Skip header and navigation

Refine By

682 records – page 1 of 69.

2-substituted 1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones. A new class of antitumor agent.

https://arctichealth.org/en/permalink/ahliterature24099
Source
J Med Chem. 1993 Mar 19;36(6):765-70
Publication Type
Article
Date
Mar-19-1993
Author
S M Sami
R T Dorr
D S Alberts
W A Remers
Author Affiliation
Department of Pharmaceutical Sciences and Cancer Center, University of Arizona, Tucson 85721.
Source
J Med Chem. 1993 Mar 19;36(6):765-70
Date
Mar-19-1993
Language
English
Publication Type
Article
Keywords
Animals
Antineoplastic Agents - chemical synthesis - chemistry - therapeutic use
Female
Humans
Isoquinolines - chemical synthesis - chemistry - therapeutic use
Leukemia L1210 - drug therapy
Leukemia P388 - drug therapy
Male
Melanoma, Experimental - drug therapy
Mice
Mice, Inbred DBA
Ovarian Neoplasms - drug therapy
Research Support, U.S. Gov't, P.H.S.
Structure-Activity Relationship
Tumor Cells, Cultured - drug effects
Abstract
A new class of antitumor agents, having structural analogy to amonafide, but differing by the addition of a fourth ring in the nucleus, was synthesized conveniently from anthracene. Compounds with a variety of substituents, containing a basic nitrogen atom and located on the imide nitrogen, were prepared. Thirteen of 19 new compounds had greater growth inhibitory potency than amonafide in a panel of cultured murine and human tumor cells using the sulforhodamine B and MTT dye assays. The most active agents were similarly more toxic than amonafide to normal neonatal rat myocytes in vitro, but they had better chemotherapeutic indexes. From these compounds, the one with a 2-(dimethylamino)ethyl side chain (named azonafide) was chosen for further study. It showed high potency against a panel of cultured human colon cancer cells and it was active against ip P388 leukemia and subcutaneous B16 melanoma in mice. Preliminary structure-activity correlations suggest that the basicity of the side-chain nitrogen and the length of side chain are important determinants of antitumor potency in vitro. Steric hindrance and rigidity of the side chains might be other determinants.
PubMed ID
8459403 View in PubMed
Less detail

6- and 7-substituted 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h] isoquinoline-1,3-diones: synthesis, nucleophilic displacements, antitumor activity, and quantitative structure-activity relationships.

https://arctichealth.org/en/permalink/ahliterature22674
Source
J Med Chem. 1996 Apr 12;39(8):1609-18
Publication Type
Article
Date
Apr-12-1996
Author
S M Sami
R T Dorr
A M Sòlyom
D S Alberts
B S Iyengar
W A Remers
Author Affiliation
Department of Pharmacology and Toxicology, University of Arizona, Tucson, 85721, USA.
Source
J Med Chem. 1996 Apr 12;39(8):1609-18
Date
Apr-12-1996
Language
English
Publication Type
Article
Keywords
Animals
Antineoplastic Agents - chemical synthesis - pharmacology
Humans
Isoquinolines - chemical synthesis
Male
Mice
Mice, Inbred DBA
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Structure-Activity Relationship
Tumor Cells, Cultured
Abstract
New 2-[2'-(dimethylamino)ethyl]-3H-dibenz[de,h]isoquinoline-1,3-diones with substituents at the 6- and 7-positions were prepared. Nucleophilic aromatic displacement was a key reaction in the syntheses. Ten of the new compounds were more potent than the unsubstituted compound, azonafide, in a panel of tumor cells including human melanoma and ovarian cancer and murine sensitive and MDR L1210 leukemia. They also were less cardiotoxic in cell culture. Four of these compounds were not cross-resistant with the MDR leukemia, and one of them, 6-ethoxyazonafide, was nearly as potent against solid tumor cells as leukemia cells. These compounds also had good potency against human breast, colon, and lung cancer cells, including doxorubicin and mitoxantrone resistant cell lines. Advantages of the new analogues over azonafide were less in vivo, but 6-ethoxyazonafide was more effective against L1210 leukemia and subcutaneous B16 melanoma in mice. Although correlations of antitumor potency in cells and physicochemical properties of substituents were not found, there were statistically significant correlations of DNA melt transition temperature (delta Tm) with potency in solid tumor cells and sensitive and MDR resistant L1210 leukemia cells for 6-substituted azonafides and with solid tumors for 7-substituted azonafides.
PubMed ID
8648600 View in PubMed
Less detail

