DOCSLIB.ORG

Chemical Compounds As Carcinogenic Agents Second Supplementary Report: Literature of 1938 and 1939 Biological Considerations

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Chemical Compounds As Carcinogenic Agents Second Supplementary Report: Literature of 1938 and 1939 Biological Considerations CHEMICAL COMPOUNDS AS CARCINOGENIC AGENTS SECONDSUPPLEMENTARY REPORT: LITERATURE OF 1938 AND 1939 J. W. COOK AND E. L. KENNAWAY (From the Royal Cancer Hospital (Free), London, and the University of Glasgow) BIOLOGICALCONSIDERATIONS (Continued from page 428, Jitly 1940) II. Action of Carcinogenic Compounds in Difierent Species and Tissues A number of reports of the action of carcinogenic compounds on human tis- sues have appeared. Klar (601) developed a nodule on the forearm after completion of a series of experiments with 3:4-benzpyrene. He applied a solution of the hydrocarbon (0.25 per cent in benzol) to the skin of mice with a paint brush and for at least part of the period wore rubber gloves. He also conducted experiments, of which no description is given, with the powdered hydrocarbon contained in a glass vessel. Three months after the completion of the experiments a small nodule appeared on the dorsum of the left forearm, This was excised in May 1938 and described by Professor Huckel as a “ so- called benign calcifying epithelioma.” The growth extended into the subcu- taneous fatty tissue; the connection with the superficial epithelium is not described nor is it evident in the two photomicrographs which illustrate the report. The author does not state his age. Gordonoff and Walthard (562) record the occurrence of a tumor in a labo- ratory assistant, aged forty-two, engaged in applying methylcholanthrene (0.3 per cent in benzol) to the skin of mice. The site was in the nasolabial fold, at a spot often touched by the patient when smoking. The microscopic ap- pearance was that of a “ still well delimited stage of an incipient squamous- cell sarcoma.” Cottini and Mazzone (479) deliberately applied 3 :4-benzpyrene ( 1 per cent in benzene) to the skin, generally of the arm or thigh, of 26 patients with various cutaneous diseases, usually daily for periods up to 120 days. The changes observed were ( 1) pigmentation (“ an increase in melanin in the basal layer of the epidermis ”), which was more distinct in older people and in parts exposed to light, and (2) verrucae. The latter are described as “ an accentua- tion of the relief pattern of the skin secondary to a deepening of the sulci,” but no dimensions are given. The changes retrogressed completely within two months after cessation of the applications. In a child aged four, suffering from xeroderma pigmentosum with multiple squamous-cell cancers of the face, the skin reacted to the hydrocarbon in the ordinary way, though the reaction to ultraviolet radiation was intense. This latter effect was less in areas treated with the hydrocarbon. Application of an ointment containing 1 per cent 3:4- benzpyrene to one of the ulcerated cancers in this patient had at first a favour- 521 522 J, W. COOK AND E. L. KENNAWAY able effect, but after 30 applications no definite retardation was observed. A similar result was obtained in a man of sixty with an x-ray cancer. Oberling, SanniC, GuCrin and GuCrin (726) have published data upon carci- nogenesis by 3 :4-benzpyrene in several species. (1) The hydrocarbon (1 per cent benzene) was applied twice weekly to the skin of 5 rabbits. Towards the third month 2 animals developed nodules which on biopsy showed squamous epithelioma, but in spite of continuation of the painting these tumours disappeared. At the end of one year the 3 sur- viving rabbits began to show malignant growths; 2 died, in the 18th and 19th months, with infiltrating epithelioma, while the third showed, in the 2 1st month, far-advanced ulcerating and vegetating