Showing papers on "In vivo published in 1978"
TL;DR: An in vitro tumor-colony assay developed to measure sensitity of human-tumor stem cells to anticancer drugs shows sufficient promise to warrant larger-scale testing to determine its efficacy for selection of new agents and individualized cancer chemotherapy regimens.
Abstract: With a direct in vitro tumor-colony assay developed to measure sensitity of human-tumor stem cells to anticancer drugs, we performed 32 retrospective or prospective clinical studies in nine patients with myeloma and nine with ovarian cancer treated with standard agents that were tested in vitro. The results were clearly correlated (P is less than 0.00001). Unique patterns of sensitivity and resistance to the six drugs tested were observed for individual patients. In eight cases of myeloma and three of obarian carcinoma in vitro sensitivity corresponded with in vivo sensitivity whereas in one case of myeloma it did not. In vitro resistance correlated with clinical resistance in all five comparisons in myeloma and all 15 in ovarian cancer. We conclude that this assay shows sufficient promise to warrant larger-scale testing to determine its efficacy for selection of new agents and individualized cancer chemotherapy regimens.
992 citations
TL;DR: It is suggested that interferon may be the mediator by which many different agents increase NK cell activity in vivo, as a positive correlation exists between in vivo resistance to syngeneic tumours and the levels of NK cellActivity in the individual mice.
Abstract: NATURAL KILLER (NK) cells constitute a distinct subgroup of cells within the immune system1,2. They are found in the lymphoid organs of several species including man and are cytolytic on contact in short-term in vitro assays for several cell types, in particular tumour cells1–5. Although the level of NK cell activity is under genetic control6,7, several extraneous agents, including bacterial adjuvants, animal viruses and NK-sensitive tumour cells induce an increase in in vivo NK cell activity6–10. Several of these agents are also known to increase the resistance of mice to transplantable tumours. This effect may be mediated by NK cells, as a positive correlation exists between in vivo resistance to syngeneic tumours and the levels of NK cell activity in the individual mice11,12. Viruses as well as several immunoadjuvants are also inducers of interferon. Here we present evidence that interferon and interferon inducers markedly enhance NK cell activity in mice, and suggest that interferon may be the mediator by which many different agents increase NK cell activity in vivo.
729 citations
Journal Article•
TL;DR: The rapid excretion of F-18-DG from liver, lungs and kidneys, and the retention by the heart and brain, is the result of metabolic trapping within certain organs and is reflective of glucose utilization.
Abstract: Initially, [18F]2-deoxy-2-fluoro-D-glucose (F-18-DG) distributes to the kidneys, heart, brain, lungs, and liver of the mouse, and clears rapidly from all except the heart and, to a much lesser extent, the brain. The heart and brain showed the highest rates of phosphorylation both in vivo and in vitro. No detectable glucose-6-phosphatase activity was present in these organs when hexokinase activity was high and at pH 6.5. The rank order for hexokinase activity, measured in vitro, was brain > heart ≃ kidney > lung > liver, whereas glucose-6-phosphatase activity was found only in the liver and to a lesser extent in the kidney, at pH 6.5. The rate of appearance of F-18-DG-6 phosphate (F-18-DG-6-P) in vivo was significantly slower in the lungs, liver, and kidneys than in the heart and brain, and represented a small proportion of the initial radioactivity. The F-18-DG that clears from the organs is excreted into the urine mostly unchanged, apparently due to the lack of tubular resorption. The rapid excretion of F-18-DG from liver, lungs and kidneys, and the retention by the heart and brain, is the result of metabolic trapping within certain organs and is reflective of glucose utilization. These results may contribute to the clinical utility of F-18-DG by providing a basis for metabolic studies in vivo. Metabolic trapping can be considered as a principle in the design of radiopharmaceuticals as metabolic probes for function or tumor location.
585 citations
Journal Article•
TL;DR: It is suggested from the quantitative measurements that the predominant chemotactic activity generated in human serum during C activation is associated with the C5ades Arg molecule, which exhibits the potential for playing a predominant functional role under physiologic conditions as a major humoral chemOTactic factor.
