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Biomedical subjects

A Luz

Publications and source records attributed to A Luz.

At least 55 records · Page 3Linked to original sources
PubMed1994

Disruption of the murine p53 gene by insertion of an endogenous retrovirus-like element (ETn) in a cell line from radiation-induced osteosarcoma.

The mammalian genome harbors a large number of endogenous retroviruses and retrovirus-like elements. Increasing evidence is found that such elements can be activated and act as insertional mutagens. The activation of endogenous retroviral elements can be induced by a variety of environmental factors including irradiation. We have observed the insertion of a murine endogenous retrovirus-like ETn element into intro 4 of the p53 gene in an osteosarcoma cell line derived from a radiation-induced osteosarcoma. The insertion resulted in a p53-ETn-p53 fusion mRNA, a novel form of p53 mutation. This is the first report on insertion of an endogenous retroviral element into the p53 tumor suppressor gene. The data suggest that activated endogenous retroviruses and retrovirus-like elements might pose an enhanced risk for individuals exposed to noxae, which activate endogenous retroviral elements.

Animals↗
PubMed1994

Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene.

The parathyroid hormone-related peptide (PTHrP) gene was disrupted in murine embryonic stem cells by homologous recombination, and the null allele was introduced into the mouse germ line. Mice homozygous for the PTHrP null mutation died postnatally, probably from asphyxia, and exhibited widespread abnormalities of endochondral bone development. Histological examination revealed a diminution of chondrocyte proliferation, associated with premature maturation of chondrocytes and accelerated bone formation. Analysis of earlier developmental stages revealed that disturbance in cartilage growth preceded abnormal endochondral bone formation. There were no morphological abnormalities apparent in other tissues. These results provide direct evidence implicating PTHrP in normal skeletal development and serve to emphasize its potential involvement in human osteochondrodysplasias.

Animals↗
PubMed1994

Osteosarcomagenic doses of radium (224Ra) and infectious endogenous retroviruses enhance proliferation and osteogenic differentiation of skeletal tissue differentiating in vitro.

Cartilage tissue from embryonic mice which undergoes osteogenic differentiation during in vitro cultivation was used to study the effect of osteosarcomagenic doses of alpha-irradiation and bone-tumor-inducing retroviruses on proliferation and phenotypic differentiation of skeletal cells in a defined tissue culture model. Irradiated mandibular condyles showed dose-dependent enhancement of cell proliferation at day 7 of the culture and increased osteogenic differentiation at day 14. Maximal effects were found with 7.4 Bq/ml of 224Ra-labeled medium. Doses of 740 and 7400 Bq/ml of 224Ra-labeled medium induced increasing cell death. Retrovirus infection enhanced osteogenic differentiation and extended the viability of irradiated cells. After transplantation none of the treated tissues developed tumors in syngeneic mice.

Animals↗
PubMed1994

[Murine leukemia virus Akv promotes bone tumor development in fos-transgenic mice].

Newborn hMT-fos-LTR transgenic C3H mice and their non-transgenic siblings were infected with Akv, derived from the ecotropic provirus of the AKR mouse. Bone sarcomas in non-infected transgenics were observed in 20% (3/15) of females at 448 +/- 25 days and in 8% (1/12) of males at 523 days. Akv-infected transgenics developed bone tumors with higher frequency and at younger age: Females in 69% (20/28) at 268 +/- 122 days, males in 83% (24/29) at 279 +/- 109 days. In the majority of the bone tumors of Akv-infected transgenics (70% in females, 59% in males) cellular atypia was lacking and the histological pattern resembled human parosteal osteosarcoma. Only 50% (12/24) of bone tumors in Akv-infected transgenics revealed newly integrated virus sequences by Southern analysis. PCR analysis detected Akv sequences in DNAs of all tumors. Obviously, the insertion of Akv in a few cells induced the considerably accelerated bone tumor growth.

Animals↗
PubMed1994

Radiation-induced systemic and local bone tumors: two types of late effects with possible different origins?

