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Proceedings of the National Academy of... Jan 1979Conclusive proof that the mouse egg is capable of carrying out repair of genetic lesions present in the male genome was obtained through dominant-lethal studies of...
Conclusive proof that the mouse egg is capable of carrying out repair of genetic lesions present in the male genome was obtained through dominant-lethal studies of chemically treated spermatozoa and spermatids and through cytological analysis of first-cleavage metaphases. The maximum difference in repair capability between stocks of females, found for isopropyl methanesulfonate treatment, was large; considerably smaller differences were found for ethyl methanesulfonate, triethylenemelamine, and benzo[a]pyrene treatments; and no difference was found for x-ray treatment.
Topics: Animals; DNA Repair; Female; Genes, Dominant; Genes, Lethal; Male; Metaphase; Mice; Mice, Inbred Strains; Mutagens; Ovum; Spermatids; Spermatozoa
PubMed: 284360
DOI: 10.1073/pnas.76.1.435 -
Archives of Disease in Childhood Feb 1968
Topics: Blood Cell Count; Child; Child, Preschool; Chlorambucil; Cyclophosphamide; Female; Humans; Leukemia; Leukemia, Lymphoid; Liver; Male; Mercaptopurine; Methotrexate; Organ Size; Prednisone; Prognosis; Spleen; Triethylenemelamine; Vincristine
PubMed: 5238739
DOI: 10.1136/adc.43.227.107 -
Immunology Jan 1964Mice were injected with T.A.B. vaccine and, 2 days later, with various doses of different compounds. The relation between dose of compound, mortality and antibody...
Mice were injected with T.A.B. vaccine and, 2 days later, with various doses of different compounds. The relation between dose of compound, mortality and antibody production was studied, and therapeutic indices were calculated for a number of compounds. The most effective agent in suppressing antibody production at relatively non-toxic doses was cyclophosphamide, with next amethopterin (the effect of which was, however, inexplicably erratic), 6-thioguanine and 6-mercaptopurine, in that order. Vincaleukoblastine, triethylene melamine, triethylenethiophosphoramide, mannomustine and 5-fluorouracil were less effective. Compounds of a miscellaneous group (boric acid, caffeine, sodium nitrite, bacitracin, neomycin and polymyxin `B') were studied in the same way: they had no effect on antibody production, even in lethal doses.
Topics: Allergy and Immunology; Antibody Formation; Antineoplastic Agents; Autoimmune Diseases; Cyclophosphamide; Fluorouracil; Immunity; Mannomustine; Mercaptopurine; Methotrexate; Mice; Mortality; Research; Thioguanine; Toxicology; Transplantation; Triethylenemelamine; Typhoid-Paratyphoid Vaccines; Vinblastine
PubMed: 14113077
DOI: No ID Found -
British Journal of Pharmacology and... Jun 1959The effects of tumour inhibitory doses of tretamine (triethylenemelamine), busulphan, and melphalan on the fertility of male rats have been examined. The aromatic...
The effects of tumour inhibitory doses of tretamine (triethylenemelamine), busulphan, and melphalan on the fertility of male rats have been examined. The aromatic nitrogen mustard, melphalan, was inactive, but busulphan has a highly selective action on spermatogenesis which contrasts strikingly with that of tretamine. The main action of tretamine was exerted upon spermatocytes or spermatids, but, with increasing dose, the effects spread to involve a wide range of spermatogenic cells including mature sperm, so that infertility could be induced very rapidly. Busulphan, however, interfered with the development of spermatogonia for several weeks, although other germinal cells were unaffected and continued to develop into mature spermatozoa. This accounted for the continuation of normal fertility for 7 weeks after a dose, before sterility suddenly developed. The antifertility activity of tretamine could be simulated by a variety of other ethyleneimino compounds, potency being greatest in trifunctional and least in monofunctional compounds. The latter were, however, very destructive to the seminiferous epithelium with increasing dose. In the rat, there appeared to be no definite relationship between the ability of alkylating substances to interfere with the activity of normal and pathological proliferating tissues, as represented by the germinal epithelium, haematopoietic, and tumour tissue. Although carcinogenicity was a biological property of alkylating agents, other chemical types of carcinogen did not interfere with fertility.
Topics: Alkylating Agents; Animals; Fertility; Fertility Agents; Germ Cells; Infertility; Male; Mechlorethamine; Rats; Spermatogenesis; Spermatogonia; Spermatozoa; Triethylenemelamine
PubMed: 13662565
DOI: 10.1111/j.1476-5381.1959.tb01375.x -
OncoTargets and Therapy 2011Despite significant progress made in the overall cure rate, the prognosis for relapsed and refractory malignancies in children remains extremely poor. Hence, there is an...
Systematic in-vitro evaluation of the NCI/NIH Developmental Therapeutics Program Approved Oncology Drug Set for the identification of a candidate drug repertoire for MLL-rearranged leukemia.
