Presence of oncornavirus-like particles in the P388 murine leukemic cell line

A culture of P388 murine lymphoblastoid cells has been shown to contain type C oncornavirus-like particles budding at the plasma membrane. Occasionally intracytoplasmic type A and immature type B particles were also observed by electron microscope techniques. The discovery of oncornavirus-like particles in the P388 cell line increases the utility of this neoplastic system for detecting potential antineoplastic agents.     

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.     

The isolation and structure of 13,18-dehydroglaucarubinone,a new antineoplastic quassinoid fromSimarouba amara

Summary An investigation of the Guyana plantSimarouba amara Aubl. (Simaroubaceae) for antineoplastic quassinoids led to isolation and structural determination of the new quassinoids 2-acetylglaucarubine (1a) and 13,18-dehydroglaucarubinone (2). The previously known 2-acetylglaucarubinone (3a) and glaucarubinone (3b) were also obtained. The new quassinoid2 was found significantly to inhibit growth of the murine lymphocytic leukemia P388.Antineoplastic agents 59. For part 58 refer to M. T. Edgar, G.R. Pettit and T.H. Smith, J. org. Chem., in preparation.Acknowledgments. We wish to thank Mr B. Septe for providing the¹³C-NMR-data. Dr Jean H. Schmidt and Miss Linda M. Lange for assistance with biological studies.—G.R. Pettit is grateful to the National Cancer Institute (performed pursuant to contract No. N01-67048 with the Division of Cancer Treatment, NCI, National Institutes of Health, Dept. of Health, Education and Welfare), Public Health Services Research grant No. CA 16049-03 from the National Cancer Institute, the Fannie E. Rippel Foundation, Talley Industries, and the Phoenix Coca-Cola Bottling Co., for partial support of this investigation.     

Time-qualified reference intervals — chronodesms

Summary Methods are presented for qualifying clinical reference intervals, for individuals as well as peer groups, according to circadian and other rhythms, using chronobiologically-defined single samples or time series.Supported by the Hoechst Italia Foundation, US Environmental Protection Agency (R804512-01-0), US Public Health Service (5-K6-GM-13, 981), National Cancer Institute (1R01-CA-14446-01), Cancer Supplement (CA-14445-01S1), National Institute of Aging (A6-00158) and National Institute of Occupational Safety and Health (OH 00631).     

6-Geranyloxy-3-methyl-1,8-dihydroxyanthrone,a novel antileukemic agent fromPsorospermum febrifugum Sprach var.ferrugineum (Hook. fil)

Summary A systematic fractionation of the root extract ofPsorospermum febrifugum was carried out in an attempt to reisolate the antitumor xanthone psorospermin and related compounds for further structural work and testing. This activitydirected fractionation led to the isolation of 6-geranyloxy-3-methyl-1,8-dihydroxyanthrone (1). Compound (1) was characterized based on spectroscopic and chemical evidence and showed borderline but reproducible activity in the P-388 mouse leukemia system.The authors acknowledge the support from USDA for collection of the plant material and the National Cancer Institute for support of this work under contract No. NO1-CM-97296. This is paper 15 in the series Potential Antitumor Agents.Cytotoxicity was assayed under the auspices of contract No. NO1-CM-97296. The Division of Cancer Treatment, National Cancer Institute, National Institute of Health, Bethesda, Maryland awarded support for this work.     

The structure of amoorastatone and the cytotoxic limonoid 12-hydroxyamoorastatin

Summary 2 new limonoid-type terpenes have been isolated from an aqueous extract of seeds produced by the Eastern Himalayan (India) plantAphanamixis grandifolia Bl. By interpreting principally mass spectral and nuclear magnetic resonance data, the structures of 12-hydroxyamoorastatin (2b) and amoorastatone (3) were elucidated. Unequivocal evidence for the 12-hydroxyamoorastatin structural assignment was obtained by chemical conversion to sendanin (4). Amoorastatin derivative2b was found to significantly inhibit growth of the murine P388 lymphocytic leukemia cell lines but amoorastatone in the same system was inactive. In a comparative biological study, sendanin (4) and anthothecol (7) were also found significantly to inhibit growth of the P388 cell line, while rohitukin (8) and limonin (9) were found to be inactive.Part 63 of the series Antineoplastic Agents. For the previous contribution refer to G.R. Pettit, T.S. Krupa and R.M. Reynolds, Int. J. Peptide Protein Res., in preparation. The present investigation was supported in part by Public Health Research Grant No. CA-16049-05 from the National Cancer Institute, the Fannie E. Rippel Foundation, Mrs Mary Dell Pritzlaff, the Spencer T. and Ann W. Olin Foundation, Mr John F. Schmidt, and the Phoenix Coca-Cola Bottling Company.     

Isometachromin, a new cytotoxic sesquiterpenoid from a deep water sponge of the family Spongiidae.