epithelioma. (2) Application of the same solution to the skin of rats produced, in 3 animals which died between the nineteenth and the twenty-eighth month, epi- theliomas partly of basal-cell and partly of squamous type. The production of such tumours in the skin of the rat by methylcholanthrene was previously described and illustrated by Bachmann et d. (208). (3) In guinea-pigs the same solution applied to the skin produced only traces of papilloma even when the experiment lasted more than two years. (4) Of 5 fowls similarly treated one developed an erythroblastic blood re- action, another an erythroblastic leukaemia and a tumor of the ovary, and a third, after two years, an atypical spinocellular epithelioma. (5) 3:4-Benzpyrene dissolved in lard was given with the food to 20 mice. Of 3 which lived more than six months, 2 showed epithelioma of the squamous portion of the stomach (cf. Waterman, 359, 360). Rats similarly treated de- veloped no tumours of the alimentary tract. (6) Negative results were also obtained in rats by intrahepatic and intra- renal injections of a colloidal solution 1 in 10,000 and by injection into the kidney of a “ solution huileuse.” Of 4 rats in which a crystal of 3:4- benzpyrene was inserted into the kidney, one developed a keratinizing renal carcinoma with peritoneal metastasis, which was transmitted by grafting. (7) In an attempt to ascertain the minimum effective dose the authors found that 0.05 mg. produced sarcoma subcutaneously in one of 5 rats in a year and a half (cf. Dobrovolskaia-Zavadskaia, 501). The importance of concentration is shown by an experiment in which the same quantity of hydro- carbon was carcinogenic when injected in 0.5 C.C. of oil, but was inactive in 5.0 C.C. of the same medium. Strong and Smith (807) injected methylcholanthrene subcutaneously ( 1.O mg. in sesame oil) into male and female mice, two months old, of strains NH, HE, CBA, C57, JK, CBAN, and N. These mice had received an injection of India ink within twenty-four hours after birth. Tumours appeared in 42 of them as follows: in 16 males and 18 females, sarcoma; in 6 females of strain NH, between the 82nd and the 199th days, and in 2 females of strain JK on the 203rd and 217th days, adenocarcinoma of the mammary gland at the in- jection site. Females of the two closely related strains NH and JK have an extremely low incidence of spontaneous tumours, none having been met with in the former strain since its origin three years ago. The experiment was repeated without the use of India ink, and at the time of the report 2 NH mice (T CHEMICAL COMPOUNDS AS CARCINOGENIC AGENTS 523 females) had developed mammary cancer. A female of this strain painted with a 1 per cent methylcholanthrene solution ( ? solvent) had also developed a mammary cancer near the site of painting. These tumours showed many areas of squamous metaplasia and were thought to have arisen from ducts. Mider and Morton (685) applied methylcholanthrene twice weekly to nine areas of the skin in turn in 65 breeding females of sub-line 212 of the dilute brown strain of mice. This sub-line has a lower incidence of mammary cancer than other members of the strain. Cancers were obtained in 13 mice between the 106th and 268th days of life (average 181st day), while 14 of 42 control breeding females developed mammary cancer between the 250th and 475th days (average 371st day). “ The number of observations does not permit any comparison of the breast tumor incidence in the two groups. The con- stant marked reduction in the latent period, however, is unquestionably sig- nificant.” Mammary tumours were not obtained in 75 virgin females, nor in males, treated similarly. [On the production of mammary cancers by applications to the skin, cf. Widmark, 842 (see p. 405 in the previous installment of this paper) and Maisin and Coolen, 17 1.1 Larionow (633) added 3 :4-benzpyrene or 