Exposure to measles in utero and Crohn's disease: Danish register study.
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Adolescent↗
Biomedical subjects
L L Nielsen
Publications and source records attributed to L L Nielsen.
Adenovirus-mediated p53 gene therapy and paclitaxel have synergistic efficacy in models of human head and neck, ovarian, prostate, and breast cancer.
Synergy (or antagonism) between two chemical agents is an in vitro empirical phenomenon, in which the observed effect of the combination is more (or less) than what would be predicted from the effects of each agent working alone. Although mathematical synergy is not directly provable in the clinical setting, it does predict a favorable outcome when the two therapeutics are combined in vivo and strongly suggests the presence of in vivo synergy. In contrast, overt antagonism warns of future problems. Sophisticated three-dimensional statistical modeling was used to evaluate the presence of synergistic, additive, or antagonistic efficacy between adenovirus (Ad)-mediated p53 gene therapy (p53 Ad) and paclitaxel (Taxol) in a panel of human tumor cell lines. Cells were either pretreated with paclitaxel 24 h before p53 Ad or treated with both agents simultaneously. Cell proliferation was measured 3 days later. Paclitaxel had synergistic or additive efficacy with p53 gene therapy. In no case was the interaction antagonistic. Cell cycle analysis demonstrated that p53 Ad arrested cells in G0/G1 prior to apoptotic cell death, whereas paclitaxel arrested cells in G2-M prior to apoptotic cell death. When combined, the relative concentration of each agent determined the dominant cellular response. These results are consistent with the previously reported cell cycle effects of p53 or paclitaxel, respectively; however, these data fail to explain the observed drug synergy. We found that low concentrations of paclitaxel (1-14 nM) increased the number of cells transduced by recombinant Ad 3-35% in a dose-dependent manner, which is one possible mechanism for the observed synergy. Of particular note, the concentrations of paclitaxel responsible for increased Ad transduction were lower than the concentrations required for microtubule condensation. The efficacy of combination therapy was also evaluated in vivo. In the p53null SK-OV-3 xenograft model of ovarian cancer, a dosing schedule of p53 Ad that, by itself, had a relatively minimal effect on tumor burden (16%) caused a much greater decrease in tumor burden (55%) when combined with paclitaxel. Greater combined efficacy was also observed in the p53mut DU-145 prostate, p53mut MDA-MB-468 breast, and p53mut MDA-MB-231 breast cancer xenograft models in vivo. In summary, p53 Ad for cancer shows enhanced efficacy when combined with paclitaxel. This combination is recommended for clinical cancer trials.
Adenoviridae↗
Radiographic detection of cavitation in approximal surfaces of primary teeth using a digital storage phosphor system and conventional film, and the relationship between cavitation and radiographic lesion depth: an in vitro study.
The need for operative treatment of approximal carious lesions may depend on whether or not the surface is cavitated. The aims of this in vitro study were to compare the accuracy of cavity detection in approximal surfaces of primary molars using a storage phosphor system (Digora) and Ektaspeed Plus film, and to relate radiographic lesion depth to the presence or absence of cavitation in the tooth surface. The material consisted of 72 approximal surfaces in 46 exfoliated/extracted primary molars. The teeth were radiographed using Ektaspeed Plus film and then the Digora system with 10% of the film exposure dose. Three examiners independently scored the radiographs for the presence or absence of cavitation on a 5-point confidence scale and for lesion depth on a four-category disease severity scale. Validation of the radiographic diagnosis of cavitation was done by inspecting the dried and cleaned surfaces in direct light using a sharp probe. The surfaces were scored: 0 = sound, 1 = discoloration without cavitation, 2 = cavitation. Diagnostic accuracy of the two radiographic methods was evaluated by ROC curve analysis. There was no statistically significant difference between the accuracy of the two methods for detection of cavitation. There was also no significant difference in the proportion of lesions in outer enamel, inner enamel and dentine detected by the two methods. The majority of lesions diagnosed radiographically to be in dentine were cavitated.
