摘要:

AbstractThe effect of benzamide (B) and 3‐aminobenzamide (3‐AB) on sister chromatid exchanges (SCEs) and cell kinetics induced in vitro by melphalan (MELPH) or thiotepa (THIO) was studied in normal human lymphocytes. The combined treatments with either MELPH or THIO plus B or 3‐AB showed the potentiating ability on SCE rates and the ability to induce cell division delays of the latter chemicals.In a combined in vivo and in vitro study, lymphocytes taken from six cancer patients who had been given cytoxan by injection 2 hr before and then treated with theophylline (THEOPH) or B or 3‐AB in vitro were found to have synergistically increased exchange rates and cell division delays. The frequency of SCEs in the patients own lymphocytes with and without exposure to inhibitor of Poly(ADP‐ribose) polymerase (P(ADPR)polymerase) was determined before the cytostatic therapy and was used as a control for later comparison in each individual case. These results further substantiate the use of this approach for detecting the induction of cytogenetic damage concerning controlled mutagen human exposure in combined in vivo and in vitro studies.Chemically induced cytotoxicity manifested as an alteration (division delay) in cell kinetics and as synergistic DNA damage by cytostatics and inhibitors of P(ADPR)polymerase may be of use in the treatment of hum

ISSN:0270-3211    

DOI:10.1002/tcm.1770060602

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1986

数据来源: WILEY

摘要:

AbstractStress or heat shock proteins (hsp) are synthesized by most cells in response to adverse environmental conditions. In mammalian cells, the major proteins synthesized in response to stress have relative molecular weights (Mr) in the range of 68 to 74 kilodaltons (kD) and are encoded by a small multi‐gene family collectively referred to as hsp 70 genes. In unfertilized mouse eggs, no members of the hsp 70 family appear to be synthesized under normal or stressful (heat shock) conditions. At the two‐cell stage, two proteins with Mr = 74 kD and Mr = 70 kD are expressed as a consequence of developmentally activated transcription of these hsp 70 genes. No stressinduced synthesis in response to heat shock is observed at this stage. At the eight‐cell stage, constitutive synthesis of the 70‐kD protein continues, but, as in the two‐cell embryo, no heat shock induced synthesis of a novel heat shock protein is observed. By the blastocyst stage, however, an inducible protein with Mr = 68 kD is synthesized in response to heat shock in addition to constitutive synthesis of the 70‐kD protein. The constitutively synthesized cognate proteins are coded for by a set of mRNAs about 2,000 nucleotides in length. The induced hsp 68 proteins are coded for by mRNAs of larger size (about 2,600 nucleotides). Only the smaller mRNA class is detectable on Northern blots of RNA extracted from control or heat shock cleavage stage embryos and control blastocysts. As predicted from protein synthetic studies, both classes are resolved in RNA preparations derived from heat‐shocke

ISSN:0270-3211    

DOI:10.1002/tcm.1770060603

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1986

数据来源: WILEY

摘要:

AbstractA series of nitroimidazo[2,1‐b]thiazole derivatives was investigated for directacting mutagenic potency with the Salmonella assay. All of the nine derivatives tested were mutagenic. The compounds induced predominantly base displacements resulting in frame‐shift mutations. The mutagenic activity did not require the S9 fraction but was largely dependent on “classical” bacterial nitroreductase. The primary basis of the mutagenic activity of nitroimidazo[2,1‐b]thiazoles appears to be a reduction of the nitro‐function to the corresponding hydroxylamine. Mutagenicity seems to be paralleled by an increase of the nitro groups: dinitroderivatives were more active than nitroderivatives. Other electrophiles and sterically constrained nitro groups could account for differences in g

ISSN:0270-3211    

DOI:10.1002/tcm.1770060604

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1986

数据来源: WILEY

ISSN:0270-3211    

DOI:10.1002/tcm.1770060605

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1986

数据来源: WILEY

摘要:

AbstractExposure of prokaryotic and eukaryotic cells to heat shock (hyperthermia) or to a number of diverse environmental stresses such as teratogens, anoxia, and inhibitors of oxidative phosphorylation results in the enhanced synthesis of a number of proteins which have been previously referred to as heat shock proteins (hsps). More recently, in view of the diverse types of agents that can induce these proteins, they have also been referred to as stress proteins. This phenomenon is one of the most basic regulatory mechanisms in living organisms. Exposure ofDrosophilaembryos, larvae, or pupae to these types of stresses also results in a variety of developmental abnormalities in the ensuing adult. Although the function(s) of these heat shock proteins has yet to be determined, they are widely thought to play an important role in cell survival and protection following some types of environmental stress. In our laboratory, we have developed an in vitro assay for detecting agents that act as teratogens, utilizingDrosophilaembryonic cultures.Drosophilaembryonic cells differentiate in vitro to a number of functional cell types including myotubes and ganglia. A number of drugs that have been shown to act as teratogens in mammals have also been found to inhibit muscle and/or neuron differentiation inDrosophilaembryonic cultures. We have examined, by twodimensional gel electrophoresis, the effects of such teratogens on protein synthesis inDrosophilaembryonic cells. Inhibition of muscle and/or neuron differentiation correlates well with the induction of two proteins of about 20 kilodaltons. These are identical to two of the heat shock proteins (hsp 23, 22) as shown by electrophoretic mobilities and peptide mapping by partial proteolysis. Heat shock and other treatments such as exposure to some of the metal ions and ether induces the entire set of seven major heat shock proteins in theDrosophilaembryonic cells. Dose‐response studies of several teratogens show a correlation between the degree of inhibition of differentiation and the level of induction of hsps. Since heat shock proteins have been suggested as possibly serving a protecting role, our present studies are aimed at identifying the role of hsps in teratogenesis and investigating the differential regulation of heat shock genes in response to different external stimul