Despite significant progress made in the overall cure rate, the prognosis for relapsed and refractory malignancies in children remains extremely poor. Hence, there is an urgent need for studies that enable the timely selection of appropriate agents for Phase I clinical studies. The Pediatric Oncology Experimental Therapeutics Investigators' Consortium (POETIC) is systematically evaluating libraries of known and novel compounds for activity against subsets of high-risk pediatric malignancies with defined molecular aberrations for future clinical development. In this report, we describe the in-vitro activity of a diverse panel of approved oncology drugs against MLL-rearranged pediatric leukemia cell lines. Agents in the Approved Oncology Drug Set II (National Cancer Institute/National Institutes of Health Developmental Therapeutics Program) were evaluated by in-vitro cytotoxicity assays in pediatric acute lymphoblastic leukemia and acute myeloid leukemia cell lines with MLL gene rearrangements. Validation studies were carried out with patient leukemia cells in culture. Comparative analysis for toxicity against nonmalignant cells was evaluated in normal bone marrow stromal cells and normal human lymphocytes. Results from this study show that 42 of the 89 agents tested have measurable cytotoxicity against leukemia cells, and among these, 12 were effective against all five MLL-rearranged cell lines (IC(50) [half maximal inhibitory concentration] < 1 μM). These 12 agents include cladribine, dactinomycin, daunorubicin, docetaxel, etoposide, gemcitabine, mitomycin C, mitoxantrone, teniposide, topotecan, triethylenemelamine, and vinblastine. We show that the Approved Oncology Drug Set II contains a number of agents with potent antileukemic activity in the tested cell lines. As approved drugs, these agents have been used in clinical settings for many years for other malignancies, thus their toxicity profile, pharmacokinetics, and other properties are readily available. Further evaluation of their use in future clinical trials for pediatric leukemia with MLL abnormalities should be considered.
PubMed: 21949608
DOI: 10.2147/OTT.S21553 -
Genetics Jan 1977Induction of chromosome aberrations in pachytene spermatocytes of mice by 2 mg/kg TEM was compared with induction by 400 R X rays. These doses induced comparably high...
Induction of chromosome aberrations in pachytene spermatocytes of mice by 2 mg/kg TEM was compared with induction by 400 R X rays. These doses induced comparably high dominant lethal effects in pachytene spermatocytes of mice. Cytological analysis at diakinesis-metaphase I stage showed that whereas 76.4% of the cells treated with X rays at pachytene stage had aberrations, the frequencies observed in two TEM experiments were only 0.8 and 2.2%. On the other hand, 5% of the progeny from TEM-treated pachytene spermatocytes were found to be translocation heterozygotes. This is the first report on the recovery of heritable translocations from treated spermatocytes of mice. The aberration frequencies observed for TEM in diakinesis-metaphase I were much too low to account for all the lethal mutations and heritable translocations. Thus, the formation of the bulk of aberrations induced by TEM in pachytene spermatocytes was delayed--a marked contrast to the more immediate formation of X-ray-induced aberrations. It is postulated that the formation of the bulk of TEM-induced aberrations in pachytene spermatocytes and in certain postmeiotic stages occurs sometime during spermiogenesis, and not through the operation of postfertilization pronuclear DNA synthesis.
Topics: Animals; Chromosome Aberrations; Male; Meiosis; Mice; Mutagens; Spermatocytes; Spermatozoa; Triethylenemelamine; X-Rays
PubMed: 838271
DOI: 10.1093/genetics/85.1.65 -
California Medicine Feb 1953X-radiation remains the treatment of choice in most cases of leukemia and lymphoma, but new agents are playing an increasing role in therapy. Radioactive phosphorus does...
X-radiation remains the treatment of choice in most cases of leukemia and lymphoma, but new agents are playing an increasing role in therapy. Radioactive phosphorus does not produce radiation sickness and results with it are comparable to those of x-ray therapy in chronic leukemia. Urethane and nitrogen mustard may produce remissions in patients with chronic leukemia who have become resistant to radiation. Triethylene melamine may be administered orally with nitrogen mustard-like effects and is undergoing further trial. Aminopterin, ACTH and cortisone often cause short remissions in acute leukemia. Urethane is the best treatment available for multiple myeloma. Polycythemia vera is well controlled by radioactive phosphorus combined with venesection. Nitrogen mustard is often effective and triethylene melamine shows promise in Hodgkin's disease. Antianemic substances such as iron and liver extract are of no value in the treatment of anemia caused by leukemia, lymphoma and myeloma.
Topics: Aminopterin; Chronic Disease; Hodgkin Disease; Humans; Leukemia; Lymphoma; Mechlorethamine; Multiple Myeloma; Neoplasms; Phlebotomy; Polycythemia; Triethylenemelamine; Urethane; X-Ray Therapy
PubMed: 13019601
DOI: No ID Found -
Journal of Clinical Oncology : Official... Oct 2014Hereditary retinoblastoma (Rb) survivors have increased risk of subsequent malignant neoplasms (SMNs). Previous studies reported elevated radiotherapy (RT) -related SMN...