Chi-Square Distribution↗
Lung carcinoma and malignant mesothelioma in patients exposed to Thorotrast: incidence, histology and p53 status.
In a previous registry-based survey of 999 patients injected with alpha-emitting 232ThO2 (Thorotrast), we identified elevated risks for lung carcinoma and malignant mesothelioma. Since injected Thorotrast is retained lifelong mostly in liver, spleen and lymph nodes, the mesothelial surfaces of these organs are constantly irradiated. Thorotrast-administered patients also perpetually exhale 220Rn, a 232Th-daughter. Study of Thorotrast-exposed patients may, therefore, provide data with regard to carcinogenicity of radon exposure, a current public health concern, as well as the pathogenesis of malignant mesothelioma. The incidence and histologic types of lung carcinoma and malignant mesothelioma within the cohort were examined by review of available histopathologic material and medical records. Further, mutations of the p53 gene were analyzed whenever possible as it has previously been suggested that radon-associated lung carcinomas exhibit specific mutational patterns. The cumulative risk for lung carcinoma reached 11.0% based on 20 confirmed cases. Nine were small cell lung cancer (SCLC), whereas the expected frequency was 18%. The risk for malignant mesothelioma reached 2.5% based on 7 cases. The actuarial risk of malignant mesothelioma for patients given more than 20 ml Thorotrast was 7.8% compared to 1.4% for patients administered smaller amounts. Seven lung carcinomas and 5 malignant mesotheliomas were analyzed for p53 mutations; only 1 (in a lung adenocarcinoma) was detected. A possible association between Thorotrast and SCLC is suggested. In addition, a possible dose-response gradient exists for Thorotrast and malignant mesothelioma.
Adolescent↗
Strategy for developing transgenic assays for screening antineoplastic drugs that affect tubulin polymerization.
In this study we evaluated the antitumor efficacy of taxol in four solid tumor models derived from wap-ras line 69 transgenic mice. Taxol inhibited the growth of spontaneous salivary and mammary gland adenocarcinomas in wap-ras mice. In nude mice it was also effective against solid tumors caused by WR21 cells derived from a wap-ras salivary gland tumor. Taxol was not able to prevent tumor emergence in wap-ras/F mice, a subline of the wap-ras strain in which all males develop palpable mammary gland tumors between 1.5 and 3.0 months of age. Our data indicate the range of results that can be expected when this panel of related transgenic tumor models is used to study the antitumor effects of taxol and other therapeutic drugs that act by affecting tubulin polymerization. These models of ras-mediated neoplasia should prove useful for testing anticancer compounds with taxol-like mechanisms of action.
Animals↗
Agents that increase phosphatidic acid inhibit the LH-induced testosterone production.
The results of the present study point to phosphatidic acid (PtdOH) as a possible intracellular messenger, which might be involved in local modulation of testicular testosterone production in vivo. Propranolol (27-266 microM) induced an increased level of [3H]PtdOH in isolated rat Leydig cells, prelabeled with [3H]myristate, and at the same time a strong dose-dependent inhibition of the acute testosterone production stimulated by luteinizing hormone (LH). The inhibition was not bypassed by the addition of dibutyryl-cAMP but was overcome, when 22(R)-hydroxycholesterol was added as a direct substrate for cytochrome P-450 side chain cleavage enzyme. Thus, the inhibition appears to be exerted at a point distal to cAMP-generation but before the first enzyme in the testosterone synthetic pathway. Treatment with other agents (4 beta-phorbol 12-myristate 13-acetate (PMA), A23187, and sphingosine) giving rise to increases in the PtdOH-level resulted in the inhibition of the LH-induced testosterone formation as well, thus indicating a connection between the two effects. Furthermore, we were able to demonstrate a highly significant correlation between the PtdOH-increase and the inhibition of the LH-stimulated testosterone production. This may suggest a causal relationship between these two parameters.