6-Bromoindole Derivatives from the Icelandic Marine Sponge Geodia barretti: Isolation and Anti-Inflammatory Activity.

https://arctichealth.org/en/permalink/ahliterature298348
Source
Mar Drugs. 2018 Nov 08; 16(11):
Publication Type
Journal Article
Date
Nov-08-2018
Author
Xiaxia Di
Caroline Rouger
Ingibjorg Hardardottir
Jona Freysdottir
Tadeusz F Molinski
Deniz Tasdemir
Sesselja Omarsdottir
Author Affiliation
Faculty of Pharmaceutical Sciences, University of Iceland, Hagi, Hofsvallagata 53, IS-107 Reykjavik, Iceland. xid1@hi.is.
Source
Mar Drugs. 2018 Nov 08; 16(11):
Date
Nov-08-2018
Language
English
Publication Type
Journal Article
Keywords
Alkaloids - chemistry - isolation & purification - pharmacology
Animals
Anti-Inflammatory Agents - chemistry - isolation & purification - pharmacology
Aquatic Organisms
CD4-Positive T-Lymphocytes - drug effects - metabolism
Cell Differentiation - drug effects
Cells, Cultured
Coculture Techniques
Dendritic Cells
Geodia
Humans
Iceland
Indoles - chemistry
Inhibitory Concentration 50
Interleukin-10 - metabolism
Interleukin-12 Subunit p40 - metabolism
Peptides, Cyclic - chemistry - isolation & purification - pharmacology
Stereoisomerism
Abstract
An UPLC-qTOF-MS-based dereplication study led to the targeted isolation of seven bromoindole alkaloids from the sub-Arctic sponge Geodia barretti. This includes three new metabolites, namely geobarrettin A?C (1?3) and four known compounds, barettin (4), 8,9-dihydrobarettin (5), 6-bromoconicamin (6), and l-6-bromohypaphorine (7). The chemical structures of compounds 1?7 were elucidated by extensive analysis of the NMR and HRESIMS data. The absolute stereochemistry of geobarrettin A (1) was assigned by ECD analysis and Marfey's method employing the new reagent l-Na-(1-fluoro-2,4-dinitrophenyl)tryptophanamide (l-FDTA). The isolated compounds were screened for anti-inflammatory activity using human dendritic cells (DCs). Both 2 and 3 reduced DC secretion of IL-12p40, but 3 concomitantly increased IL-10 production. Maturing DCs treated with 2 or 3 before co-culturing with allogeneic CD4? T cells decreased T cell secretion of IFN-?, indicating a reduction in Th1 differentiation. Although barettin (4) reduced DC secretion of IL-12p40 and IL-10 (IC50 values 11.8 and 21.0 µM for IL-10 and IL-12p40, respectively), maturing DCs in the presence of 4 did not affect the ability of T cells to secrete IFN-? or IL-17, but reduced their secretion of IL-10. These results indicate that 2 and 3 may be useful for the treatment of inflammation, mainly of the Th1 type.
PubMed ID
30413031 View in PubMed
Less detail

17beta-estradiol induces the proliferation of the in vitro cultured human urothelium.