Bone sarcomas may be induced throughout the skeleton (systemic) in mice by relatively low internal alpha-particle doses that are distributed over the whole skeleton. The induction of local (periosteal) bone sarcomas after paratibial deposition of insoluble radiocolloids required much higher doses, and in addition high energies of emitted particles. Paratibial deposition of alpha-particle-emitting radiocolloids of 227Th and 228Th resulted in formation of both local and systemic bone sarcomas. The latter were most probably induced by the released radium daughters of the thorium isotopes and were distributed about the skeleton. Paratibial injections with beta-particle emitters 144Ce+ 144Pr (29 kBq per mouse) showed an incidence of local bone sarcomas of more than 80%. An estimation of the local effective doses led to values of more than 1000 Gy for the beta-particle emitter 144Ce and around 150 Gy for the thorium isotopes. Thus induction of local bone sarcomas required doses considerably greater than those needed for systemic bone sarcomas. The local induction of bone sarcomas has been reported for high-energy beta particles using similar high doses of 144Ce+ 144Pr in rats and for external 90Sr+ 90Y irradiation in mice. We conclude that the processes involved in the induction of local and systemic bone sarcomas by radiation may be quite different.

Animals↗
PubMed1992

Elevated p53 RNA expression correlates with incomplete osteogenic differentiation of radiation-induced murine osteosarcomas.

An important role for the p53 gene in osteogenic sarcomas has been imputed by identification of somatically acquired gene alterations in human osteosarcomas and by the development of osteosarcomas in p53 transgenic mice. To study the involvement of p53 in radiation-induced osteosarcomagenesis, we have investigated gene alterations and expression of p53 in radiation-induced murine osteosarcomas and tumor-derived cell lines. Eighteen of 31 tumors and 8 of 9 cells lines showed alterations in the p53 gene region, or elevated levels of p53 RNA. Expression of the osteoblast marker gene bone gla protein was substantially reduced in tumors which simultaneously showed high steady-state levels of p53 RNA. Our data indicate that p53, in addition to its function in regulating DNA synthesis, may be involved in the control of osteogenic differentiation in osteosarcomagenesis.

Animals↗
PubMed1992

Molecular cloning of osteoma-inducing replication-competent murine leukemia viruses from the RFB osteoma virus stock.

We report the molecular cloning of two replication-competent osteoma-inducing murine leukemia viruses from the RFB osteoma virus stock (M. P. Finkel, C. A. Reilly, Jr., B. O. Biskis, and I. L. Greco, p. 353-366, in C. H. G. Price and F. G. M. Ross, ed., Bone--Certain Aspects of Neoplasia, 1973). Like the original RFB osteoma virus stock, viruses derived from the molecular RFB clones induced multiple osteomas in mice of the CBA/Ca strain. The cloned RFB viruses were indistinguishable by restriction enzyme analysis and by nucleotide sequence analysis of their long-terminal-repeat regions and showed close relatedness to the Akv murine leukemia virus.

Animals↗
PubMed1992

Metastatic growth of v-fos-induced osteosarcoma, following in vitro cultivation.

A tumour cell line was established from a non-metastatic osteosarcoma which had developed in the right femur after infection of a newborn mouse with FBR osteosarcoma virus (FBR MSV). After 20 cell culture passages and injection of the cells into newborn syngeneic mice, the animals developed fibrosarcomas on the site of injection. Metastatic lung tumours were detected in 50% of the mice. Metastatic tumour growth was preferentially observed in the walls of large blood vessels and in subpleural zones. Large areas of the metastatic tumours resembled mature connective tissue. This model of in vitro progression from a primary non-metastasizing osteosarcoma to a neoplasm with particular metastatic potency, though with a growth pattern similar to fibromatosis may serve as a useful system to study the different steps of metastatic progression, distinct tropism of invasive cells and fibrous maturation of metastatic tumours.

Animals↗
PubMed1991

Mutational activation of the c-Ha-ras gene in liver tumors of different rodent strains: correlation with susceptibility to hepatocarcinogenesis.