Animals↗
Evaluation of the wap-ras transgenic mouse as a model system for testing anticancer drugs.
Transgenic mouse models have provided many valuable insights into the molecular mechanisms of tumorigenesis; unfortunately, there is a paucity of published information on the utility of these models for evaluating potential anticancer therapeutics. Line 69 wap-ras transgenic mice have an activated, human c-Ha-ras gene on their Y chromosome. Adult males develop salivary and/or mammary adenocarcinomas. Both tumor types express high levels of human ras oncoprotein. Two new sublines, designated wap-ras/F, were created by selective breeding. Subline 69-2 wap-ras/F males developed multiple mammary tumors at puberty. Tumor onset was delayed by cyclophosphamide treatment prior to puberty. Mammary tumors from cyclophosphamide-treated mice weighed 0.57 +/- 0.09 g/mouse (SD +/- SEM; n = 8), while tumors from control mice weighed significantly more at 2.36 +/- 0.25 g/mouse (n = 8; P less than or equal to 0.001; SD +/- SEM). These results suggest that subline 69-2F mice will be valuable for testing therapeutic regimes designed to interfere with processes occurring early in tumorigenesis, before palpable tumor presentation. Tumor sensitivity to several clinically relevant cytotoxins was also tested in adult wap-ras males with palpable tumors. Both salivary and mammary tumors were sensitive to cyclophosphamide and 5-fluorouracil, but not methotrexate. This suggests that wap-ras transgenic mice will indeed be useful in the discovery of novel therapeutics against neoplasia.
Animals↗
Effect of dietary fiber on the disposition and excretion of a food carcinogen (2-14C-labeled MeIQx) in rats.
We studied to what extent dietary fiber may affect uptake, retention, and excretion of a food carcinogen (2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, MeIQx) occurring in fried meat. Four diets--one fiber-free control and three containing either insoluble dietary fiber isolated from sorghum (100 g/kg) and wheat bran (100 g/kg) or the highly soluble pectin (50 g/kg)--were investigated. The fiber diets were given in amounts of 10 g/day to rats. Thus, each rat received 1 or 0.5 g fiber and 100 micrograms 2-14C-labeled MeIQx uniformly mixed in its daily diet. A 4-day adaptation period with unlabeled MeIQx was followed by a 5-day experimental period with 14C-labeled MeIQx, during which urine and feces were collected separately for analysis of radioactivity and mutagenicity. Furthermore the composition and the fermentability of the dietary fiber were determined. The present study shows that a diet containing fiber, especially fiber isolated from sorghum and wheat bran, affects the excretion pattern of the food carcinogen MeIQx in a manner suggesting a lower uptake and a decreased transit time through the gastrointestinal tract in a more diluted form than a nonfiber diet. Furthermore, less radioactivity was retained in the kidneys with sorghum and wheat bran than with the other two diets. On the other hand, none of these types of dietary fiber affected the retention of the hepatocarcinogen MeIQx in the liver 24 hours after the last oral intake. DNA adducts were formed to a higher extent in the kidney than in the liver. The highest levels were found in animals given the wheat bran diet.
Animals↗
Histopathology of salivary and mammary gland tumors in transgenic mice expressing a human Ha-ras oncogene.
Mutated ras genes are powerful transforming agents in vitro and are found in a wide variety of human tumors in vivo. We characterized the histopathology and p21 protein expression associated with tumorigenesis in line 69 transgenic mice carrying an activated, human c-Ha-ras gene on the Y-chromosome (A. C. Andres, C. A. Schonenberger, B. Groner, L. Hennighausen, M. LeMeur, and P. Gerlinger, Proc. Natl. Acad. Sci. USA, 84: 1299-1303, 1987). Male mice developed salivary and/or mammary gland tumors. The salivary tumors were adenosquamous carcinomas arising from serous areas of the submandibular gland. They characteristically exhibited densely packed cords and sheets of moderately anaplastic cells. Tumorigenic tissue had a high mitotic index, and all tumor-bearing animals had an ongoing inflammatory response as evidenced by extensive immune cell infiltration of affected tissue. Half of the mammary gland tumors were adenosquamous carcinomas with multiple foci of squamous metaplasia, while the rest were adenocarcinomas containing glandular tissue. Most tumors had a high mitotic index, and abnormal mitotic figures were common. All tumors produced p21 ras, as confirmed by immunohistochemistry and Western blots. Both tumor types expressed elevated levels of p21 protein. Microscopic lung metastases were present in 5 of 35 animals (14%). Our results suggest that this transgenic mouse will provide a useful model for testing therapies directed against ras-associated tumorigenesis.