https://arctichealth.org/en/permalink/ahliterature89268
Source
Scand J Urol Nephrol. 2009;43(3):179-85
Publication Type
Article
Date
2009
Author
Koskela Sanna
Lehtonen Siri
Santala Markku
Venhola Mika
Parpala-Spårman Teija
Lehenkari Petri
Author Affiliation
Department of Anatomy and Cell Biology, University of Oulu, Oulu, Finland. sannako@paju.oulu.fi
Source
Scand J Urol Nephrol. 2009;43(3):179-85
Date
2009
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Aged
Blotting, Western
Cell Nucleus - metabolism
Cell Proliferation - drug effects
Cells, Cultured
Child
Child, Preschool
Cytoplasm - metabolism
Estradiol - pharmacology
Female
Humans
Immunohistochemistry
Keratin-7 - metabolism
Male
Middle Aged
Urothelium - cytology
Young Adult
Abstract
OBJECTIVE: The genitourinary tract is considered to be a target for the actions of sex steroid hormones. Decreased ovarian function and lack of estrogen after menopause are associated with lower genitourinary tract symptoms as well as bladder dysfunctions such as incontinence. Estrogen may also affect urothelial cells. The estrogen receptors (ERs) are found in the mucosa of the urinary tract. The purpose of this study was to culture human urothelial cells (HUCs) originating from urothelial tissue biopsies and to use them as a reproducible test platform to evaluate the effect of 17beta-estradiol (E2). MATERIAL AND METHODS: Urothelial tissue biopsies were obtained from 95 patients undergoing gynaecological open surgery for urinary incontinence, paediatric vesicoureteral reflux or transurethral resection of the prostate (TURP) for benign prostatic hyperplasia. HUCs originating from biopsies were cultured in vitro in the absence or in the presence of 0.1 nmol, 0.01 micromol and 1 micromol of E2. ER expression of the cultured HUCs was examined by Western analysis and immunofluorescence microscopy, which was also used for HUC characterization. The effect of E2 in the proliferation of the HUCs was determined by tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT)-assay. RESULTS: HUCs were cultured successfully in four to six passages but there was variation between samples. The cultured cells showed expression of beta(4)-integrin, E-cadherin and cytokeratins 7, 8, 9 and 19, indicating the epithelial origin of the cells. Both types of ERs, ERalpha and ERbeta, were found in the in vitro cultured HUCs. E2 treatment of HUCs did not affect remarkably the expression of ERalpha but cell proliferation was induced. However, no concentration-dependent effect was seen. CONCLUSIONS: This study indicates that HUCs originating from small tissue biopsies can be cultured in several passages in vitro and could have potential in repairing or restoring urinary tract tissue by tissue engineering therapy. HUCs serve as a good in vitro test platform, as shown by analysing E2-treated HUCs. E2 induced the proliferation of cultured HUCs even though concentration dependency was not observed. The findings of this study may have relevance in determining the mechanisms of estrogen therapy in postmenopausal urinary tract symptoms and in the future development of tissue engineering technology.
PubMed ID
19384677 View in PubMed
Less detail

17 beta-hydroxysteroid dehydrogenase gene expression in human breast cancer cells: regulation of expression by a progestin.

https://arctichealth.org/en/permalink/ahliterature24541
Source
Cancer Res. 1992 Jan 15;52(2):290-4
Publication Type
Article
Date
Jan-15-1992
Author
M. Poutanen
B. Moncharmont
R. Vihko
Author Affiliation
Department of Clinical Chemistry, University of Oulu, Finland.
Source
Cancer Res. 1992 Jan 15;52(2):290-4
Date
Jan-15-1992
Language
English
Publication Type
Article
Keywords
17-Hydroxysteroid Dehydrogenases - genetics - metabolism
Breast Neoplasms - enzymology - genetics
Gene Expression Regulation, Neoplastic - drug effects
Humans
Isoenzymes - genetics
Placenta - enzymology
Pregnenediones - pharmacology
Progesterone Congeners - pharmacology
RNA, Messenger - genetics
RNA, Neoplasm - genetics
Receptors, Estrogen - metabolism
Receptors, Progesterone - metabolism
Research Support, Non-U.S. Gov't
Tumor Cells, Cultured
Abstract
The expression of the 17 beta-hydroxysteroid dehydrogenase (17-HSD) gene in a series of human breast cancer cell lines was studied by Northern blot hybridization with a cDNA probe and by a time-resolved immunofluorometric assay using polyclonal antibodies against the enzyme protein. The 17-HSD enzyme protein concentration was measured in the 800 x g cell extract. A high concentration was measured in the BT-20 cell line, corresponding to one-fourth of the average concentration in placental tissue. Western blot analysis indicated that the antigen corresponded to a single Mr 35,000 band. In 2 other cell lines (MDA-MB-361 and T-47D), the 17-HSD protein concentration was much lower, but still measurable, whereas in the remaining 5 cell lines (HBL-100, MCF-7, MDA-MB-231, MDA-MB-468, and ZR-75-1) it was below the detection limit of the assay. Treatment of the cells for 5 days with the synthetic progestin, ORG2058, resulted in an increase of the 17-HSD protein concentration only in the T-47D cell line. By Northern blot analysis, a low level of 2.3-kilobase mRNA transcripts was detected in all 8 cell lines. In addition, a 1.3-kilobase 17-HSD mRNA was present in the samples from the 3 cell lines containing measurable amounts of 17-HSD protein in the cell extract, and the band intensities were proportional to the amount of protein measured with the immunofluorometric assay. Only in the T-47D cell line did progestin treatment correspond to an increased amount of the 17-HSD 1.3-kilobase mRNA. These results suggest that the 1.3-kilobase mRNA for 17-HSD is the form most closely associated with protein expression and is also the only form responding to the progestin induction of the 17-HSD gene.
PubMed ID
1728403 View in PubMed
Less detail