The frequency and pattern of mutations at codon 61 of the c-Ha-ras gene have been analyzed in 195 liver tumors and 132 precancerous liver lesions from various rodent strains with differing susceptibility to hepatocarcinogenesis. By using the polymerase chain reaction and allele-specific oligonucleotide hybridization, C----A transversions at the first base and A----T transversions or A----G transitions at the second base of c-Ha-ras codon 61 were detected in 20-60% of spontaneous or carcinogen-induced liver tumors of the C3H/He, CBA, CF1, and B6C3F1 mouse strains, which are highly susceptible to hepatocarcinogenesis. No such mutations, however, could be found in any of the 31 liver tumors of the insensitive C57BL/6J and BALB/c mouse strains or in any of the 35 liver tumors of the comparatively resistant Wistar rat. Further analyses of c-Ha-ras codon 12 mutations in liver tumors from the three insensitive rodent strains also failed to give any positive results. In early precancerous liver lesions, c-Ha-ras codon 61 mutations were found in 13-14% of lesions of the sensitive C3H/He and B6C3F1 mouse strains but not in any of the 34 lesions of the insensitive C57BL/6J mouse. Taken together, our results indicate a close correlation between the mutational activation of the c-Ha-ras gene in liver tumors of the different rodent strains and their susceptibility to hepatocarcinogenesis, whereby the mutations appear to provide a selective growth advantage, leading to a clonal expansion of the mutated liver cell population, only in livers of sensitive but not of insensitive strains.

Animals↗
PubMed1991

Bone tumor induction after incorporation of short-lived radionuclides.

Temporally-limited internal irradiation after incorporation of short-lived bone-seeking radionuclides is a useful experimental tool for the investigation of extrinsic and intrinsic factors which modify the dose dependence of bone tumor risk. Here we describe some of the results obtained in experiments with female mice (mainly NMRI). The future aim of such experiments should be the prediction of risk of late effects using early molecular-biological changes. Molecular-biological descriptions in our model are at present very limited.

Animals↗
PubMed1991

SL3-3 enhancer factor 1 transcriptional activators are required for tumor formation by SL3-3 murine leukemia virus.

The transcriptional enhancers of retroviruses that lack an oncogene are important determinants of their oncogenicity. However, no specific cellular transcriptional activator has yet been found to determine the oncogenicity for any of these viruses. The SL3-3 enhancer factor 1 (SEF1) cellular transcriptional activators are expressed preferentially in T lymphocytes. In the SL3-3 murine leukemia virus enhancer, two different sequences can bind SEF1 activators. We show that mutation of the SEF1 binding sites disrupts the disease potential of SL3-3 murine leukemia virus, implying that SEF1 transcriptional activators are required for tumor induction by SL3-3. The SEF1 site mutations did not appear to affect the pathogenicity of SL3-3 by impairment of virus multiplication, but rather by a specific defect in the ability of neoplastic transformation.

Animals↗
PubMed1990

Simultaneous induction of mutagenic and cancerogenic effects in T x HT mice with transplacental ethylnitrosourea treatment.

The relationship between mutagenesis and carcinogenesis was investigated in T x HT crossbred mice using diaplacental application of ethylnitrosourea (ENU) at different stages of embryonal development. Mutagenesis was detected by induction of coat color spots, and the carcinogenic response was investigated in a long-term follow-up study of the F1-generation. The animals were particularly sensitive to induction of tumors at the central nervous system (CNS)-skull/vertebra interface (30% and 20% in ENU-treated male and female offspring, respectively, compared with less than 1% in controls). There was a correlation between the appearance of these tumors and the presence of color spots. This correlation was low but statistically significant in female offspring. Three other types of tumors showed a correlation with the presence of coat color spots. Liver tumors were significantly increased in color spot-positive females but unchanged in males. Lung tumors were reduced in color spot-positive males and appeared earlier in color spot-positive females. There was a lower incidence of lymphoma/leukemia in all spot-positive mice. The reduction in tumor incidence beyond the spontaneous rate in spot-positive animals might be caused by a high cytolethal response to ENU in the relevant organs and tissues.