Abstract: Human C5a was maximally active over a narrow concentration range of 2 to 6 × 10-7 M as estimated in rabbits by utilizing a skin window assay technique (Otani and Hugli, 1977). Human C5ades Arg also stimulated neutrophil accumulation under simulated in vivo conditions but at a slightly higher concentration range of 0.2 to 1.2 × 10-6 M. The C5ades Arg did not require added serum to produce an apparent leukotactic response in vivo, but, as in vitro, activity was not observed at levels above or below the effective concentration ranges indicated for C5a and C5ades Arg C3a was inactive over a concentration range of 5.5 × 10-9 to 5.5 × 10-6 M as an attractant for rabbit neutrophils in the skin window assay. The concentrations of C5a or C5ades Arg that are required to induce chemotaxis under simulated in vivo conditions correspond to the potential serum levels of these factors (e.g., 4 to 5 × 10-7 M). It is suggested from our quantitative measurements that the predominant chemotactic activity generated in human serum during C activation is associated with the C5ades Arg molecule. Therefore, C5ades Arg exhibits the potential for playing a predominant functional role under physiologic conditions as a major humoral chemotactic factor.
568 citations
TL;DR: The findings indicate that the responses induced by substance P were mainly mediated by histamine released from the dermal mast cells, and that substance P is a potent histamine liberator in human skin.
451 citations
388 citations
TL;DR: The control of proliferation of mesoderm-derived cells by EGF and FGF has been examined taking, as an example, the vascular endothelium.
Abstract: The control of proliferation of mesoderm-derived cells by EGF and FGF has been examined taking, as an example, the vascular endothelium. The mechanisms by which cell proliferation can be brought to a stop in vivo and in vitro have been reviewed.
323 citations
Journal Article•
TL;DR: Three distinct subpopulations of tumor cells derived from a single parent strain BALB/cfC3H mammary adenocarcinoma were tested in vivo for sensitivity to cyclophosphamide, methotrexate, and 5-fluorouracil, finding marked differences in sensitivity to inhibition of cell division by the drugs.
Abstract: Three distinct subpopulations of tumor cells derived from a single parent strain BALB/cfC3H mammary adenocarcinoma were tested in vivo for sensitivity to cyclophosphamide, methotrexate, and 5-fluorouracil. Treatment was begun either 2 days after s.c. tumor cell injection or at the time when the tumors became palpable. It was given on a weekly basis for 4 weeks. The mice were observed for growth of the primary implant and for development of spontaneous metastases. The three subpopulations differed markedly in their sensitivity to the drugs. The effects of the drugs ranged from induction of regression of the "primary" to enhancement of metastases. The effect on primary growth was independent of that on metastasis. The effect of the time of administration of the drugs also varied among the subpopulations. The sublines were also tested in vitro with methotrexate and 5-fluorouracil. Again there were marked differences in sensitivity to inhibition of cell division by the drugs. The relative sensitivities in vitro did not correlate with observations in vivo. The existence of subpopulations of tumor cells, differing in sensitivity to therapeutic agents, within a single neoplasm, presents a challenge to development of assays capable of predicting drug response and to the selection of combination therapies.
300 citations
TL;DR: An in vitro agar colony technique has been developed for the growth of tumour cells taken directly from human tumours grown in immune-suppressed mice, with the addition of a replenishable liquid phase which permits the maintenance of relatively slowly growing cells.
Abstract: An in vitro agar colony technique has been developed for the growth of tumour cells taken directly from human tumours grown in immune-suppressed mice. The novel feature of the technique is the addition of a replenishable liquid phase which permits the maintenance of relatively slowly growing cells. A number of different xenografted tumours have been cultured successfully in this system, with red blood cells added to the agar and using 5% O2 in the gas phase. The technique has been used to assay cell survival in tumours treated in vivo with cytotoxic agents, and examples are given of survival curves obtained from a pancreatic tumours irradiated with gamma-rays and a colonic tumour from mice treated with cyclophosphamide. The results obtained by this in vitro method are in agreement with those from the agar diffusion chamber technique. This culture method has also been successfully used for the growth of cells taken directly from human tumour biopsy samples obtained in the clinic.