1: 2 :5 :6-dibenzanthracene in ((oil” to the food of mice at intervals of from one to three days for from five to seven months, the whole amount given being from 9 to 19 mg. Of 60 mice, 41 survived a whole course of feeding and the first tumours appeared six months after the dosage had ceased, ie., a year from the beginning of the ex- periment, when 22 animals still remained alive. These mice showed: (1) papilloma of the pre-stomach in 6 instances, some multiple and one showing a transitional stage to cancer; (2) a squamous carcinoma of the pre-stomach; (3) one example each of adenoma of the sebaceous gland, mammary adenoma, and mammary adenocarcinoma; (4) adenoma of the lung in 5 instances; a single adenocarcinoma of the lung with metastases. No data are given in the French or English summaries of this paper on the incidence of tumours in control mice. Bonser and Orr (438) have described the histology of 160 tumours induced in the subcutaneous tissue of mice by methylcholanthrene (in lard or paraffin) or by 3 :4-benzpyrene or 1: 2 :5 :6-dibenzanthracene (in paraffin), which were distributed between the two sexes as follows: Male Female Sarcoma 65 60 Sarcoma and carcinoma of breast - 13 Sarcoma and squamous carcinoma 2 4 Carcinoma of breast - 9 Squamous carcinoma 1 5 Sarcoma, breast carcinoma and squamous carcinoma - 1 __ 68 92 “ The occurrence of a considerable series of mammary adenocarcinomas in female mice at the site of injection of a carcinogenic hydrocarbon and, from the histological appearances, directly attributable to the action of the hydro- carbon is a phenomenon which has not been described before. As the tumours occurred close to the injected material and were as frequent in IF TABLEXIII: Obserrwltions on Eighl Highly Inbrcd Strains of Mice, Showing SyscCPribilitr lo SpMJancous Mammary and Pulmonary Tumours and Induced Sub- cvtanu~wand Pdlrrmrcrry Tumoovs. and Naiurot~mulo TranrplrmbMc Tu~rs(Andrro6nt) CaH 95 to 100 per cent ? Medium High LOW Develop spontaneous and induced hepatomas C Less than 5 per cent 20 to 30 per cent High LOW LOW An incidence of 50 per cent of spontaneous
Load more

Recommended publications
  • Clomifene Citrate(BANM, Rinnm) ⊗
    2086 Sex Hormones and their Modulators Profasi; UK: Choragon; Ovitrelle; Pregnyl; USA: Chorex†; Choron; Gonic; who received the drug for a shorter period.6 No association be- 8. Werler MM, et al. Ovulation induction and risk of neural tube Novarel; Ovidrel; Pregnyl; Profasi; Venez.: Ovidrel; Pregnyl; Profasi†. tween gonadotrophin therapy and ovarian cancer was noted in defects. Lancet 1994; 344: 445–6. Multi-ingredient: Ger.: NeyNormin N (Revitorgan-Dilutionen N Nr this study. The conclusions of this study were only tentative, 9. Greenland S, Ackerman DL. Clomiphene citrate and neural tube 65)†; Mex.: Gonakor. defects: a pooled analysis of controlled epidemiologic studies since the numbers who developed ovarian cancer were small; it and recommendations for future studies. Fertil Steril 1995; 64: has been pointed out that a successfully achieved pregnancy may 936–41. reduce the risk of some other cancers, and that the risks and ben- 10. Whiteman D, et al. Reproductive factors, subfertility, and risk efits of the procedure are not easy to balance.7 A review8 of epi- of neural tube defects: a case-control study based on the Oxford Clomifene Citrate (BANM, rINNM) ⊗ Record Linkage Study Register. Am J Epidemiol 2000; 152: demiological and cohort studies concluded that clomifene was 823–8. Chloramiphene Citrate; Citrato de clomifeno; Clomifène, citrate not associated with any increase in the risk of ovarian cancer 11. Sørensen HT, et al. Use of clomifene during early pregnancy de; Clomifeni citras; Clomiphene Citrate (USAN); Klomifeenisi- when used for less than 12 cycles, but noted conflicting results, and risk of hypospadias: population based case-control study.
