Search PubMed⌕ Search

Biomedical subjects

J V Frei

Publications and source records attributed to J V Frei.

At least 55 records · Page 3Linked to original sources
PubMed1978

Alkylation of deoxyribonucleic acid in vivo in various organs of C57BL mice by the carcinogens N-methyl-N-nitrosourea, N-ethyl-N-nitrosourea and ethyl methanesulphonate in relation to induction of thymic lymphoma. Some applications of high-pressure liquid chromatography.

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.

Alkylation↗
PubMed1978

Diagnostic efficacy of tests for the detection of iron overload in chronic liver disease.

The value of tests for the detection of body iron overload was investigated in 8 patients with clinically manifest primary hemochromatosis, 12 patients with cirrhosis and iron overload and 20 patients with liver disease and low or normal iron stores. Iron overload was defined as the presence of stainable iron in more than 50% of hepatocytes in a liver biopsy specimen. The percentages of patients with a true-positive (abnormal) or true-negative (normal) result were: serum iron concentration 65%, transferin saturation 85%, serum ferritin concentration 78%, serum ferritin:serum glutamic oxaloacetic transaminase (SGOT) index 78%, percent iron absorption 58%, percent iron absorption in relation to serum ferritin concentration 80% and percent iron absorption in relation to serum ferritin:SGOT index 93%. The calculated predictive value of a normal test result for the exclusion of iron overload in patients with liver disease, a group with an assumed prevalence of iron overload of 10%, was 98% to 99% for transferrin saturation and serum ferritin concentration used alone and 100% for these measures used together; the predictive value of an abnormal result for the diagnosis of iron overload was less than 50% for all of the above measures used alone or in combination. Hence, in patients with an increased serum ferritin concentration or transferrin saturation, or both, determination of the hepatocellular iron content of a specimen from a percutaneous liver biopsy is required for the diagnosis of iron overload.

Adolescent↗
PubMed1977

Lower limb paralysis induced in mice by a temperature-sensitive mutant of Moloney leukemia virus.

A temperature-sensitive mutant of Moloney murine leukemia virus defective in an early function and injected into newborn mice produced lower limb paralysis. Susceptible mice were inbred strains CFW/D, CBA/H, C3H/Bi/Ka, and outbred NIH Swiss stock. Inbred W/Fu rats and C57BL/Ka mice did not develop the paralysis, though the latter were infected with virus; the sera from these mice produced paralysis in susceptible CFW mice.

Animals↗
PubMed1977

The effect of radiotherapy in the treatment of adenoid cystic carcinoma of the head and neck arising in minor salivary glands.

Eighteen cases of adenoid cystic carcinoma of the minor salivary glands are reviewed. Noteworthy in the history is the report of pain at the site of the lesion which radiates elsewhere, or of numbers or tingling in its area. Radiation therapy is as able to control the primary as local surgery. Involvement of a much wider field than is required to treat the primary may control the perineural spread common to this tumor and avoid the massive procedures necessary to cure it by surgical means. Metastases to the lung, bone, and brain by venous spread can probably be avoided only by early diagnosis.

Adult↗
PubMed1976

Some mechanisms operative in carcinogenesis a review.

Multiple factors contribute to the development of neoplasia. Sometimes a single agency can bring about a tumour if it has many different effects, but at other times a tumour arises more insidiously due to a succession of events [240,241] which by themselves may be innocent. Alterations in the genome of the cell are at the fore-front of our interest because they can be brought about by most of the carcinogenic agents we know. The cell can repair some such alterations but both forward and destructive mutations do appear. The roles of cell proliferation, cell differentiation, the immune mechanism and carcinogen-activating enzymes are beginning to be understood. The effects of dose, route of administration, and of other agents given at the same time [242-245] must not be lost sight of. Other factors no doubt will be added as we begin to look at the structure and function of cell-surface membranes [246-248], at host susceptibility genetics [26, 249], and at the generation of carcinogens inside the body [250,251]. We are only beginning to understand carcinogenesis. In no single instance do we as yet know how a tumour comes about in full details of molecular biology. It is possible that fully rational treatment of cancer will not be possible until we have such an understanding. Once a tumour becomes independent of carcinogenic factors, it continues to develop in a bizarre fashion which makes its study and treatment by all means other than surgery difficult.