Isometachromin (1), a new sesquiterpene-quinone that is related structurally to metachromin C (2), and the known compounds ilimaquinone (3) and 5-epi-ilimaquinone (4), were isolated from a deep water sponge in the family Spongiidae; the structure of isometachromin was elucidated by spectral methods. Isometachromin exhibits in vitro cytotoxicity against the human lung cancer cell line A549 (IC50 = 2.6 micrograms/ml), but not against P388 murine leukemia (IC 50 > or equal to 10 micrograms/ml) and also exhibits antimicrobial activity.     

Growth-modulating serum tripeptide is glycyl-histidyl-lysine

Summary The structure of a growth-modulating tripeptide from human serum and plasma has been determined to be H-glycyl-histidyl-lysine-OH.Acknowledgment. This work was supported by grants from the U.S. Public Health Service (HD-03148 and P17AM 18520) and from the National Cancer Institute (NO-1-CB53868).     

The structure of amoorastatone and the cytotoxic limonoid 12-hydroxyamoorastatin.

2 new limonoid-type terpenes have been isolated from an aqueous extract of seeds produced by the Eastern Himalayan (India) plant Aphanamixis grandifolia B1. By interpreting principally mass spectral and nuclear magnetic resonance data, the structures of 12-hydroxyamoorastatin (2b) and amoorastatone (3) were elucidated. Unequivocal evidence for the 12-hydroxyamoorastatin structural assignment was obtained by chemical conversion to sendanin (4). Amoorastatin derivative 2b was found to significantly inhibit growth of the murine P388 lymphocytic leukemia cell lines but amoorastatone in the same system was inactive. In a comparative biological study, sendanin (4) and anthothecol (7) were also found significantly to inhibit growth of the P388 cell line, while rohitukin (8) and limonin (9) were found to be inactive.     

Comments on the significance of the quasi-valence number for chemical carcinogenesis

Summary A quasi-valence number of less than 3.20 was reported to be significant in correlating carcinogenicity. This criterion has no meaningful relationship since such a large proportion of organic compounds fall in this group, that it provides no selectivity.Acknowledgment. The authors express appreciation to the American Cancer Society (CH-57), the National Institute of Environmental Health Sciences (1-RO1-ES01975-01 PTHB) and the Robert A. Welch Foundation (B-702) for financial assistance of projects related to this paper.     

Cytogenetic evidence for hemizygosity at the thymidine kinase locus in P388 mouse lymphoma cells

A detailed cytogenetic investigation was carried out on P388 mouse lymphoma cells. The cells have a mean chromosome number of 36.86 with a mode and median of 37 chromosomes. G-banding analysis of 12 spreads revealed a total of 15 marker chromosomes with chromosome 11, the determinant of thymidine kinase, being present only in single copy per cell. It is therefore concluded that the P388 cell line is hemizygous at the thymidine kinase locus. Thymidine kinase activities were assayed in P388 cells and two other malignant cell lines, clone 707 Friend mouse leukaemia cells and L5178Y mouse lymphoma cells. No clear relationship was observed between enzyme activity and gene dosage.     

The effects of follicle-stimulating hormone on the uptake of labelled glycine by the chick embryo

Résumé On a étudié par autoradiographie l'incorporation de la glycine-1-C¹⁴ par l'embryon du poussin. L'incorporation était la plus élevée dans le tissu neural et puis dans le notochorde et les somites. Après traitement avec le FSH, une incorporation plus grande s'est produite dans les mésodermes chordal et somitique. On propose qu'il peut s'agir d'un effet morphogénétique. Il est particulièrement significatif que le mésoderme axial, qui joue un rôle si important dans l'induction du système nerveux, paraît être également le point d'action de l'hormone.

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Supported by Grant No. DRG-913 from the Damon Runyon Memorial Fund for Cancer Research and also by grants from the Medical Research Council, British Empire Cancer Campaign for Research and the U.S. Public Health Service to the Chester Beatty Research Institute (Institute of Cancer Research: Royal Cancer Hospital). The authors also wish to thank the National Institutes of Health, USA for the FSH preparations.     

Carcinogenic activation of benzo(a)pyrene by iodine and ferric chloride in the respiratory tract of Syrian golden hamsters

Summary Benzo(a)pyrene (0.5 mg), in itself weakly carcinogenic, when given in combination with ferric chloride (0,16 mg) or iodine (0,2 mg), alone noncarcinogenic, induced a number of tumors of different parts of the respiratory tract of Syrian golden hamsters.Partially supported by Public Health Service contracts PHS 43-68-959 and NO1 CP33278 from the Division of Cancer Cause and Prevention. The authors wish to thank Mrs Virginia Ooten for her technical assistance.     