Animals↗
Drosophila alcohol dehydrogenase: a novel reporter gene for use in mammalian embryos.
A reporter gene construct containing the Drosophila alcohol dehydrogenase (ADH) gene under regulation of the Rous sarcoma virus long terminal repeat (RSV LTR) was microinjected into mouse zygote pronuclei. ADH activity after injection of the RSV-ADH construct was visualized in cultured embryos by means of a simple histochemical enzyme assay. The RSV LTR was an efficient promoter that led to abundant ADH activity at all stages of preimplantation development. There was a high incidence of mosaicism among stained embryos.
Alcohol Dehydrogenase↗
Induction of c-fos transcripts in early postimplantation mouse embryos by TGF-alpha, EGF, PDGF, and FGF.
The activity of growth factor receptors in the early postimplantation mouse embryo was studied by analyzing changes in expression of mRNA transcripts of an early response gene, c-fos, after binding of specific ligands. Reverse transcription of mRNA coupled with the polymerase chain reaction was used to detect gene transcription in single embryos after exposure to growth factors. Postimplantation embryos (at 7.5 days of gestation) had physiologically active receptors for transforming growth factor-alpha (TGF-alpha), epidermal growth factor (EGF), human platelet-derived growth factor (PDGF), recombinant PDGF-AA homodimer, and basic fibroblast growth factor (FGF), as indicated by induced expression of c-fos mRNA, c-fos expression was not induced in untreated embryos or in embryos incubated with active recombinant PDGF-BB homodimer. These results show that growth factor receptors are functional during early mammalian embryogenesis.
Animals↗
Mineralocorticoid concentrations in unstressed female rabbits and embryonic sodium transport.
Plasma aldosterone, corticosterone, and cortisol were measured during the first week of pseudopregnancy or pregnancy in New Zealand White rabbits to determine whether any sustained elevations of adrenal steroids occur. There were no pregnancy-specific alterations in circulating adrenal steroid concentrations during the preimplantation stages of embryonic development. Elevation of plasma aldosterone in vivo did not induce amiloride-sensitive Na+ transport across the embryonic trophectoderm. It therefore seems unlikely that an increase in maternal adrenal steroid concentrations is necessary for the development of amiloride-sensitive Na+ transport in rabbit blastocysts. Sodium efflux from Day 6 post coitum (p.c.) blastocysts was lower than Na+ influx. By day 7 p.c. Na+ efflux was equivalent in magnitude to the component of Na+ influx not inhibited by amiloride. This suggests that between Days 6 and 7 p.c. the amiloride-sensitive component of Na+ influx becomes essential for blastocyst expansion.
Adrenal Cortex Hormones↗
NK cells mediate the anti-tumor effects of E1-deleted, type 5 adenovirus in a human tumor xenograft model.