PURPOSE
Hereditary retinoblastoma (Rb) survivors have increased risk of subsequent malignant neoplasms (SMNs). Previous studies reported elevated radiotherapy (RT) -related SMN risks, but less is known about chemotherapy-related risks.
PATIENTS AND METHODS
In a long-term follow-up study of 906 5-year hereditary Rb survivors diagnosed from 1914 to 1996 and observed through 2009, treatment-related SMN risks were quantified using cumulative incidence analyses and multivariable Cox proportional hazards regression models with age as the underlying time scale.
RESULTS
Nearly 90% of Rb survivors were treated with RT, and almost 40% received alkylating agent (AA) -containing chemotherapy (predominantly triethylenemelamine). Median follow-up time to first SMN diagnosis was 26.3 years. Overall SMN risk was not significantly elevated among survivors receiving AA plus RT versus RT without chemotherapy (hazard ratio [HR], 1.27; 95% CI, 0.99 to 1.63). AA-related risks were significantly increased for subsequent bone tumors (HR, 1.60; 95% CI, 1.03 to 2.49) and leiomyosarcoma (HR, 2.67; 95% CI, 1.22 to 5.85) but not for melanoma (HR, 0.74; 95% CI, 0.36 to 1.55) or epithelial tumors (HR, 0.89; 95% CI, 0.48 to 1.64). Leiomyosarcoma risk was significantly increased for survivors who received AAs at age < 1 (HR, 5.17; 95% CI, 1.76 to 15.17) but not for those receiving AAs at age ≥ 1 year (HR, 1.75; 95% CI, 0.68 to 4.51). Development of leiomyosarcoma was significantly more common after AA plus RT versus RT (5.8% v 1.6% at age 40 years; P = .01).
CONCLUSION
This comprehensive quantification of SMN risk after chemotherapy and RT among hereditary Rb survivors also demonstrates an AA-related contribution to risk. Although triethylenemelamine is no longer prescribed, our findings warrant further follow-up to investigate potential SMN risks associated with current chemotherapies used for Rb.
Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Longitudinal Studies; Male; Neoplasms, Second Primary; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Risk; Survival Rate; Survivors; Triethylenemelamine; United States
PubMed: 25185089
DOI: 10.1200/JCO.2013.54.7844 -
Cytometry Mar 1994Exposure to the mutagen triethylenemelamine on rat bone marrow, blood, and testis was studied using flow cytometry of DAPI-stained nuclei. Increased coefficients of...
Exposure to the mutagen triethylenemelamine on rat bone marrow, blood, and testis was studied using flow cytometry of DAPI-stained nuclei. Increased coefficients of variation (CVs) of the G1 peaks were observed in bone marrow and blood after both 1 d and 5 d exposures. After 5 d exposure and 7 d recovery both tissues had recovered, in some cases to significantly lower CVs. Increased CVs of the 1C peak of testis were observed only after 5 d exposure to the high dose with no subsequently observed recovery. Bone marrow cells also were stained with Hoechst 33258 and Propidium Iodide. No differences among dyes were observed indicating that increased CVs likely are due to DNA damage resulting from interactions with the mutagen rather than differences in how the dyes bind to DNA relative to mutagen binding. This study demonstrates that differences occur among tissues in how quickly they respond and recover from mutagen exposure. Increased CVs, cell cycle alterations, and decreased CVs after recovery are all potentially useful biomarkers of effect for laboratory and field studies in environmental toxicology.
Topics: Animals; Bisbenzimidazole; Blood Cells; Bone Marrow; Bone Marrow Cells; Cell Cycle; Cell Nucleus; DNA; Dose-Response Relationship, Drug; Flow Cytometry; Indoles; Male; Propidium; Rats; Rats, Sprague-Dawley; Testis; Time Factors; Triethylenemelamine
PubMed: 7514522
DOI: 10.1002/cyto.990150307 -
Genetics Jan 1974Using mutagens on sperm and spermatids we have produced nineteen chromosomal inversions in mice. The levels of radiation and chemical mutagen we used induced inversions... (Comparative Study)
Comparative Study
Using mutagens on sperm and spermatids we have produced nineteen chromosomal inversions in mice. The levels of radiation and chemical mutagen we used induced inversions in about one per cent of the animals screened. Nine inversions have been transmitted through successive generations, and the particular frequency of first meiotic anaphase bridges manifested by each inversion remained constant. The cytological properties of first meiotic anaphases varied considerably among the inversions. Chromosomal locations of five inversions are known. Four of the five are fully viable in homozygous condition.
Topics: Animals; Chromosome Aberrations; Chromosomes; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Female; Gene Frequency; Heterozygote; Homozygote; Infertility, Male; Male; Mesylates; Mice; Mice, Inbred Strains; Mutagens; Mutation; Radiation Genetics; Spermatozoa; Triethylenemelamine
PubMed: 4361911
DOI: 10.1093/genetics/76.1.109