Enhancement of fibronectin expression by herbimycin A

Summary Herbimycin A specifically inrreased the level of fibronectin mRNA in Rous sarcoma virus-infected rat kidney cells, and the time course of fibronectin expression was found to be closely related to that of morphological change induced by herbimycin A.Acknowledgments. The authors wish to thank Dr Y. Uehara, National Institute of Health, Tokyo, and Dr K. Hayashi, National Cancer Center Research Institute, Tokyo, for valuable suggestions. This work was supported in part by grants from the Ministry of Education, Science and Culture and the Ministry of Health and Welfare of Japan.     

Influence of presensitization with allogeneic lymphoma cells on the growth and response to therapy of radiation-induced lymphomas in mice

Summary Congenic mice were sensitized with viableH-2-incompatible radiation-induced lymphomas (RIL), challenged with syngeneic RIL and treated with bis-chloroethyl-nitrosourea. Either enhancement or inhibition of RIL was found in presensitized mice, depending on the tumor-host system used.This work was supported by Progetto Finalizzato Virus, CNR (Rome, Italy), Contract No. 770025284/1152505.Acknowledgments. I wish to thank Dr J. Mayo and Mr C.R. Reeder of the Mammalian Genetics and Animal Production Section, Division of Cancer Treatment (DCT), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda (Maryland, 20014, USA) for providing the mice used in this study. I also thank Dr H.B. Wood of the Drug Synthesis and Chemistry Branch, DCT, NCI, NIH, for furnishing the BCNU used.     

Cytotoxic action of nucleic acids

Zusammenfassung Mit einer letalen Dosis von Dimethyl-Myleran vorbehandelte Mäuse überleben nach Transfusion isologer Knochenmarkzellen. Wirken Nukleinsäurenin vitro auf die Knochenmarkzellen ein, so ist ihre lebenserhaltende Kapazität vermindert.

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This investigation was supported by grants to the Chester Beatty Research Institute (Institute of Cancer Research: Royal Cancer Hospital, London) from the Medical Research Council, the British Empire Cancer Campaign, the Anna Fuller Fund and the National Cancer Institute of the National Institutes of Health, U.S. Public Health Service.     

Epstein-barr virus and inflammatory bowel disease

Zusammenfassung Die Häufigkeit und der Antikörpertiter gegen Epstein-Barr-Virus (EBV) wurde in Patienten mit Ulkus-Colitis und Crohn's Krankheit, eine granulomatische Abnormalität ähnlich zur Sarkoidose untersucht und normale Häufigkeit und Antikörpertiter gegen EBV bei ihnen gefunden.

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Supported by Research Contract No. NIH-69-2078 within the Special Virus Cancer Program of the National Cancer Institute, National Institutes of Health, USPHS, National Institutes of Health Grant No. AM 05126 and the National Foundation for Ileitis and Colitis, Inc., New York, New York.

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Dr.Grotsky is a recipient of a National Institutes of Health Graduate Training Grant in Gastroenterology, No. Am 05126.

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Dr.Hirshaut is a recipient of a National Cancer Institute Grant No. CA 08748 an a grant from the New York Cancer Research Institute.

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Dr.Glade is a recipient of a Research Career Development Award No. A1-46371 of the USPHS.     

Abnormally soluble collagen produced in fibroblasts cultures

Summary Abnormally soluble collagen is synthesized in vitro not only by skin fibroblasts of Marfan patients but also by those of patients with Ehlers-Danlos type V and cutis laxa. The excessive solubility of collagen is corrected by the addition to the culture medium of a synthetic flavonoid, (+)-catechin.Supported by grants from the National Institutes of Health (Nos. AM-10811, HL-05435, GM-19513 and GM-00081), the National Fondation-March of Dimes, and Zyma, S.A., Nyon, Switzerland.     

Structural diversity of communicating intercellular junctions (gap junctions) in the posterior cecal epithelium of the crustacean Orchestis]

Two types of gap junction are described, they are different in the size, the spacing and the polarity of their intramembrane particles. The dense type shows two kinds of particles which rather remain joined to the P fracture face. The loose type shows larger and more spaced out particles which rather are held by the E fracture face. These observations demonstrate that one needs to shade the distinction between P-type gap (Vertebrate) and E-type gap (Arthropoda).     

Analysis of nucleic acid derivatives at the subnanomolar level. II. Quantitative analysis of ribose derivatives by tritium labeling

Zusammenfassung Es wird eine Methode zur quantitativen Analyse von Ribosederivaten beschrieben, welche etwa fünftausendmal empfindlicher ist als die spektrophotometrischen Standardverfahren.

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This work was supported by grants-in-aid from the U.S. Atomic Energy Commission (No. AT(30-1)2643), the U.S. Public Health Service (No. CA 05018), and the American Cancer Society (No. E-51-J). This is publication No. 1325 of the Cancer Commission of Harvard University.

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The first paper of this series³ described a procedure for detecting subnanomolar quantities of mono- and oligonucleotides on PEI-cellulose thin layers.