SCH58500 (ACN53) is a recombinant adenovirus expressing human p53 for gene therapy of cancer. In preclinical studies, SCH58500 has shown efficacy against many tumor-types with non-functional p53. This activity arises from both p53-mediated and adenovirus vector-mediated mechanisms. The importance of NK cells for adenovirus-mediated tumor suppression after intratumoral dosing was demonstrated using MDA-MB-231 human breast cancer xenografts in scid (defective T and B cell response) and scid-beige (defective T, B, and NK cell response) mice. There was no adenovirus vector-mediated anti-tumor activity in scid-beige mice. Dexamethasone (Dex) is a potent suppressor of the cellular immune response to recombinant adenovirus in mice and rats. Dex abolished growth suppression caused by adenovirus vector, but did not interfere with the anti-tumor efficacy of p53. Supression of NK cell activity in scid mice using intravenous administration of a neutralizing antibody had the same effect as Dex. These data support a role for NK cells in adenovirus vector-mediated anti-tumor efficacy.
Adenoviridae↗
Combination therapy with SCH58500 (p53 adenovirus) and cyclophosphamide in preclinical cancer models.
SCH58500 (ACN53) is a replication-deficient, recombinant adenovirus which expresses human p53 tumor suppressor. In preclinical models, SCH58500 has therapeutic efficacy against a wide range of human tumor types containing nonfunctional p53 and it has enhanced activity in combination with many chemotherapeutic drugs. However, the anti-tumor efficacy of SCH58500 combined with the DNA-damaging chemotherapeutic cyclophosphamide has not been previously reported. Cyclophosphamide did not enhance the activity of SCH58500 in three out of four human tumor xenograft models studied. Furthermore, combination therapy with SCH58500 and cyclophosphamide was not any better than single drug treatment in transgenic H-ras mice and in FVB mice bearing syngeneic MidT2-1 tumors. This is in sharp contrast to previous combination studies in these models where SCH58500 had enhanced efficacy when given with the farnesyl protein transferase inhibitor SCH66336, paclitaxel, cisplatin, cisplatin/paclitaxel, or doxorubicin. Further evaluation of this combination is required before it can be recommended for clinical trials in cancer patients.
Adenoviridae↗
In wap-ras transgenic mice, tumor phenotype but not cyclophosphamide-sensitivity is affected by genetic background.
Male wap-ras transgenic mice develop adenocarcinomas in salivary and/or mammary tissue by age 1 year. When the wap-ras transgene was bred into the FVB/N strain, males developed multiple mammary tumors between 1.5 and 3 mo. of age, but no salivary tumors. Crosses between ras/FVB mice and other strains produced moderate changes in mammary tumor onset and severity, but no salivary tumors. Histopathological analysis of 62 adenocarcinomas from 18 mice yielded: 14 tumors with areas of squamous metaplasia, many tumors with epithelium-lined cysts, few immune cells in tumors, and no lung metastases. Cyclophosphamide delayed tumor onset and inhibited the growth of established tumors. Our results suggest that wap-ras mice will be useful for studying ras-mediated tumor genetics and should be a good assay system for both preventative and curative anticancer therapies.
Adenocarcinoma↗
Development of a nude mouse model of ras-mediated neoplasia using WR21 cells from a transgenic mouse salivary tumor.
A novel cell line (WR21) was derived from a salivary tumor in a male wap-ras transgenic mouse. Salivary tumors in wap-ras transgenic mice are extremely aggressive and express high levels of oncogenic ras protein from the activated, human Ha-ras transgene. WR21 cells also expressed high levels of oncogenic ras protein in vitro and in vivo. They gave rise to aggressive, highly anaplastic solid tumors when injected subcutaneously into athymic nude mice and approximately 90% of the mice had lung metastases by the fifth week of tumor growth. WR21 tumors were inhibited by cyclophosphamide, 5-fluorouracil, adriamycin, mitomycin C and actinomycin D, but not methotrexate. Our results suggest that the WR21/nude mice model will be useful for testing the efficacy of drug therapies against ras-mediated neoplasias.
Animals↗
Mutations in the tumor suppressor gene p53 in human liver cancer induced by alpha-particles.