299 citations
TL;DR: Accumulation of lysophosphoglycerides induced by ischemia may contribute to the genesis of malignant dysrhythmia early after its onset.
Abstract: Lysophosphoglycerides, products of membrane phospholipid catabolism known to influence membrane function in several systems, appeared in the effluents of anoxic isolated rabbit hearts perfused at low flow and accumulated in perfused hearts and myocardium rendered ischemic in situ. Comparable concentrations of lysophosphoglycerides bound to albumin markedly and reversibly altered action potentials of isolated canine Purkinje fibers in vitro. Changes induced included diminution of the maximum diastolic potential, peak dV/dt of phase zero, amplitude, and action potential duration--alterations resembling those seen in ischemic myocardium in vivo. These electrophysiological alterations are compatible with changes implicated in predisposing to dysrhythmia dependent on reentry, a phenomenon potentiated by the presence of zones of decreased conduction. Thus, accumulation of lysophosphoglycerides induced by ischemia may contribute to the genesis of malignant dysrhythmia early after its onset.
292 citations
TL;DR: Phage lambda repressor is inactivated and cleaved into two detectable fragments during incubation with purified Escherichia coli recA gene protein in vitro, in a reaction that requires ATP.
Abstract: Phage lambda repressor is inactivated and cleaved into two detectable fragments during incubation with purified Escherichia coli recA gene protein in vitro, in a reaction that requires ATP. This reaction reproduces the recA-dependent inactivation of repressor that occurs in vivo during induction of the SOS functions. The proteolytic activity may reside in the recA protein itself and may be a fundamental activity of it.
TL;DR: It is shown that purified T-helper cells induce cells of another T-cell set-, expressing the Ly123+Qa1+ surface phenotype, to exert potent suppressive activity, and this interaction represents an important barrier to protocols intended to augment the immune status of individuals by adoptive (or active) immunotherapy.
Abstract: We have shown that (a) purified T-helper cells induce cells of another T-cell set-, expressing the Ly123+Qa1+ surface phenotype, to exert potent suppressive activity, (b) this T-T interaction plays an important role in regulating in vivo immune responses, and (c) this interaction represents an important barrier to protocols intended to augment the immune status of individuals by adoptive (or active) immunotherapy. Our results also indicate that the Ly123+ T-cell set mediating feedback suppression in vivo is sensitive to both low doses of cyclophosphamide and removal of the thymus in adult life. The importance of this T-T interaction to normal, physiologic regulation of the immune system is emphasized by the finding that the major T-cell deficit of NZB mice (an inbred strain of mice that spontaneously develops an autoimmune disorder) is the absence or malfunction of an Ly123+ T-cell set responsible for feedback inhibition.
TL;DR: The effect of intercalating agents on mammalian DNA in vivo was examined by the technique of alkaline elution and data suggest that DNA single-strand scission may be a feature common to intercalators.
TL;DR: The combined data from in vivo clearance studies and from studies of enzyme uptake by isolated rat macrophages suggest that a mannose/N-acetylglucosamine-glycoprotein uptake system is expressed on fixed tissue macrophage in the rat, and that this system mediates plasma clearance of infused human placental β-glucuronidase.
TL;DR: Quantitative studies of formation of the principal covalent product formed in liver DNA of rats treated with AFB1 proved that the major adduct formed between DNA and AFB1 in vivo is identical to that produced in vitro when AFB1 is incubated with DNA in the presence of a rat liver microsomal activating system.
Abstract: The products of in vivo covalent binding of activated aflatoxin B1 (AFB1) to DNA have been investigated in rats. The principal covalent product formed in liver DNA of rats treated with AFB1 has been identified as 2,3-dihydro-2-(N7-guanyl)-3-hydroxy-aflatoxin B1. This compound was isolated from the liver DNA of rats dosed with AFB1 (2.0 mg/kg) in sufficient quantity for characterization by physicochemical techniques, including field-desorption mass spectrometry. This information together with results of chemical methylation of the compound proved that the major adduct formed between DNA and AFB1 in vivo is identical to that produced in vitro when AFB1 is incubated with DNA in the presence of a rat liver microsomal activating system. Quantitative studies of formation of this compound revealed a dose-dependent relationship between the level of its occurence in liver DNA and AFB1 doses over the range 0.125-1.0 mg/kg.
