivors after i.p. injection to the ascites tumors, Taper liver, Sarcoma 180J and Ehrlich.     

Radioimmunoassay of some hormones simultaneously measured in serum and breast cyst fluid

Summary Blood and breast cyst fluid were drawn simultaneously for hormonal determination. There was no difference between serum and cyst fluid values of PRL and TSH. A significant difference was noted for LH (p<0.01) and FSH (p<0.05), serum concentrations being higher than cyst fluid concentrations.The authors are indebted to Miss J. Meister, E. Dullaert and J. Beck for their skillful technical help. We are also indebted to the National Institutes of Health, NIAMDD and the World Health Organization, International Laboratory for Biological Standards.     

The delta sleep inducing peptide (DSIP). Comparative properties of the original and synthetic nonapeptide

Summary Both the original and the synthetic nonapeptide Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu enhance, in recipient rabbits, spindle and delta EEG activity as in orthodox slow wave sleep.Acknowledgment. This work was supported by grants from the Swiss National Foundation for Scientific Research (No. 3.871.72, 3.527.75,3.443.074, 3.780.076), Fonds für Lehre und Forschung der Universität Basel, Merck Sharp and Dohme (USA), Ciba-Stiftung Basel, Hoffmann La Roche Ltd Basel, Sandoz Ltd Basel. We received valuable help from Dr S. Roncari, Dr B. Wilson and Dr C. D. Bennett for chemical research, and from Prof. A. Cerletti, Dr H. J. Tobler and Mr J. J. Regez (Division of Application and Research Development, Sandoz Ltd) for data processing.     

Defensive secretions of Nematinae larvae (Symphyta - Tenthredinidae)

Summary The composition of the defensive secretion of larvae of 8 Nematinae species is reported. 7 derivatives have been identified: benzaldehyde, (E)-2-hexenol, (E)-2-hexenal, (E)-4-oxo-2-hexenal, geranial, neral andcis, trans-dolichodial.Maître de recherches du Fonds National de la Recherche Scientifique.We gratefully acknowledge the Fonds National de la Recherche Scientifique for financial support. We express our sincere thanks to Professor B. Zwanenburg and Dr J. M. J. Verlaak for helpful suggestions.     

Distribution of free and conjugated ecdysteroids between follicle cell sheath and ooplasm in oocytes of the cockroachNauphoeta cinerea

Summary It is shown that both follicle cell sheath and ooplasm contain only small quantities ofHelix-hydrolyzable ecdysteroid conjugates and that 20-hydroxy-ecdysone is the predominant free ecdysteroid. Its concentration is very high in the follicle cell sheath immediately before chorion formation (6825 ng/g) and much lower after chorion formation (150 ng/g), while it is 234 ng/g and 95 ng/g in the ooplasm at the same stages respectively.Thanks are due to Dr J.D. O'Connor (Los Angeles) for the ecdysone antiserum, to Dr J. Koolman (Marburg) for 23,24-[³H]-ecdysone and to Mrs A. Tschan for technical assistance. A fellowship to X. Zhu from the Chinese Ministry of Education and financial support from the Swiss National Science Foundation (grant no. 3.714-0.80 to B. Lanzrein) are gratefully acknowledged.     

Effects of palytoxin on the electrical activity of dog and rabbit heart

Summary Reversible effects of palytoxin, extracted from colonies of the soft coralPalythoa caribaeorum, are described. There is a decrease of both membrane resting potential and overshoot during activity. Rise time of the action potential is prolonged, while repolarization is shortened. The electrical events resemble those seen with metabolic poisons.This work was supported by grant 10897 from the National Heart and Lung Institute, Bethesda, Md., and by grant 3.758. 72 from the Swiss National Science Foundation.I wish to thank Dr W. C. De Mello for hospitality in his department, Dr T. Morales for allowing me to use his equipment, Dr. J. Santos Martínez for providing me with hearts of poisoned and unpoisoned dogs, and Drs E. Toro-Goyco and A. M. Preston of the Department of Biochemistry for letting me have a sample of toxin.     

Estrogen-induced uterine metaplasia in rats given oral supplements of vitamin A

Zusammenfassung An der Ratte wurde der Einfluss von oral verabreichtem Vitamin A auf die östrogeninduzierte Metaplasie der Uterusschleimhaut untersucht. Kleine Dosen von Vitamin A (250 IE pro Woche) sind zur Vermeidung dieser Metaplasie wirksamer als grosse Dosen von Vitamin A (100 000 IE pro Woche).

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This research was completed while the author was a student in the Department of Anatomy, Bowman Gray School of Medicine, Winston-Salem, N.C. It was supported by a grant from the National Vitamin Foundation. The author is indebted to Dr. W. J. Bo for suggesting the problem and for making himself available for consultation.     