17 beta-hydroxysteroid dehydrogenases and cancers.

https://arctichealth.org/en/permalink/ahliterature18539
Source
J Steroid Biochem Mol Biol. 2002 Dec;83(1-5):119-22
Publication Type
Article
Date
Dec-2002
Author
P. Vihko
P. Härkönen
O. Oduwole
S. Törn
R. Kurkela
K. Porvari
A. Pulkka
V. Isomaa
Author Affiliation
Biocenter Oulu and Research Center for Molecular Endocrinology, University of Oulu, P.O. Box 5000, FIN-90014 Oulu, Finland. pvihko@whoccr.oulu.fi
Source
J Steroid Biochem Mol Biol. 2002 Dec;83(1-5):119-22
Date
Dec-2002
Language
English
Publication Type
Article
Keywords
17-Hydroxysteroid Dehydrogenases - metabolism
Breast Neoplasms - enzymology
Cell Line
Colonic Neoplasms - enzymology - pathology
Disease Progression
Female
Humans
Male
Neoplasms - enzymology
Oxygen - metabolism
Prostatic Neoplasms - enzymology
Protein Isoforms
Research Support, Non-U.S. Gov't
Tumor Cells, Cultured
Abstract
17 beta-Hydroxysteroid dehydrogenases (17HSDs) catalyze the interconversions between active 17 beta-hydroxysteroids and less-active 17-ketosteroids thereby affecting the availability of biologically active estrogens and androgens in a variety of tissues. The enzymes have different enzymatic properties and characteristic cell-specific expression patterns, suggesting differential physiological functions for the enzymes. Epidemiological and endocrine evidence indicate that estrogens play a key role in the etiology of breast cancer while androgens are involved in mechanisms controlling the growth of prostatic cells, both normal and malignant. Recently, we have developed, using LNCaP prostate cancer cell lines, a cell model to study the progression of prostate cancer. In the model LNCaP cells are transformed in culture condition to more aggressive cells, able to grow in suspension cultures. Our results suggest that substantial changes in androgen and estrogen metabolism occur in the cells during the process. These changes lead to increased production of active estrogens during transformation of the cells. Data from studies of breast cell lines and tissues suggest that the oxidative 17HSD type 2 may predominate in human non-malignant breast epithelial cells, while the reductive 17HSD type 1 activity prevails in malignant cells. Deprivation of an estrogen response by using specific 17HSD type 1 inhibitors is a tempting approach to treat estrogen-dependent breast cancer. Our recent studies demonstrate that in addition to sex hormone target tissues, estrogens may be important in the development of cancer in some other tissues previously not considered as estrogen target tissues such as colon. Our data show that the abundant expression of 17HSD type 2 present in normal colonic mucosa is significantly decreased during colon cancer development.
PubMed ID
12650708 View in PubMed
Less detail

The 68K protease has beta-secretase-like activity for lymphocyte precursor protein but not for brain substrate.