    [Show full text]
  • The Reactivity of Human and Equine Estrogen Quinones Towards Purine Nucleosides
    S S symmetry Article The Reactivity of Human and Equine Estrogen Quinones towards Purine Nucleosides Zsolt Benedek †, Peter Girnt † and Julianna Olah * Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary; [email protected] (Z.B.); [email protected] (P.G.) * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: Conjugated estrogen medicines, which are produced from the urine of pregnant mares for the purpose of menopausal hormone replacement therapy (HRT), contain the sulfate conjugates of estrone, equilin, and equilenin in varying proportions. The latter three steroid sex hormones are highly similar in molecular structure as they only differ in the degree of unsaturation of the sterane ring “B”: the cyclohexene ring in estrone (which is naturally present in both humans and horses) is replaced by more symmetrical cyclohexadiene and benzene rings in the horse-specific (“equine”) hormones equilin and equilenin, respectively. Though the structure of ring “B” has only moderate influence on the estrogenic activity desired in HRT, it might still significantly affect the reactivity in potential carcinogenic pathways. In the present theoretical study, we focus on the interaction of estrogen orthoquinones, formed upon metabolic oxidation of estrogens in breast cells with purine nucleosides. This multistep process results in a purine base loss in the DNA chain (depurination) and the formation of a “depurinating adduct” from the quinone and the base. The point mutations induced in this manner are suggested to manifest in breast cancer development in the long run.
    [Show full text]
  • Materializing Estrogen and Regulation Under Canada's Food and Drugs Act, 1939-1953 Lara Jessie Tessaro
    Osgoode Hall Law School of York University Osgoode Digital Commons LLM Theses Theses and Dissertations 8-27-2018 Toxic Enactments: Materializing Estrogen and Regulation Under Canada's Food and Drugs Act, 1939-1953 Lara Jessie Tessaro Follow this and additional works at: https://digitalcommons.osgoode.yorku.ca/llm Part of the Legal History Commons TOXIC ENACTMENTS: MATERIALIZING ESTROGEN AND REGULATION UNDER CANADA’S FOOD AND DRUGS ACT, 1939-1953 LARA TESSARO A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF LAWS GRADUATE PROGRAM IN LAW OSGOODE HALL LAW SCHOOL, YORK UNIVERSITY TORONTO, ONTARIO August 2018 © Lara Tessaro, 2018 ABSTRACT The study describes how estrogen was standardized in Canada, in the 1940s and early 1950s, under the Food and Drugs Act. Contributing to interdisciplinary conversations, it provides an empirical case of how regulatory practices enact material realities. Using archival material, the study describes how estrogen was achieved, in part, through heterogeneous practices of the Canadian Committee on Pharmacopoeial Standards, National Health, and government solicitors. These regulators disagreed on whether, how, and by whom estrogens should be standardized. Rather than resolve these disagreements, Canada enacted multiple regulations purporting to standardize estrogen, and government solicitors practiced “techniques of validating” to render the regulations as lawful. I argue that these regulatory enactments materialized estrogen as a potent, unpredictable, and multiple object. Further, I show how estrogen spawned novel regulatory techniques in Canada, particularly the use of consumer product labels. In this way, estrogen catalyzed an early example of risk regulation in Canada.