Alkylating Agents↗
PubMed1976

Tissue distribution and mode of DNA methylation in mice by methyl methanesulphonate and N-methyl-N' -nitro-N-nitrosoguanidine: lack of thymic lymphoma induction and low extent of methylation of target tissue DNA at 0-6 of guanine.

The methylating agents methyl methanesulphonate (MMS) and N-methyl N'-nitro-N-nitrosoguanidine (MNNG), administered by single i.p. injection in mice failed to yield thymic lymphoma at doses around 60% of the LD50 values, in contrast to MNUA which gives a high yield of tumours by this route. Comparison of the tissue distribution and mode of DNA methylation by these agents showed a positive correlation with ability to methylate the 0-6 atom of guanine in DNA of the target tissues thymus and bone marrow and tumorigeneis. MMS gave a low yield of this product due to its relatively low Sn1 reactivity but was able to methylate DNA extensively at other sites in the target tissues and other organs examined. MNNG despite its ability to methylate 0-6 of guanine in DNA in vitro to the same relative extent as the potent carcinogen MNUA, methylated DNA of thymus and bone marrow to a very small extent in vivo but was able to methylate DNA in certain other tissues nearer the site of i.p. injection. These findings contrast with the general relatively extensive methylation of 0-6 of guanine in DNA of the target tissues and other organs by N-methyl-N-nitrosourea (MNUA).

Animals↗
PubMed1975

Methylation of DNA in various organs of C57B1 mice by a carcinogenic dose of N-methyl-N-nitrosourea and stabiltty of some methylation products up to 18 hours.

Female 6-8-week-old (57B1 mice were injected i.p. with N-methyl-N-nitrosourea (MNUS) (14C or 3H-methyl-labelled) in saline (80 mg/kg) and DNA was isolated from bone marrow, small bowel, kidneys, liver, lungs, spleen and thymus at various times thereafter up to 18 h. Methylation of DNA was found in all organs examined, and by analyses using column or paper chromatography of DNA hydrolysates, the extent of methylation of DNA purines was determined. Methylated guanine residues (at N-3, N-7 and 0-6 positions) were stable in DNA up to 18 h, but methylated adenines (at N-3 or N-7) were removed from DNA of all organs examined; the overall half-life of methyladenines was about 3 h, but removal appeared to occur in a biphasic manner, with a proportion of methyladenine remaining relatively stable. This relative stability was somewhat more marked in bone marrow than in other organs.

Adenine↗
PubMed1975

Chromosome damage in the bone marrow of mice treated with the methylating agents methyl methanesulphonate and N-methyl-N-nitrosourea in the presence or absence of caffeine, and its relationship with thymoma induction.

A single dose (0.8 mmole/kg) of N-methyl-N-nitrosourea (MNUA) causes significantly more chromosome damage in the bone marrow of mice than a dose of equal toxicity to the animals, (1.1 mmole/kg) of methyl methanesulphonate (MMS) 6, 24 and 48 h after treatment. At these doses both agents alkylate bone-marrow DNA to similar extents, but only MNUA induces thymic lymphomata. The greater chromosome-damaging effects of MNUA are ascribed to the known differences in the pattern of DNA alkylation by each agent, in particular the much higher levels of O-6 methylguanine and phosphotriesters produced by MNUA. The greater chromosome-damaging effect of MNUA may account for its higher toxicity to the bone marrow which in turn may be a significant factor in the induction of thymomata. The enhancement by caffeine of chromosome damage seen particularly 48 h after MMS-treatment suggests that post-replication repair protects cells from the effects of DNA-methylation in vivo.

Animals↗
PubMed1974

Induction of liver cell adenomata in the rat by a single treatment with N-methyl-N-nitrosourea given at various times after partial hepatectomy.

A single treatment of adult animals with the potent carcinogen NMU was known to induce tumours in a wide variety of organs, with the notable exception of liver. Administration of NMU after partial hepatectomy gave rise to the first liver cell adenomata ever observed in rats due to this carcinogen. The tumours were induced when NMU was given during the period of increased DNA synthesis but not when given early in the pre-replicative period. Although tumours were induced in other organs, the incidence of these did not correlate with the timing of NMU administration. It is suggested that replication of damaged DNA may be a relevant event in carcinogenesis.

Adenoma↗