https://arctichealth.org/en/permalink/ahliterature199515
Source
Neuroreport. 2000 Feb 7;11(2):373-7
Publication Type
Article
Date
Feb-7-2000
Author
A. Matsumoto
Author Affiliation
Department of Radiation Biophysics and Genetics, Kobe University School of Medicine, Japan.
Source
Neuroreport. 2000 Feb 7;11(2):373-7
Date
Feb-7-2000
Language
English
Publication Type
Article
Keywords
Aged
Aged, 80 and over
Alzheimer Disease - enzymology
Amino Acid Sequence
Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor - metabolism
Aspartic Acid Endopeptidases - metabolism
Blotting, Western
Cells, Cultured
Cerebral Cortex - enzymology
Chondroitin ABC Lyase - metabolism
Endopeptidases
Female
Humans
Isoenzymes - metabolism
Lymphocytes - cytology - enzymology
Male
Middle Aged
Molecular Sequence Data
Organ Specificity
Peptide Fragments - chemistry
Polysaccharide-Lyases - metabolism
Protein Processing, Post-Translational
Sequence Analysis, Protein
Serine Endopeptidases - metabolism
Substrate Specificity
Abstract
Processing and metabolism of beta-amyloid precursor protein (APP) and generation of a variety of beta-amyloid (Abeta) peptides in the human brain is essentially associated with pathophysiology of Alzheimer's disease (AD). APP degradation activity of the 68 kDa serine protease, which was originally prepared from familial AD lymphoblastoid cells and harbors beta-secretase-like activity, was analyzed by Western blot using anti Abeta 1/40 antibody and anti APP cytoplasmic domain (CT) antibody. Native lymphocyte APP (LAPP) prepared from normal or AD-derived lymphoblastoid cells was degraded by the protease, generating a 16 kDa Abeta-bearing C-terminal fragment of APP. N-terminal amino acid sequencing of the fragment indicated that the protease cleaves LAPP at the Abeta-N-terminus. When the LAPP was treated with chondroitinase ABC prior to proteolysis, the activity to generate the fragment was inhibited, but pretreatment with heparitinase resulted in no effect. Native hippocampal APP prepared from normal brain, however, did not generate the 16 kDa peptide by the protease treatment. These results suggest that the process of APP degradation and Abeta-peptides generation, including beta-secretase activity, is associated with tissue specificity of both APP substrate and proteases. They also indicate that sulfated glycoconjugates attached to a portion of APP isoforms may play a role as a molecular determinant in the proteolysis.
PubMed ID
10674489 View in PubMed
Less detail

Abnormal glycosylation and altered Golgi structure in colorectal cancer: dependence on intra-Golgi pH.

https://arctichealth.org/en/permalink/ahliterature19175
Source
FEBS Lett. 2002 Apr 10;516(1-3):217-24
Publication Type
Article
Date
Apr-10-2002
Author
Sakari Kellokumpu
Raija Sormunen
Ilmo Kellokumpu
Author Affiliation
Department of Biochemistry, University of Oulu, P.O. Box 3000, FIN-90014, Oulu, Finland. sakari.kellokumpu@oulu.fi
Source
FEBS Lett. 2002 Apr 10;516(1-3):217-24
Date
Apr-10-2002
Language
English
Publication Type
Article
Keywords
Animals
Antigens, Tumor-Associated, Carbohydrate - metabolism
Breast Neoplasms - immunology - metabolism - ultrastructure
COS Cells
Cells, Cultured
Colorectal Neoplasms - immunology - metabolism - ultrastructure
Female
Glycosylation
Golgi Apparatus - immunology - metabolism - ultrastructure
Humans
Hydrogen-Ion Concentration
Ion Transport
Microscopy, Electron
Rats
Research Support, Non-U.S. Gov't
Tumor Cells, Cultured
Abstract
Abnormal glycosylation of cellular glycoconjugates is a common phenotypic change in many human tumors. Here, we explore the possibility that an altered Golgi pH may also be responsible for these cancer-associated glycosylation abnormalities. We show that a mere dissipation of the acidic Golgi pH results both in increased expression of some cancer-associated carbohydrate antigens and in structural disorganization of the Golgi apparatus in otherwise normally glycosylating cells. pH dependence of these alterations was confirmed by showing that an acidification-defective breast cancer cell line (MCF-7) also displayed a fragmented Golgi apparatus, whereas the Golgi apparatus was structurally normal in its acidification-competent subline (MCF-7/AdrR). Acidification competence was also found to rescue normal glycosylation potential in MCF-7/AdrR cells. Finally, we show that abnormal glycosylation is also accompanied by similar structural disorganization and fragmentation of the Golgi apparatus in colorectal cancer cells in vitro and in vivo. These results suggest that an inappropriate Golgi pH may indeed be responsible for the abnormal Golgi structure and lowered glycosylation potential of the Golgi apparatus in malignant cells.
PubMed ID
11959136 View in PubMed
Less detail