On the distribution of plasma L-asparaginase

Summary The guinea-pig,Cavia porcellus, is unusual in possessing plasma L-asparaginase, an enzyme with anti-tumor activity. 21 additional species have been examined as to the presence of this enzyme: the results confirm and extend its remarkably limited species distribution.This work was supported in part by grant GM/CA 25378 from the National Institute of General Medical Sciences, National Institutes of Health.We are grateful to dr Hanna Hensch, Philadelphia Zoological Garden, and Ms Joan Whitla and Dr Richard J. Montali, National Zoological Park/Smithsonian Institution, for samples of frozen serum.To whom correspondence should be addressed.     

The measurement of transketolase activity in heart preparations

Zusammenfassung Methodenvergleich zur Transketolase-Analyse in Rattenherzen. Die neue Methode benützt als Substrat Hydroxypyruvat und Erythrose-4-Phosphat und bestimmt das Verhältnis der Transketolaseaktivität an der Bildung von Fructose-6-Phosphat. Der Wechsel der Myocard-Transketolaseaktivität während Hypertrophie wird beschrieben.

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M.G.C. acknowledges the support of an Imperial Chemical Industries of Australia and New Zealand Postgraduate Fellowship. J.F.W. and J.B.H. acknowledge the financial support of the National Heart Foundation of Australia and J.F.W. acknowledges the financial support of the Australian Research Grants Committee. G.K. is a Postgraduate Medical Scholar of the National Heart Foundation of Australia.     

Lack of correlation between structural features and function of synthetic agents tested for leukocyte chemotaxis

Summary A number of proteins, poly-L-amino acids, oligopeptides and lipids were tested for neutrophil, cosinophil and macrophage chemotactic activity. One myoglobin preparation was active. Based on the negative findings for all other substances, primary structure, secondary structure, degree of hydrophobicity, size and charge of a molecule, could be ruled out as structural features recognized by chemotactically responding phagocytes.I thank Dr J. H. Wissler for suggesting the reported experiments and Dr M. Landy and Prof. E. Sorkin for advice and criticism during preparation of this article. The excellent assistance by Mrs J. Kerschbaumer-Bech and Miss Margrit Bühlmann is gratefully acknowledged. This work was supported by Swiss National Foundation for Scientific Research, grant 3.8750.72, and by Sandoz-Stiftung, Basel.     

Hypoxic tachycardia in the rat

Summary Awake, freely breathing rats subjected to moderate hypoxia (10% O₂) manifest prompt tachycardia which is essentially unaffected by atropine and is blocked by propranolol, and is thus apparently mainly of sympathetic origin.This work was supported by grants from American Heart Association — Greater Los Angeles Affiliate (437IG), and National Science Foundation (GB-41390). J. D. L. was a Summer Scholar selected by the Committee for Advance Science Training. We thank Mr D. Ward and Miss L. J. Berg for much valuable assistance and Dr. J. L. Kinney for help in the statistical analysis of the data.     

Prostaglandin analogue protects pancreatic B-cells against cyclosporin A toxicity

Summary Cyclosporin A toxicity on pancreatic B-cells and its prevention by rioprostil, a prostaglandin E₁ analogue, were studied in the model of the isolated perfused pancreas of rats treated with both compounds for 8 days. At toxic doses of cyclosporin (10 and 20 mg/kg b.wt), the B-cells showed severe hydropic degeneration of the endoplasmatic reticulum and slight degranulation of the B-cells. Accordingly, the insulin secretion was markedly impaired. Administration of rioprostil ameliorated the insulin secretion significantly, but not the ultrastructural changes. At therapeutic levels of cyclosporin (5 mg/kg b.wt), the hydropic degeneration and the drop in insulin secretion were completely prevented by rioprostil. This observation might have therapeutic implications in the treatment of patients, in particular those undergoing pancreatic transplantation.     

Localization of bovine pancreatic polypeptide (BPP)-like immunoreactivity in rat pancreatic monolayer culture

Summary Antiserum to bovine pancreatic polypeptide (BPP) has been used for immunofluorescent staining in the light microscope. With this technique it is possible to detect the presence of specific cells in monolayer culture from neonatal rat pancreas which contain BPP or a closely related peptide.This work was supported by a grant (No. 3.553.75) from the Fonds National Suisse de la Recherche Scientifique. We are very grateful to Dr.R. E. Chance, Eli Lilly, for his generous gift of BPP and anti-BPP serum. We are also very obliged to Dr.R. H. Unger for providing glucagon, to Dr.J. Rivier and Dr.R. Guillemin for somatostatin, to Dr.N. Yanaihara for secretin, to Dr.W. Gepts for gastrin and to Dr.A. J. Moody for GLI.     