TL;DR: Although active in vitro, nerve growth factor and formylated synthetic peptides were not stimulatory in vivo and implants sequestering 1 microgram of fibroblast growth factor or epidermal growth factor variably stimulated the proliferation of keratocytes and epithelial cells in vivo.
TL;DR: Mechanisms for the initiation of free radical reactions in vivo are reviewed, including ozone and 1O2 reactions, radiation, one‐electron transfer processes, and enzymatic reactions.
Abstract: — Mechanisms for the initiation of free radical reactions in vivo are reviewed, including ozone and 1O2 reactions, radiation, one-electron transfer processes, and enzymatic reactions. The roles that radical reactions might play in aging processes and in carcinogenesis are discussed.
TL;DR: The carcinogenic effectiveness of the agents was positively correlated with the extents of alkylation of guanine in DNA of target tissues at the O-6 atom and the ratio of equipotent doses to that for N-methyl-N-nitrosourea would be equal.
Abstract: 1. Methods were developed for analysis of alkylpurines, O2-alkylcytosines, and representative phosphotriesters [alkyl derivatives of thymidylyl(3'-5')thymidine], in DNA alkylated in vivo, using high-pressure liquid chromatography. 2. The patterns of alkylation products in DNA in vivo at short times were closely similar to those found for reactions in vitro. Alkylation by the nitrosoureas was complete in vivo within 1 h, but with ethyl methanesulphonate was maximal at 2--4h. 3. The time course of persistence of alkylation products in vivo was determined for several tissues. In addition to the rapid loss of 3- and 7-alkyladenines reported previously for all tissues, a relatively rapid loss of O6-alkylguanines from DNA of liver was found which was more rapid at lower doses. In brain, lung and kidney, excision of O6-alkylguanine was much less marked, but was not entirely excluded by the data. In thymus, bone marrow and small bowel, all alkylated bases were lost with half-lives of 12--24h, at non-cytotoxic doses of alkylation. 4. No evidence for any marked excision of other minor products from alkylated DNA in vivo was found; thus 1-methyladenine, O2-ethylcytosine (found in appreciable amount only with N-ethyl-N-nitrosourea), 3-methylguanine, and dTp(Alk)dT persisted in alkylated DNA, including DNA of liver. 5. The induction of thymic lymphoma was determined over the range of single doses by intraperitoneal injection up to about 60% of the LD50 values, and related to the extent of alkylation of target tissues thymus and bone marrow. With N-methyl-N-nitrosourea over 90% tumour yield was attained at 60 mg/kg, and with N-ethyl-N-nitrosourea up to 52% at 240 mg/kg, but with ethyl methanesulphonate at up to 400 mg/kg only a few per cent of tumours were obtained. 6. The carcinogenic effectiveness of the agents was positively correlated with the extents of alkylation of guanine in DNA of target tissues at the O-6 atom. On the basis that at doses giving equal carcinogenic response these extents of alkylation would be equal, the chemical analyses showed that the ratio of equipotent doses to that for N-methyl-N-nitrosourea would be, for N-ethyl-N-nitrosourea, 5.3 for ethyl methanesulphonate about 21, and for methyl methanesulphonate [Frei & Lawley (1976) Chem.-Biol. Interact. 13, 215--222] about 144. These predictions were in reasonably good agreement with the observed dose-response data for these agents.
TL;DR: In this article, the colony size distributions obtained from fetal, young adult, and old adult human cell cultures at the same low level of in vitro passage are indicative of the in vivo age of the cell culture donor.
Abstract: Individual human diploid cells plated at low cell density and incubated for 2 weeks develop into colonies ranging in size from one cell to several thousand cells. The resultant colony size distribution is an accurate indicator of the number of subsequent in vitro population doublings that can be attained by the parent culture. This relationship holds for both human fetal lung and adult skin fibroblast cultures. In addition, the colony size distributions obtained from fetal, young adult, and old adult human cell cultures at the same low level of in vitro passage are indicative of the in vivo age of the level of in vitro passage are indicative of the in vivo age of the cell culture donor. Cell cultures of fetal origin give rise to the highest percentage of colonies with significant proliferative abilities, whereas cultures from old adults give rise to the lowest percentage of large colonies. Therefore, colony size distributions appear to be good indicators of both in vitro and in vivo human cellular aging.