Animals↗
PubMed1990

Pathogenicity of BALB/c-derived N-tropic murine leukemia viruses.

N-tropic murine leukemia viruses have been observed in connection with radiation-induced osteosarcomagenesis in BALB/c mice. We have investigated the bone disease-inducing potential of molecularly cloned, BALB/c-derived N-tropic viruses in the random-bred NMRI mouse strain. The germ-line virus and an exogenous virus isolate were found to induce high incidences of osteopetrosis and lymphomas and a lower incidence of osteomas. Two viruses derived from somatically acquired proviruses of independent radiation-induced osteosarcomas induced lower incidence of osteopetrosis and lymphomas. Nucleotide sequence analysis of the long terminal repeat regions and RNase T1 fingerprint analysis revealed only few differences between the isolates. The possible involvement of N-tropic murine leukemia viruses in radiation-induced osteosarcomagenesis in the BALB/c mouse strain is discussed.

Animals↗
PubMed1990

Diaplacental induction by ethylnitrosourea of tumours at the pial border of the central nervous system in (T X HT)F1 mice.

Ethylnitrosourea (ENU) was diaplacentally applied to (T X HT)F1 mice at a dose of 40 mg/kg on different gestation days during organogenesis and early fetal stages by i.p. injection to the dams. The animals were particularly sensitive to induction of tumours at the central nervous system (CNS)-skull-vertebra interface (30 and 20% in ENU-treated male and female offspring respectively, compared with 1% in controls). ENU treatment during the late organogenesis stage (gestation days 8-11) proved to be less efficient in tumour induction than during the subsequent early fetal period (gestation days 12-14). Ninety-two per cent of the CNS tumours were located at the interface between the CNS and the osseous surrounding. The distribution of these tumours at the pial border was inhomogeneous: 69% were found at the brain-skull border, 6% of the tumours occurred within the cervico-thoracal districts and 25% within the lumbo-sacral districts of the spinal cord-vertebra interface. Histological classification revealed a preferential occurrence of neuroepithelial tumours in male offspring (approximately 20%) and only approximately 7% Schwann cell tumours and approximately 3% tumours of meningomesenchymal origin. In female offspring neuroepithelial tumours and Schwann cell tumours were observed at about an equal rate (9-10%), in contrast to meningo-mesenchymal tumours (1%). Nearly 98% of these tumours were situated at the basal districts of the space between the CNS-skull and spinal cord-vertebra. This indicates a particular sensitivity of the basal neurothelium, a derivative of neural crest cells, for ENU-induced carcinogenesis. The pluripotency of these cells during the mid-gestation period apparently enables growth of different histopathological tumour types, which arise independently from each other.

Animals↗
PubMed1990

Induction of lymphoma and osteosarcoma in mice by single and protracted low alpha doses.

Internal doses from the short-lived alpha-emitter 22Ra were given to 4-wk-old female NMRI mice. One group of about 300 animals received a single injection of 18.5 kBq 22Ra kg-1 body weight, corresponding to a mean skeletal alpha dose of 0.15 Gy. A second group of about 300 animals received the same total amount of 224Ra in the form of 72 fractions of 257 Bq kg-1 each, applied twice weekly during 36 wk. The fractionated group received the same final mean total skeletal dose of 0.15 Gy as the single injected group, but with a mean skeletal dose rate of 1 mGy d-1. A rather high incidence, 13.5% (40/296), of early malignant lymphomas was observed in the fractionated group during and shortly after the injection period, followed by a 7% incidence (21/296) of osteosarcomas during the second half of the animals' lifetime. The group with a single injection did not develop early lymphomas but did develop osteosarcomas later with an incidence of 5.8% (17/295). The occurrence of osteosarcomas was similar up to day 800 in the two experimental groups. Surprisingly, however, after this period no additional case of osteosarcoma was observed in the single-injected group, whereas one-third of all osteosarcomas occurred after day 800 in the protracted group. The additional later occurrence of osteosarcomas occurred after indicates a longer lasting induction effect on osteosarcomas, or a promoting effect in older age, for this kind of treatment.

Alpha Particles↗