    [Show full text]
  • Pp375-430-Annex 1.Qxd
    ANNEX 1 CHEMICAL AND PHYSICAL DATA ON COMPOUNDS USED IN COMBINED ESTROGEN–PROGESTOGEN CONTRACEPTIVES AND HORMONAL MENOPAUSAL THERAPY Annex 1 describes the chemical and physical data, technical products, trends in produc- tion by region and uses of estrogens and progestogens in combined estrogen–progestogen contraceptives and hormonal menopausal therapy. Estrogens and progestogens are listed separately in alphabetical order. Trade names for these compounds alone and in combination are given in Annexes 2–4. Sales are listed according to the regions designated by WHO. These are: Africa: Algeria, Angola, Benin, Botswana, Burkina Faso, Burundi, Cameroon, Cape Verde, Central African Republic, Chad, Comoros, Congo, Côte d'Ivoire, Democratic Republic of the Congo, Equatorial Guinea, Eritrea, Ethiopia, Gabon, Gambia, Ghana, Guinea, Guinea-Bissau, Kenya, Lesotho, Liberia, Madagascar, Malawi, Mali, Mauritania, Mauritius, Mozambique, Namibia, Niger, Nigeria, Rwanda, Sao Tome and Principe, Senegal, Seychelles, Sierra Leone, South Africa, Swaziland, Togo, Uganda, United Republic of Tanzania, Zambia and Zimbabwe America (North): Canada, Central America (Antigua and Barbuda, Bahamas, Barbados, Belize, Costa Rica, Cuba, Dominica, El Salvador, Grenada, Guatemala, Haiti, Honduras, Jamaica, Mexico, Nicaragua, Panama, Puerto Rico, Saint Kitts and Nevis, Saint Lucia, Saint Vincent and the Grenadines, Suriname, Trinidad and Tobago), United States of America America (South): Argentina, Bolivia, Brazil, Chile, Colombia, Dominican Republic, Ecuador, Guyana, Paraguay,
    [Show full text]
  • Conjugated Estrogens Sustained Release Tablets) 0.3 Mg, 0.625 Mg, and 1.25 Mg
    PRODUCT MONOGRAPH PrPREMARIN® (conjugated estrogens sustained release tablets) 0.3 mg, 0.625 mg, and 1.25 mg ESTROGENIC HORMONES ® Wyeth Canada Date of Revision: Pfizer Canada Inc., Licensee December 1, 2014 17,300 Trans-Canada Highway Kirkland, Quebec H9J 2M5 Submission Control No: 177429 PREMARIN (conjugated estrogens sustained release tablets) Page 1 of 46 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION .........................................................3 SUMMARY PRODUCT INFORMATION ...........................................................................3 INDICATIONS AND CLINICAL USE ................................................................................3 CONTRAINDICATIONS ......................................................................................................4 WARNINGS AND PRECAUTIONS ....................................................................................4 ADVERSE REACTIONS ....................................................................................................14 DRUG INTERACTIONS ....................................................................................................20 DOSAGE AND ADMINISTRATION ................................................................................23 OVERDOSAGE ...................................................................................................................25 ACTION AND CLINICAL PHARMACOLOGY ...............................................................25 STORAGE AND STABILITY ............................................................................................28
    [Show full text]
  • Pharmaceutical and Veterinary Compounds and Metabolites
    PHARMACEUTICAL AND VETERINARY COMPOUNDS AND METABOLITES High quality reference materials for analytical testing of pharmaceutical and veterinary compounds and metabolites. lgcstandards.com/drehrenstorfer [email protected] LGC Quality | ISO 17034 | ISO/IEC 17025 | ISO 9001 PHARMACEUTICAL AND VETERINARY COMPOUNDS AND METABOLITES What you need to know Pharmaceutical and veterinary medicines are essential for To facilitate the fair trade of food, and to ensure a consistent human and animal welfare, but their use can leave residues and evidence-based approach to consumer protection across in both the food chain and the environment. In a 2019 survey the globe, the Codex Alimentarius Commission (“Codex”) was of EU member states, the European Food Safety Authority established in 1963. Codex is a joint agency of the FAO (Food (EFSA) found that the number one food safety concern was and Agriculture Office of the United Nations) and the WHO the misuse of antibiotics, hormones and steroids in farm (World Health Organisation). It is responsible for producing animals. This is, in part, related to the issue of growing antibiotic and maintaining the Codex Alimentarius: a compendium of resistance in humans as a result of their potential overuse in standards, guidelines and codes of practice relating to food animals. This level of concern and increasing awareness of safety. The legal framework for the authorisation, distribution the risks associated with veterinary residues entering the food and control of Veterinary Medicinal Products (VMPs) varies chain has led to many regulatory bodies increasing surveillance from country to country, but certain common principles activities for pharmaceutical and veterinary residues in food and apply which are described in the Codex guidelines.