ISSN:0270-3211    

DOI:10.1002/tcm.1770060606

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1986

数据来源: WILEY

摘要:

AbstractThe anticonvulsant drugs carbamazepine, Na valproate, and phenytoin have been suspected as a cause of human congenital defects. The malformations produced may include cleft lip and/or palate, heart defects, skeletal defects, and low body weights. Since the toxic effects of these anticonvulsant drugs manifest themselves in terms of fetal growth retardation, evaluation of the state of ossification attained in the fetus is important. In the present study, pregnant CD‐1 mice received on gestational days 8–16 an oral dose of 375, 563, 938 mg/kg of carbamazepine; or 225, 338, 563 mg/kg of Na valproate; or 50, 75, 125 mg/kg of phenytoin. These groups were compared to two control groups. On day 17, the dams were killed by cervical dislocation and one‐third of the live fetuses were weighed and fixed for skeletal examination. Photographs were taken of the fore‐ and hindlimb skeletons. From these photographs, the length and width measurement of ossified regions of the humerus and femur were determined using a Zeiss Video‐Plan Morphometrics Computer. Of the three anticonvulsant drugs studied, the greatest correlation between reduced fetal weights and retarded ossification of the long bones was phenytoin at the 125 mg/kg dosage. Our results also showed that long bone ossification, when compared to the fetal weight, indicated that 59–66% of variability in weight is predictable by bone m

ISSN:0270-3211    

DOI:10.1002/tcm.1770060607

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1986

数据来源: WILEY

摘要:

AbstractDay 9.5 rat embryos were exposed in culture to xanthine/xanthine oxidase generated active oxygen species. Growth and development were assessed after 46 hr of culture. The treatment induced abnormalities of the neural suture, the severity of which increased in a dose‐related manner with the concentration of substrate or enzyme. Glutathione (10 mM) or catalase (50 μg/ml) either partially or completely abolished the effects of xanthine/xanthine oxidase, whereas the addition of superoxide dismutase (50 μg/ml) or desferrioxamine (1mM) did not reduce the number of malformed embryos. These findings suggest that hydrogen peroxide and/or hydroxyl radicals are responsible for the effects of xanthine and xanthine oxid

ISSN:0270-3211    

DOI:10.1002/tcm.1770060608

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1986

数据来源: WILEY

摘要:

AbstractAccording to the embryonic stress hypothesis of teratogenesis, anatomical malformation can be the consequence of the induction of a heat‐shock response (HSR) in the embryo at some critical stage during the determination or differentiation of organs. This hypothesis states that a teratogen is any agent (i) that is capable of inducing a HSR and (ii) that can reach the developing embryo. As a first step in determining whether the hypothesis is tenable, it was necessary to determine whether the embryo in fact is capable of making the HSR during the period of organogenesis. Pregnant mice were treated with two classical inducers of the HSR, one a physical and the other a chemical agent—namely, hyperthermia and sodium arsenite. The embryos, while still in the living mouse, responded with heat‐shock protein induction, as did control bone m

ISSN:0270-3211    

DOI:10.1002/tcm.1770060609

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1986

数据来源: WILEY

摘要:

AbstractAlthough hyperthermia is teratogenic in birds, all the common laboratory animals, farm animals, and primates and satisfies defined criteria as a teratogen, its study as a human teratogen has been neglected. Homeothermic animals, including humans, can experience body temperature elevations induced by febrile infections, heavy exercise and hot environments which exceed the thresholds (1.5–2.5°C elevation) which are known to cause a syndrome of embryonic resorptions, abortions, and malformations in experimental animals. Hyperthermia is particularly damaging to the central nervous system, and if a threshold exposure occurs at the appropriate stages of embryonic development, exencephaly, anencephaly, encephalocoele, micrencephaly, microphthalmia, neurogenic talipes, and arthrogryposis can be produced in a high proportion of exposed embryos, the incidence and type of defect depending on the species and strain within species, the stage of development, and the severity of hyperthermic exposure. Other defects which can be induced experimentally include exomphalos, hypoplasia of toes and teeth, renal agenesis, vertebral anomalies, maxillary hypoplasia, facial clefting, cataract, coloboma, and heart and vascular defects. Proliferating cells are particularly sensitive to temperature elevations, resulting in arrest of mitotic activity and immediate death of cells in mitosis with threshold elevations (1.5–2.5°C) and delayed death of cells probably in S phase with higher elevations (3.5°C). In general, lower temperature elevations (2.5°C) require longer durations of elevation to cause defects than a simple spike at a higher elevation (4.5°C). The death of cells is largely confined to the brain and in the day 21 guinea pig embryo to the alar regions of the brain. Cell death probably accounts for most of the defects in the central nervous system, but microvascular disturbances leading to leakage, oedema and haemorrhage, placental necrosis, and infarction are other known effects of hyperthermia; and these are probably involved in the pathogenesis of many defects of the heart, limbs, kidneys, and body wall. Recent experiments have demonstrated protection of rat embryos in culture against a known teratogenic exposure by a brief nonteratogenic exposure given at least 15 min earlier. This protection is associated with the synthesis of heat‐shock proteins, and temporary arrest of the cell proliferative cycle. Hyperthermia appears to be capable of causing congenital defects in all species and may act alone or synergistically with other agents. With minimally teratogenic doses of heat plus arsenic, lead, or vitamin A, the combined responses with heat have been clearly augmented compared with the additive responses of single treatments. The contribution of hyperthermia to abortions is well documented, and its effect on human birth defects needs careful

ISSN:0270-3211    

DOI:10.1002/tcm.1770060610

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1986

数据来源: WILEY

ISSN:0270-3211    

DOI:10.1002/tcm.1770060601

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1986

数据来源: WILEY