Journal Article•
TL;DR: The balloon catheter technique is used to abrade a defined portion of the lining of the aorta in rats to suggest that the "diffusion barrier" mechanism proposed for control of monolyaer regeneration in vitro does not explain contact inhibition of endothelium in vivo and that regeneration of endot Helium is controlled either by factors released from the site of injury or by cell to cell interactions.
TL;DR: P in vivo and in vitro data indicate that impaired net transepithelial transport of phosphate in the X-linked phenotype is the result of an intrinsic defect in net flux of phosphate at the brush border membrane.
Journal Article•
TL;DR: Rapamycin by the subcutaneous route yielded a higher percentage of survival than either rapamycin or amphotericin B, administered orally, after a 30-day observation period, when the above treatment was extended by an additional daily treatment for 6 days.
Abstract: The activity of rapamycin, a new anti-Candida antibiotic, was not affected by pH values between 6 and 8; at pH 4, however, activity was abolished. The MIC of rapamycin did not vary drastically with the size of inoculum: a ten-fold dilution of the inoculum reduced the MIC only two-fold. Serum binding was extensive. Serum levels obtained in mice were higher on subcutaneous injection than with oral administration. Dogs absorbed rapamycin after oral administration. Rapamycin cured systemic candidosis in mice: PD50 s.c. was 9.5 mg/kg: PD50 p.o. was 11 mg/kg. In the same experimental infections amphotericin B and nystatin exhibited PD50 values of less than 0.25 mg and greater than 4,000 units/kg respectively. Rapamycin and amphotericin B, administered at 1, 4 and 24 hours after infection, gave approximately the same percent survival after 30 days of observation. When the above treatment was extended by an additional daily treatment for 6 days, rapamycin by the subcutaneous route yielded a higher percentage of survival than either rapamycin or amphotericin B, administered orally, after a 30-day observation period. Vaginal candidosis in female rats was treated efficiently (91% cure) by rapamycin administered orally. No increase of resistance of C. albicans was observed during treatment.
TL;DR: The increase in ATPase and carbonic anhydrase activities in rat brain with increasing age may be in part a reflection of proliferation and development of astroglia cells, and provides additional evidence that primary cultures derived from neonatal rats may closely resemble developing astrogolia in vivo.
TL;DR: Comparisons of the in vitro effects seen with hen and human enzymes facilitates extrapolations to the human in vivo situation.
Abstract: The comparative inhibitory power of organophosphorus esters in vitro against hen brain acetylcholinesterase and neurotoxic esterase correlates with their comparative effects (death or delayed neuropathy) in vivo. Further comparisons of the in vitro effects seen with hen and human enzymes facilitates extrapolations to the human in vivo situation.
TL;DR: Prostacyclin shares several of the activities of PGE2, and may be involved in the regulation of gastric mucosal function.
TL;DR: The protease inhibitors leupeptin and pepstatin appear to delay the degeneration of muscle tissue which is characteristic of this disorder and thus may have potential therapeutic value in the treatment of muscular dystrophy.
Abstract: The protease inhibitors leupeptin and pepstatin were used in vivo in genetically dystrophic chickens to determine their effects on the histological and biochemical changes observed in this disease. These compounds appear to delay the degeneration of muscle tissue which is characteristic of this disorder and thus may have potential therapeutic value in the treatment of muscular dystrophy.
TL;DR: In pharmacologically active doses sodium pentobarbital, strychnine, picrotoxin and bicuculline fail to influence [3H] flunitrazepam binding in vivo, and benzodiazepine potencies correspond to pharmacological potencies and parallel relative affinites for binding sites in isolated brain membranes.
Journal Article•
TL;DR: DNAdamagewasassessed inliver,lung,thymus,brain,kidney,stomach,duodenum,colon,bonemarrow, andmammarygland, andmunicipalgland and caused significantDNAdamageintarget and non-targettissues.