    [Show full text]
  • Estriol Prevention of Mammary Carcinoma Induced by 7,12-Dimethylbenzanthracene and Procarbazine1
    (CANCER RESEARCH 35, 1341 1353, May 1975] Estriol Prevention of Mammary Carcinoma Induced by 7,12-Dimethylbenzanthracene and Procarbazine1 Henry M. Lemon Section of Oncology, Department of Internal Medicine, The University of Nebraska Medical Center, 42nd Street and Dewey Avenue, Omaha. Nebraska 68105 SUMMARY hexestrol, 0.60 mg/pellet, did not alter breast cancer incidence in 220 additional rats. Estrogen-treated rats The concentration of estrogenic, androgenic, progesta- usually sustained a mean 0.6 to 8.9% reduction of body tional, and adrenocortical steroid hormones in body fluids growth for the first 6 to 8 months of observation; this did of mature intact Sprague-Dawley female rats was increased not correlate with the breast carcinoma-suppressive activi by s.c. implantation of 5 to 7 mg NaCl pellets containing 1 ties of individual steroids. to 20% steroid 48 hr before administration p.o. of either Single implantation of 0.60 mg estriol 48 hr before 7,12-dimethylbenz(a)anthracene or procarbazine. The inci dimethylbenzanthracene p.o. or sustained implantation dence of rats developing one or more mammary carcinomas every 2 months of 10% estriol pellets beginning 24 hr after in each treated group was compared to that observed in si carcinogen exposure failed significantly to alter mammary multaneously treated groups receiving only the carcinogen, carcinoma development after dimethylben/anthracene ad steroid, or no treatment whatsoever, with weekly observa ministration. tion of all rats until palpably growing tumors were biopsied Inhibition of mammary carcinogenesis induced by these and proven carcinomatous or until death occurred from two dissimilar carcinogens in intact mature rats using other causes determined by autopsy.
    [Show full text]
  • Steroidal Estrogens
    FINAL Report on Carcinogens Background Document for Steroidal Estrogens December 13 - 14, 2000 Meeting of the NTP Board of Scientific Counselors Report on Carcinogens Subcommittee Prepared for the: U.S. Department of Health and Human Services Public Health Service National Toxicology Program Research Triangle Park, NC 27709 Prepared by: Technology Planning and Management Corporation Canterbury Hall, Suite 310 4815 Emperor Blvd Durham, NC 27703 Contract Number N01-ES-85421 Dec. 2000 RoC Background Document for Steroidal Estrogens Do not quote or cite Criteria for Listing Agents, Substances or Mixtures in the Report on Carcinogens U.S. Department of Health and Human Services National Toxicology Program Known to be Human Carcinogens: There is sufficient evidence of carcinogenicity from studies in humans, which indicates a causal relationship between exposure to the agent, substance or mixture and human cancer. Reasonably Anticipated to be Human Carcinogens: There is limited evidence of carcinogenicity from studies in humans which indicates that causal interpretation is credible but that alternative explanations such as chance, bias or confounding factors could not adequately be excluded; or There is sufficient evidence of carcinogenicity from studies in experimental animals which indicates there is an increased incidence of malignant and/or a combination of malignant and benign tumors: (1) in multiple species, or at multiple tissue sites, or (2) by multiple routes of exposure, or (3) to an unusual degree with regard to incidence, site or type of tumor or age at onset; or There is less than sufficient evidence of carcinogenicity in humans or laboratory animals, however; the agent, substance or mixture belongs to a well defined, structurally-related class of substances whose members are listed in a previous Report on Carcinogens as either a known to be human carcinogen, or reasonably anticipated to be human carcinogen or there is convincing relevant information that the agent acts through mechanisms indicating it would likely cause cancer in humans.