Antineoplastic agents 32. The pseudoguaianolide helenalin

Zusammenfassung Aus der PflanzeHelenium autummnale (Familie compositae) wurde ein alkolischer Extrakt gewonnen, der cytotoxische und antileukämische Aktivität zeigte und die Helenalin (I) als wirksame Komponente enthielt. Die Behandlung von Mäusen, die Träger von P 388 lymphocytischer Leukämie waren, ergab eine beachtliche (T/C 220) Verlängerung ihrer Lebenserwartung. Die Substanz zeigte ausserdem einen wachstumshemmenden Einfluss auf das Walker 256 Karzinom. Helenalin ist das erste Sesquiterpen vom Pseudoguaianolid Typ, welches in vivo eine solche antineoplastische Aktivität zeigt.

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For part 31, refer toG. R. Pettit, P. Traxler andC. P. Pase, Lloydia36, in press (1973).

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This investigation was supported by Public Health Service Research Grants No. CA-10612-01 to No. CA-10612-04 from the National Cancer Institute and was performed pursuant to contract No. NCI-C-71-2308 with the Division of Cancer Treatment, National Cancer Institute, Department of Health, Education and Welfare. A grant from the C.S.I.R. (South Africa) to G.M.C. is also gratefully acknowledged. In addition, we are indebted to Dr.L. Johnston for identifying theHelenium autumnale, toBetty J. Abbot and her colleagues at the National Cancer Institute, for the biological studies, and toJ. F. Day for assisting with both the laboratory scale and preparative scale plant extraction procedures.     

Defensive substances of opilionids

Summary The defensive secretions of 4 species of opilionids were analyzed.Leiobunum ventricosum andHadrobunus maculosus produce 4-methylheptan-3-one, whileL. calcar produces E-4,6-dimethyl-6-octen-3-one.L. longipes produces E-4,6-dimethyl-6-nonen-3-one, a new natural product.Paper No. 51 of the seriesDefensive Mechanisms of Arthropods.Acknowledgments. Partial support by the National Institutes of Health (Grant Nos. AI-12020 and AI-02908 and Fellowship No. 1-F32-CA05139 to T.H.J.) and the National Science Foundation (Grant No. BMS 75-15084) is gratefully acknowledged. We thank Dr.W. A. Shear for identifying the opilionids.     

Pheromone and terpene attraction in the bark beetleIps typographus L.

Zusammenfassung Es wird gezeigt, dassIps typographus L. primär durch Terpene und sekundär durch Pheromon der Männchen zu den Brutstämmen gelockt wird.

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This study was performed while J.A.R. was at the Institute of Entomology, Prague, on the exchange program of the National Academy of Sciences, and the Czechoslovak Academy of Science and was approved for inclusion in the U.S. International Biological Program.     

Evolutionary implications of ascorbic acid production in the Australian lungfish

Summary It is shown that the Australian lungfish (Neoceratodus forsteri) synthesizes ascorbic acid in its kidney, suggesting that ascorbic acid synthesis started before the origin of the tetrapods.Acknowledgments. We would like to thank Dr G.C. Grigg, University of Sydney, Mr R. B. Humphries, Dr P.A. Janssens and Dr C.H. Tyndale-Biscoe, Australian National University, and Dr. M. Griffiths and J.C. MacIlroy C.S.I.R.O., Division of Wildlife Research for supplying the tissue.     

The history of cyclosporin A (Sandimmune®) revisited: Another point of view

The immunosuppressant cyclosporin A (Sandimmune^®) has become the first line treatment for preventing rejection of transplanted organs and for certain, autoimmune diseases. The discovery of that drug and its preclinical development are described, and it is shown that most earlier accounts of the history of this compound are, in important respects, incorrect and misleading.     

Prostaglandin E1-induced fever in rabbits pretreated with p-chlorophenylalanine

Summary The prostaglandin E₁-induced fever was neither potentiated nor attenuated at all levels of the ambient temperatures (2, 22 and 32°C) studied after pretreatment of the conscious rabbits with p-chlorophenylalanine, when compared to the untreated control.This work was supported by grants from National Science Council of Republic of China and John B. Pierce Foundation (New Haven, USA). The author is grateful to Drs J. D. Hardy, J. T. Stitt and C. Y. Chai for their advice.     

Benzoyl cyanide in the defensive secretion of polydesmoid millipeds

Summary A novel cyanogenetic compound, benzoyl cyanide, was isolated from the defensive secretion of 3 polydesmoid millipeds (Pseudopolydesmus serratus, Apheloria corrugata and A. trimaculata). The secretion of the 3 species also contains mandelonitrile and benzaldehyde, and that of P. serratus contains mandelonitrile benzoate, benzoic acid, isovaleric acid, myristic acid and stearic acid.Paper No. 52 of the series Defense Mechanisms of Arthropods.The study was supported in part by the National Institutes of Health (grants AI-12020 and AI-02908 and Fellowship 1-F-32-CA05139 to T. H. J.) and the National Science Foundation (grant BMS 75-15084).