Abnormal regulation of the LDL-R and HMG CoA reductase genes in subjects with familial hypercholesterolemia with the "French Canadian mutation".

https://arctichealth.org/en/permalink/ahliterature211598
Source
Atherosclerosis. 1996 Jul;124(1):103-17
Publication Type
Article
Date
Jul-1996
Author
L. Yu
S. Qiu
J. Genest
Author Affiliation
Cardiovascular Genetics Laboratory, Clinical Research Institute of Montréal, Québec Canada.
Source
Atherosclerosis. 1996 Jul;124(1):103-17
Date
Jul-1996
Language
English
Publication Type
Article
Keywords
Anticholesteremic Agents - pharmacology - therapeutic use
Canada - epidemiology
Cells, Cultured
Enzyme Induction
Enzyme Inhibitors - pharmacology - therapeutic use
Ethnic Groups - genetics
Female
Fibroblasts - metabolism
France - ethnology
Gene Expression Regulation - drug effects
Haploidy
Humans
Hydroxymethylglutaryl CoA Reductases - genetics
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Hyperlipoproteinemia Type II - drug therapy - ethnology - genetics
Lipoproteins, LDL - metabolism
Lovastatin - pharmacology - therapeutic use
Male
Prevalence
RNA, Messenger - biosynthesis - genetics
Receptors, LDL - genetics - metabolism
Sequence Deletion
Transcription, Genetic
Treatment Failure
Abstract
Familial hypercholesterolemia (FH) is seen with high frequency in the province of Québec, Canada. A large deletion (> 10 kb) of the 5'-end of the low density lipoprotein receptor (LDL-R) gene is the major mutation of the LDL-R in FH subjects in Québec (approximately 60% of FH subjects). No mRNA is produced from the allele bearing the mutation, and cellular cholesterol obtained by receptor-mediated endocytosis is under the control of the non-deletion allele. We have previously reported that some patients with the 10-kb deletion (approximately 9%) fail to respond to the hydroxymethylglutaryl coenzyme A reductase (HMG CoA reductase) inhibitor class of medications. We studied mRNA levels of the LDL-R and HMG CoA reductase genes in response to the HMG CoA reductase inhibitor lovastatin in a time- and dose-dependent fashion in cultured human skin fibroblasts and we devised an in vitro model to study the response to drug therapy in subjects with FH. We determined mRNA levels by RNase protection assay in skin fibroblasts obtained from controls (n = 3) and FH subjects with the > 10-kb deletion (responders, n = 3; non responders, n = 3; to drug therapy). We measured 125I-LDL binding on skin fibroblasts grown in the presence of lipoprotein-deficient serum with or without 1 microM lovastatin, using 10 micrograms/mL of 125I-LDL protein. Control subjects exhibited coordinate regulation of the LDL-R and HMG CoA reductase genes in response to lovastatin, 0.1-25 microM, for 0-24 h. Correlation coefficients between mRNA levels of both genes were > 0.9 in controls and FH subjects. However, by linear regression analysis, the corresponding slopes for the correlation between both genes were 0.98 (controls), 3.36 and 3.63 (FH responders and non-responders), indicating a pattern of dissociated but still coordinate regulation in FH subjects. The magnitude of increase of mRNA levels of the LDL-R gene was approximately five-fold over LPDS in controls, two-fold in FH responders and two-fold in non-responders. Binding studies using 125I-LDL reveal that a control subject and all responders had a 2-2.5-fold increase in binding to cell surface receptors but two out of three FH non-responders showed no increase in binding in response to 1 microM lovastatin. The LDL-R and HMG CoA reductase genes are expressed in coordinate regulation in fibroblasts from subjects with FH due to the > 10-kb deletion, but with a proportionately greater up-regulation of the HMG CoA reductase gene. Some subjects, with FH caused by the > 10-kb deletion of the LDL-R gene, who fail to respond to HMG CoA reductase inhibitors have abnormal LDL receptor binding activity at the cell surface in response to lovastatin in vitro.
PubMed ID
8800498 View in PubMed
Less detail