    [Show full text]
  • The Rabbits Are Prepared ..." - the Development of Ethinylestradiol and Ethinyltestosterone Frobenius W J
    Journal für Reproduktionsmedizin und Endokrinologie – Journal of Reproductive Medicine and Endocrinology – Andrologie • Embryologie & Biologie • Endokrinologie • Ethik & Recht • Genetik Gynäkologie • Kontrazeption • Psychosomatik • Reproduktionsmedizin • Urologie "The Rabbits are Prepared ..." - The Development of Ethinylestradiol and Ethinyltestosterone Frobenius W J. Reproduktionsmed. Endokrinol 2011; 8 (Sonderheft 1), 32-57 www.kup.at/repromedizin Online-Datenbank mit Autoren- und Stichwortsuche Offizielles Organ: AGRBM, BRZ, DVR, DGA, DGGEF, DGRM, D·I·R, EFA, OEGRM, SRBM/DGE Indexed in EMBASE/Excerpta Medica/Scopus Krause & Pachernegg GmbH, Verlag für Medizin und Wirtschaft, A-3003 Gablitz FERRING-Symposium digitaler DVR 2021 Mission possible – personalisierte Medizin in der Reproduktionsmedizin Was kann die personalisierte Kinderwunschbehandlung in der Praxis leisten? Freuen Sie sich auf eine spannende Diskussion auf Basis aktueller Studiendaten. SAVE THE DATE 02.10.2021 Programm 12.30 – 13.20Uhr Chair: Prof. Dr. med. univ. Georg Griesinger, M.Sc. 12:30 Begrüßung Prof. Dr. med. univ. Georg Griesinger, M.Sc. & Dr. Thomas Leiers 12:35 Sind Sie bereit für die nächste Generation rFSH? Im Gespräch Prof. Dr. med. univ. Georg Griesinger, Dr. med. David S. Sauer, Dr. med. Annette Bachmann 13:05 Die smarte Erfolgsformel: Value Based Healthcare Bianca Koens 13:15 Verleihung Frederik Paulsen Preis 2021 Wir freuen uns auf Sie! Development of Ethinylestradiol and Ethinyltestosterone “The Rabbits are Prepared …” – The Development of Ethinylestradiol and Ethinyltestosterone W. Frobenius In an exciting scientific neck-and-neck race, European and American scientists in the late 1920s and early 1930s isolated the ovarian, placental, and testicular hormones. At the same time the constitution of the human sex steroids was elucidated. However, it soon emerged that with oral administration the therapeutic value of the natural substances was extremely limited.
    [Show full text]
  • Ynthesis and Structure-Activity Relationships of Some 4-Substituted Pyrazole and Isoxazole Inhibitors of Liveralcohol Dehydrogenase
    AN ABSTRACT OF THE THESIS OF Douglas Robert Henry for the degree of Doctor of Philosophy in Pharmacy presented on July 10, 1980 Title: I. SYNTHESIS AND STRUCTURE- ACTIVITY RELATIONSHIPS OF SOME 4-SUBSTITUTED PYRAZOLE AND ISOXAZOLE INHIBITORS OF LIVER ALCOHOL DEHYDROGENASE II. THE USE OF MOLECULAR CONNECTIVITY IN THE MULTIVARIATE CLASSIFICATION OF DRUG MOLECULES Redacted for Privacy Abstract Approved: U Dr. John H. Block In a two part thesis, studies were made of two different types of structure-activity relationships. The first part consists of the synthesis and biological evaluation of a number of 4-substituted pyrazoles and isoxazoles as inhibitors of liver alcohol dehydrogenase. In an effort to better define the steric and electronic effects of substituents, the inhibitory potencies ofthe compounds were determined in vitro, and these were correlated with the lipophilicity parameter IFand with several steric and electronic substituent constants. Lipophilicity showed the most significant relationship with activity. Electronic terms were less significant, but a consistently negative slope coefficient for these terms suggests that a positive charge develops on the pyrazole ring during interaction with LADH, which is not consistent with a previously proposed anionic intermediate. In the second part of the thesis, retrospective research was performed to determine the usefulness of fragment and whole-molecule molecular connectivity (MC) indices in the multivariate classification of drug structures. Initially, using a template method of position assignment, a number of diphenylmethyl-based compounds from a previous study were examined using linear and quadratic discriminant analysis. Relative molar refraction was compared with several fragment MC values as descriptor indices.
