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Molecular and Cellular Biology Jan 1987We developed highly sensitive shuttle vector systems for detection of mutations formed in human cells using autonomously replicating derivatives of Epstein-Barr virus...
We developed highly sensitive shuttle vector systems for detection of mutations formed in human cells using autonomously replicating derivatives of Epstein-Barr virus (EBV). EBV vectors carrying the bacterial lacI gene as the target for mutation were established in human cells and later returned to Escherichia coli for rapid detection and analysis of lacI mutations. The majority of the clonal cell lines created by establishment of the lacI-EBV vector show spontaneous LacI- frequencies of less than 10(-5) and are suitable for studies of induced mutation. The ability to isolate clonal lines represents a major advantage of the EBV vectors over transiently replicating shuttle vectors (such as those derived from simian virus 40) for the study of mutation. The DNA sequence changes were determined for 61 lacI mutations induced by exposure of one of the cell lines to N-nitroso-N-methylurea. A total of 33 of 34 lacI nonsense mutations and 26 of 27 missense mutations involve G X C to A X T transitions. These data provide support for the mutational theory of cancer.
Topics: Cell Line; Genetic Vectors; Herpesvirus 4, Human; Humans; Kidney; Methylnitrosourea; Mutation; Plasmids
PubMed: 3031469
DOI: 10.1128/mcb.7.1.379-387.1987 -
Teratogenesis, Carcinogenesis, and... 1993Prenatal-toxic risk estimation for the alkylating model compound methylnitrosourea (MNU) was performed using different procedures. Risk of low doses was estimated using... (Comparative Study)
Comparative Study Review
Embryotoxicity induced by alkylating agents: 7. Low dose prenatal-toxic risk estimation based on NOAEL risk factor approach, dose-response relationships, and DNA adducts using methylnitrosourea as a model compound.
Prenatal-toxic risk estimation for the alkylating model compound methylnitrosourea (MNU) was performed using different procedures. Risk of low doses was estimated using linear extrapolation to zero (estimated ED0.1%: 0.1 mg/kg body wt MNU) as well as extrapolation by probit analysis based on a dose-response study (estimated ED0.1%: 1.6 mg/kg body wt). Furthermore, a "virtually safe dose" was established by means of the NOAEL risk factor approach (e.g., factor 30:0.03 mg MNU per kg body wt). In previous studies in murine embryos using MNU, we combined dose-response data and DNA adduct rate measurements and deduced that O6-methylguanine is a suitable variable for molecular dosimetry. In a tentative approach, we estimated the teratogenic risk of low doses based on the adduct rates of O6-methylguanine in the DNA of the embryos. It is concluded that in the case of steep dose-response relationships, which are typical for the majority of teratogenic effects, the NOAEL risk factor approach is more conservative than extrapolation based on probit analysis. Risk estimation using dosimetry with this model compound yields estimated incidences similar to linear extrapolation.
Topics: Abnormalities, Drug-Induced; Algorithms; Alkylating Agents; Alkylation; Animals; DNA; DNA Damage; Dose-Response Relationship, Drug; Embryo, Mammalian; Ethyl Methanesulfonate; Female; Fetal Death; Guanine; Methylnitrosourea; Mice; Models, Theoretical; Pregnancy; Risk Factors; Toxicology
PubMed: 8105554
DOI: 10.1002/tcm.1770130302 -
Chemico-biological Interactions Sep 1976The lag in phenotype expression of methylnitrosourea(MNU)-induced mutation to 6-thioguanine (6TG) resistance has been studied in a diploid human lymphoblastoid cell...
The lag in phenotype expression of methylnitrosourea(MNU)-induced mutation to 6-thioguanine (6TG) resistance has been studied in a diploid human lymphoblastoid cell line. We find that a considerable period (8-12 days) elapses before new mutants appear in treated cultures; after 2 weeks, however, a stable maximum fraction is attained, as would be expected for a genetic mutation. We present preliminary data linking this phenotypic lag to the slow degradation rate of hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and to an apparent requirement for very low (less than 0.2% normal) cellular HGPRT content in order for cells to be resistant to 10 mug 6TG/ml. A series of reconstruction experiments are presented, the results of which support the conclusion that selective pressures in the assay procedure do not bias the quantitative estimates of induced mutant fraction.
Topics: Cell Line; Cell Survival; Clone Cells; Diploidy; Humans; Hypoxanthine Phosphoribosyltransferase; Lymphocytes; Methylnitrosourea; Mutation; Nitrosourea Compounds; Phenotype; Time Factors
PubMed: 971516
DOI: 10.1016/0009-2797(76)90126-5 -
Tumour Biology : the Journal of the... Dec 2015The administration of chemical carcinogens is one of the most commonly used methods to induce tumors in several organs in laboratory animals in order to study oncologic... (Review)
Review
The administration of chemical carcinogens is one of the most commonly used methods to induce tumors in several organs in laboratory animals in order to study oncologic diseases of humans. The carcinogen agent N-methyl-N-nitrosourea (MNU) is the oldest member of the nitroso compounds that has the ability to alkylate DNA. MNU is classified as a complete, potent, and direct alkylating compound. Depending on the animals' species and strain, dose, route, and age at the administration, MNU may induce tumors' development in several organs. The aim of this manuscript was to review MNU as a carcinogenic agent, taking into account that this carcinogen agent has been frequently used in experimental protocols to study the carcinogenesis in several tissues, namely breast, ovary, uterus, prostate, liver, spleen, kidney, stomach, small intestine, colon, hematopoietic system, lung, skin, retina, and urinary bladder. In this paper, we also reviewed the experimental conditions to the chemical induction of tumors in different organs with this carcinogen agent, with a special emphasis in the mammary carcinogenesis.