The p53 tumor suppressor gene is mutated in varying fractions of almost all tumor types studied. The rate of mutations and the mutational spectrum in some tumors are specific for environmental mutagens assumed to be involved in the carcinogenic process. Thus, hepatocellular carcinomas supposedly induced by aflatoxin exposure often contain a specific point mutation in codon 249, and in lung cancers of miners with heavy radon exposure, another specific point mutation in codon 249 suggestive of an alpha-particle-specific mutation has been shown. The interpretation of studies linking the mutational spectrum with specific environmental exposures is complicated by the multifactorial or unknown genesis of most tumors. However, people given injections of the X-ray contrast medium Thorotrast (Th) in the past have experienced an enormous risk of liver tumors, and virtually all of these are supposedly induced by alpha-particles from the decay of 232Th. The examination of these tumors may provide evidence as to whether specific p53 point mutations are relevant in alpha-particle carcinogenesis. Therefore, we collected paraffin-embedded, formalin-fixed archival tissues from 18 hepatocellular carcinomas, 9 cholangiocarcinomas, and 9 hepatic angiosarcomas from Thorotrast-exposed patients. The tissues were analyzed for p53 protein expression by immunohistochemical staining by using the mAb DO-7 and for mutations of exons 5-8 by PCR and constant denaturant gel electrophoresis. G --> T transversions of the third base of codon 249 of the p53 gene were specifically screened for by restriction enzymes. No high score for p53 protein expression (i.e., positive staining of >20% of examined cells) was observed; lower scores were seen in 5 of 18 (28%) hepatocellular carcinomas, 1 of 9 (11%) cholangiocarcinomas, and 0 of 8 (0%) hepatic angiosarcomas. Only one p53 mutation, a heterozygous T --> G transversion of the first base codon 176, occurred in a hepatocellular carcinoma. The rate of p53 point mutations in alpha-particle-induced liver tumors seems to be lower than in European hepatocellular carcinomas in general. The study does not exclude the possibility that alpha-particle carcinogenesis may involve inactivation of p53 by gross deletions of the gene, but it speaks against the proposed specificity of point mutations of codon 249 in cancer supposedly induced by alpha-particles from radon progeny.
Adolescent↗
Efficacy of p53 adenovirus-mediated gene therapy against human breast cancer xenografts.
In response to DNA damage, p53 protein accumulates in the cell nucleus causing cells to undergo DNA repair or apoptosis, programmed cell death. Reintroduction of wild-type p53 into tumors with null or mutant p53 offers a novel strategy for controlling tumor growth, by inducing apoptotic death in neoplastic cells. The efficacy of a replication-deficient p53 adenovirus construct was tested against three human breast cancer cell lines expressing mutant p53, MDA-MB-231, -468, and -435. 231 and 468 cells were both highly transduced at a multiplicity of infection of 10. By contrast, 435 cells were rarely transduced. p53 adenovirus-mediated gene therapy was highly effective against 231 and 468 tumor xenografts in nude mice. At a total dose of 2.2 x 10(9) cellular infectious units (CIU), inhibition of 231 tumor growth was 86% (P < or = .01). Thirty-seven percent of that growth inhibition was due to p53, while 49% was adenovirus-specific. Inhibition of 468 tumor growth was 74% (P < or = .001). Forty-five percent of that inhibition was p53-specific, while 28% was adenovirus-specific. The ED50 values for 231 tumors and 468 tumor growth inhibition were 3 x 10(8) CIU and 2 x 10(8) CIU, respectively. Injection of p53 Ad into 231 or 468 tumors induced apoptosis. By contrast, growth inhibition in 435 tumors treated with p53 adenovirus was not significant, probably due to low adenovirus transduction. 231 and 435 cells both expressed high levels of alpha v, beta 1, beta 3, and beta 5 integrin subunits, ruling out lack of the appropriate integrins as the reason for the low infection rate in 435 cells. Our results demonstrate the ability of wild-type p53 to curtail cancerous cell growth in vivo in tumors expressing mutant p53. The ability of beta-gal Ad to infect tumor cells in vitro was generally predictive of in vivo p53 Ad efficacy.
Adenoviridae↗