    [Show full text]
  • Koong-Dissertationdoctoral
    Copyright by Luke Yun-Kong Koong 2014 The Dissertation Committee for Luke Yun-Kong Koong Certifies that this is the approved version of the following dissertation: THE DIRECT EFFECTS OF ESTRADIOL AND SEVERAL XENOESTROGENS ON CELL NUMBERS OF EARLY- VS. LATE- STAGE PROSTATE CANCER CELLS Committee: Cheryl S Watson, PhD, Mentor Darren Boehning, PhD, Chair Gracie Vargas, PhD Randall M Goldblum, MD Nancy Ing, DVM, PhD _______________________________ Dean, Graduate School THE DIRECT EFFECTS OF ESTRADIOL AND SEVERAL XENOESTROGENS ON CELL NUMBERS OF EARLY- VS. LATE- STAGE PROSTATE CANCER CELLS by Luke Yun-Kong Koong, BS Dissertation Presented to the Faculty of the Graduate School of The University of Texas Medical Branch in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy The University of Texas Medical Branch December, 2014 Dedication This dissertation is dedicated to my family, whom has supported me with love and encouragement throughout my life; my friends, who push me to greater heights; and most importantly God, who continues to bless me every day with life and joy. Acknowledgements I would like to acknowledge my mentor, Cheryl S Watson, who has guided me through my graduate work. She has shown me how to be a true scientist and a responsible steward of our environment. I am forever grateful for the avenues she has opened up for my life and career. Additionally, I would like to thank my committee members for all of their constructive ideas throughout my project, as well as encouragement along the way. Another key figure in my graduate career is Jennifer Jeng of the Watson laboratory, who helped teach me many of the assays used in this study, and who was also available for advice and suggestions.
    [Show full text]
  • PRODUCT INFORMATION Equilenin Item No
    PRODUCT INFORMATION Equilenin Item No. 23322 CAS Registry No.: 517-09-9 Formal Name: 3-hydroxy-estra-1,3,5,7,9-pentaen- O 17-one Synonyms: (+)-Equilenin, d-Equilenin, NSC 9901 MF: C18H18O2 FW: 266.3 H Purity: ≥98% Supplied as: A solid HO Storage: -20°C Stability: ≥2 years Information represents the product specifications. Batch specific analytical results are provided on each certificate of analysis. Laboratory Procedures Equilenin is supplied as a solid. A stock solution may be made by dissolving the equilenin in the solvent of choice. Equilenin is soluble in acetonitrile and DMSO, which should be purged with an inert gas. Description Equilenin is an equine estrogen found in the urine of pregnant mares.1 Unlike naturally occurring human estrogens, equilenin has no effect on nitric oxide synthase (eNOS) activity or expression and does not increase production of nitric oxide (NO). It is metabolized to 4-hydroxyequilenin, a carcinogenic compound that induces transformation of C3H 10T½ murine fibroblasts.2 Formulations containing equilenin conjugates have been widely used as hormone replacement therapies for post-menopausal women. References 1. Novensa, L., Selent, J., Pastor, M., et al. Equine estrogens impair nitric oxide production and endothelial nitric oxide synthase transcription in human endothelial cells compared with the natural 17β-estradiol. Hypertension 56(3), 405-411 (2010). 2. Spink, D.C., Zhang, F., Hussain, M.M., et al. Metabolism of equilenin in MCF-7 and MDA-MB-231 human breast cancer cells. Chem. Res. Toxicol. 14(5), 572-581 (2001). WARNING CAYMAN CHEMICAL THIS PRODUCT IS FOR RESEARCH ONLY - NOT FOR HUMAN OR VETERINARY DIAGNOSTIC OR THERAPEUTIC USE.
    [Show full text]