Topics: Animals; Breast; Carcinogens; Cell Transformation, Neoplastic; DNA; Female; Humans; Mammary Neoplasms, Experimental; Methylnitrosourea
PubMed: 26386719
DOI: 10.1007/s13277-015-3973-2 -
Cancer Oct 1975The nitrosourea group of antitumor agents was developed by the Division of Cancer Treatment of the National Cancer Institute. Three nitrosoureas (BCNU, CCNU, MeCCNU)... (Comparative Study)
Comparative Study Review
The nitrosourea group of antitumor agents was developed by the Division of Cancer Treatment of the National Cancer Institute. Three nitrosoureas (BCNU, CCNU, MeCCNU) have undergone extensive clinical trials, and two of them (BCNU, CCNU) will soon become commercially available. This paper briefly considers the preclinical development of the nitrosoureas and provides an overview and comparison of the extensive clinical data. Information is given regarding any clinical differences. We discuss general conclusions drawn from the nitrosourea development.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Breast Neoplasms; Carmustine; Chemical Phenomena; Chemistry; Colonic Neoplasms; Drug Therapy, Combination; Hodgkin Disease; Humans; Lomustine; Lung Neoplasms; Lymphoma; Melanoma; Methylnitrosourea; Mice; Neoplasms, Experimental; Nitrosourea Compounds; Rectal Neoplasms
PubMed: 1100221
DOI: 10.1002/1097-0142(197510)36:4<1258::aid-cncr2820360411>3.0.co;2-6 -
Report on Carcinogens : Carcinogen... 2002
Topics: Animals; Carcinogens; Environmental Exposure; Government Regulation; Humans; Methylnitrosourea; United States
PubMed: 15328581
DOI: No ID Found -
Report on Carcinogens : Carcinogen... 2004
Topics: Alkylating Agents; Animals; Animals, Newborn; Carcinogenicity Tests; Carcinogens; Cricetinae; Dogs; Environmental Exposure; Female; Gerbillinae; Government Regulation; Guidelines as Topic; Guinea Pigs; Haplorhini; Humans; Male; Methylnitrosourea; Mice; Models, Biological; Pregnancy; Rats; United States
PubMed: 21089933
DOI: No ID Found -
Pathology Oncology Research : POR Mar 2009Several animal models of breast cancer have been developed to study various aspects of breast cancer biology. Substantial evidence suggests that the N-methylnitrosourea...
Several animal models of breast cancer have been developed to study various aspects of breast cancer biology. Substantial evidence suggests that the N-methylnitrosourea (MNU) animal model mimics human breast cancer in many respects. It has therefore been used extensively to evaluate preventive and therapeutic agents for human breast cancer. Chemically induced rodent models are also suitable for studying malignant progression. Recently, Liska et al. [7] established two protocols of MNU administration depending on the animal's age and number of applications of carcinogen, with the aim of investigating the advanced stages of mammary gland tumours. We used the same protocol as Liska but have obtained substantially different results. These results are presented and discussed in the frame of suggested key drawbacks of the MNU induced breast cancer rat model, as a contribution to the debate about the suitability of that model for evaluating preventive and therapeutic agents.
Topics: Animals; Carcinogens; Disease Models, Animal; Female; Mammary Neoplasms, Experimental; Methylnitrosourea; Neoplasm Invasiveness; Rats; Rats, Sprague-Dawley
PubMed: 18985443
DOI: 10.1007/s12253-008-9117-x -
Toxicologic Pathology 1988
Topics: Ameloblastoma; Animals; Male; Methylnitrosourea; Odontogenic Tumors; Odontoma; Rats; Terminology as Topic
PubMed: 3187357
DOI: 10.1177/019262338801600226 -
Histology and Histopathology Jul 2010Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases in humans characterized by loss of photoreceptor cells leading to visual disturbance and... (Review)
Review
Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases in humans characterized by loss of photoreceptor cells leading to visual disturbance and eventually to blindness. A single systemic administration of N-methyl-N-nitrosourea (MNU) causes retinal degeneration in various animal species. The retinal degeneration is highly reproducible, and the photoreceptor cell loss occurs within seven days after MNU administration via apoptosis resembling human RP. Here, we describe the disease progression, disease mechanisms, and therapeutic trials of MNU-induced retinal degeneration.
Topics: Animals; Apoptosis; Methylnitrosourea; Mice; Models, Animal; Nitrosourea Compounds; Photoreceptor Cells; Rats; Retinal Degeneration; Retinitis Pigmentosa
PubMed: 20503181
DOI: 10.14670/HH-25.933