Abstract: Analkalineelutionassaypreviouslyusedtodetectsingle-strandbreaksinDMAofculturedmammaliancellshasbeenmodifiedtoallowtheanalysisofDMAdamageinvariousorgansofratsfollowingexposuretochemicalcarcinogens.Priortoexposure,theDMAofneonatalanimalswaslabeledwith[3H]thymidine.DNAdamagewasassessedinliver,lung,thymus,brain,kidney,stomach,duodenum,colon,bonemarrow,andmammarygland.Dimethylnitrosamine,diethylnitrosamine,4-nitroquinolme1-oxide,2-acetylaminofluorene, N-hydroxyacetylamino-fluorene,aflatoxinB,,1,2-dimethylhydrazine,azoxymeth-ane,benzidine-HCI,and7,12-dimethylbenz(a)anthraceneinducedthegreatestextentofDNAdamageintargetorgansforcarcinogenicity.Invivoexposuretoseveraldirect-actingalkylatingagents,includingW-methyl-N'-ni-tro-N-nitrosoguanidine, N-methyl-N-nitrosourea, N-ethyl-N-nitrosourea, methylmethanesulfonate, andethylmethanesulfonate, causedsignificantDNAdamageintargetandnon-targettissues.Dose-relatedincreasesintheDNAelutionpatternswereobserved.DNArepairtime,asmeasuredbythereturntoanormalelutionpattern,variedfromaslittleas24hrfor4-nitroquinoline1-oxidetoaslongas7daysfordimethylnitrosamine. TheinvivoDNAdamage-alkalineelutionassayoffersarapidandreliableassayforassessmentoftheabilityofacompoundtoinduceDNAdamage.INTRODUCTIONManycarcinogens havebeenshowntointeractwithcellularDNAinanumberofwaysincludingalkylation,intercalation,cross-linking,andphosphotriesterformation.Theseandothercarcinogen-macromolecule interactionshavebeenreviewedrecently(7,10,19).Invivoexposuretocarcinogensalsohasbeenshowntoinducesingle-strandbreaksinDNAfromseveralorgans.Inmostinvestigations,ASG's2wereusedtomonitorDNAdamageinratliverwhichhadbeenprelabeledwithradioactivethymidinefollowingpartialhepatectomy(1,4,5,18,21,22).Studiesdemonstrating carcinogen-induced DNAdamageinotherorgansutilizedrodentslabeledasneonates(2,3,8,13,30).Recently,nonradioactiveDNAassaysalsohavebeenmodifiedforassessmentoftheextentofobservedDNAdamage
TL;DR: Data indicate that interferon may play a central role in the augmentation of NK activity in vivo, with a shorter time course of augmented activity seen after inoculation with poly I:C.
Abstract: Natural cell-mediated cytotoxicity in rats as well as in mice has been shown to vary consistently with age, with peak levels detectable at 5-10 weeks. The levels of cell-mediated cytotoxicity against tumor cells could be augmented in strains of inbred rats with either high or low levels of natural reactivity, by IP injection of a variety of agents, including C. parvum, LCMV, KRV, and poly I:C. The specificity of the augmented cytotoxicity appeared to be the same as the specificity of natural killer cells which are found in normal rat spleen cells. Similarly, the cells mediating the augmented cellular cytotoxicity were small, non-adherent, esterase-negative lymphocytes with Fc receptors, as are rat NK cells. The kinetics and organ distribution of the augmentation of NK activity by poly I:C and C. parvum were compared and the kinetics were found to differ, with a shorter time course of augmented activity seen after inoculation with poly I:C. These data indicate that interferon may play a central role in the augmentation of NK activity in vivo.
TL;DR: It is concluded that the bile salt-stimulated milk lipase is active in the infant's intestine and may contribute to the digestion of the milk lipids, particularly the retinol esters, which must be hydrolyzed before they are absorbed.
Abstract: Bile Salt-Stimulated Lipase in Human Milk: Evidence of Activity in Vivo and of a Role in the Digestion of Milk Retinol Esters