Acetyldinaline: a new oral cytostatic drug with impressive differential activity against leukemic cells and normal stem cells--preclinical studies in a relevant rat model for human acute myelocytic leukemia.

https://arctichealth.org/en/permalink/ahliterature23997
Source
Cancer Res. 1993 Jul 1;53(13):3008-14
Publication Type
Article
Date
Jul-1-1993
Author
H M el-Beltagi
A C Martens
P. Lelieveld
E A Haroun
A. Hagenbeek
Author Affiliation
Department of Hemato-Oncology TNO, Erasmus University Rotterdam, The Netherlands.
Source
Cancer Res. 1993 Jul 1;53(13):3008-14
Date
Jul-1-1993
Language
English
Publication Type
Article
Keywords
Administration, Oral
Animals
Antineoplastic Agents - pharmacology
Bone Marrow - drug effects
Bone Marrow Cells
Cell Differentiation - drug effects
Cell Survival - drug effects
Clone Cells
Comparative Study
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Administration Schedule
Drug Evaluation
Drug Screening Assays, Antitumor
Hematopoietic Stem Cells - cytology - drug effects
Leukemia, Myelocytic, Acute - drug therapy - pathology
Male
Phenylenediamines - pharmacology
Rats
Rats, Inbred BN
Research Support, Non-U.S. Gov't
Tumor Cells, Cultured
Abstract
Acetyldinaline [CI-994; GOE 5549; PD 123 654; 4-acetylamino-N-(2'-aminophenyl)-benzamide] is the acetylated derivative form of the original compound Dinaline (GOE 1734; PD 104 208). The efficacy and toxicity of Acetyldinaline for remission-induction treatment of leukemia were evaluated and compared with those observed in previous studies of Dinaline in the Brown Norway acute myelocytic leukemia, as a preclinical model for human acute myelocytic leukemia. There were three treatment groups. Leukemic animals received either 1 or 2 courses of 5 daily p.o. administrations of Acetyldinaline with a "full dose" of 23.7 mg/kg once daily (first group), a twice daily "half dose" of 11.85 mg/kg with an interval of 8 h (second group), or a "half dose" of 11.85 mg/kg once daily (third group). The drug-free interval between the 2 courses was 2 or 9 days. With repeated daily p.o. administrations of 23.7 mg/kg either in a single daily dose or a split daily dose of 2 x 11.85 mg/kg for 1 course, at least an 8-log leukemic cell kill was achieved. In contrast, with these treatment schedules, less than a 1-log cell kill of normal pluripotent hemopoietic stem cells (CFU-S) in the femoral bone marrow was found. Split daily dose treatment was more effective resulting in 37.5% cures, while no cures were observed with the single daily treatment for one course. Treatment with single daily dose of 23.7 mg/kg or a split daily dose of 2 x 11.85 mg/kg for 2 courses, with either a 2- or 9-day interval in between, resulted in lethal toxicity in most of rats. This result was comparable with that previously observed after equimolar doses of Dinaline (20 mg/kg). The half-dose once daily treatment with Acetyldinaline (11.85 mg/kg) for 1 or 2 cycles resulted in about a 4.5 or > 8-log leukemic cell kill, respectively. Toxic side effects, i.e., damage to the gastro-intestinal tract and hemorrhages in the lungs, were more pronounced with full dose either in the single or the split daily dose regimen. No significant toxicity was observed at the half-dose treatment once daily. In conclusion, the impressive differential activity against leukemic cells and normal stem cells observed in this relevant rat model for human acute myelocytic leukemia warrants the introduction of this compound in clinical phase I/II studies.
PubMed ID
8319208 View in PubMed
Less detail

682 records – page 1 of 69.