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Biomedical subjects

O H Iversen

Publications and source records attributed to O H Iversen.

At least 19 recordsLinked to original sources
PubMed1979

Nitrosomethylurea (MNU): a powerful carcinogen for mouse skin. A study utilising the tetrazolium test (TZT) and topical skin applications.

Nitrosomethylurea (MNU) was tested with the tetrazolium test for skin carcinogens with positive results. 39 hairless mice were painted once a week with a 1% solution of MNU in acetone. After 18 weeks all the animals bore tumours and 90% had skin carcinomas. Hence, the strong carcinogenic potency of MNU was confirmed, and the validity of the tetrazolium test was given further support.

Animals↗
PubMed1979

The carcinogenic effect of TPA (12-0-tetradecanoylphorbol-13-acetate) when applied to the skin of hairless mice.

Groups of hairless mice received one, two, five and fifty applications of 20 nmoles TPA (12-0-tetradecanoylphorbol-13-acetate) on the skin of the back, and were observed for 20 months. The animals developed some papillomas, some squamous cell carcinomas, some fibrosarcomas of the dermis, and some malignant and benign tumours in internal organs. There was a small, not significantly different, incidence of benign and malignant tumours after 1, 2 and 5 paintings, and a significantly higher tumour incidence after 50 applications. Apart from reticuloses, which are commonly seen in these animals, the occurrence of other tumours is believed to be related to the TPA treatment. The results are interpreted as showing that TPA, like croton oil, should be regarded as a complete carcinogen.

Animals↗
PubMed1979

Epidermal DNA synthesis in organ culture explants. A study of hairless mouse ear epidermis.

Explants of split mouse ear were incubated in organ culture for up to 48 h, and the cell proliferation was studied by the addition of Thymidine-methyl-3-H (3HTdR) to the medium during different time periods, mainly for the first 14 h of incubation. Cultures were started at 0900, 2130 and 2300. In all cases the labelling index remained stable for 6-8 h, and then increased. The mean grain count, however, was falling and so was the epidermal DNA-specific uptake of 3HTdR. Based on the experimental results, calculations can be made of the flux of cells through S. It is concluded that the increasing LI is not due to inherent diurnal variation in cell proliferation, and is not a sign of real growth but caused instead by a complete block of the cell exit from S, probably combined with periods of an increased entrance rate into S. Other methodological factors, however, may also contribute to the increasing LI. Hence, this system is not suited for the measurement of factors that influence epidermal DNA synthesis.

Animals↗
PubMed1978

The effect of the epidermal G2 chalone on the mitotic duration in nude mouse epidermis and in a transplanted squamous cell carcinoma.

Balb/c/nu nude mice transplanted with a moderately differentiated squamous cell carcinoma were injected intraperitoneally with different doses of aqueous skin extracts containing the epidermal G2 chalone. The mitotic counts and the mitotic rates were determined in histological sections using a stathmokinetic method with vinblastine sulphate. The mitotic duration was calculated from the mitotic rates and counts. Skin extracts containing epidermal G2 chalone increased the mitotic duration in the epidermis, and a similar trend was seen in the tumour. The higher the dose of chalone, the longer the mitotic duration tended to be. A straight line of best fit used to indicate the dose/response relationship was steeper for the epidermis than for the tumour. The study thus shows that the epidermal G2 chalone not only prevents epidermal cells from entering mitosis, it also prolongs the mitotic duration. Further, the results do not contradict the theory that tumour cells may be less sensitive to chalone than normal cells.

Animals↗
PubMed1978

Epidermal cell kinetics in the nude mouse.

The epidermal cell kinetics in nude mice is investigated by determining the mitotic rate and the mitotic count, the H3Tdr labelling index, and the proportion of basal cells in the different cell cycle phases by flow cytometry. The mitotic duration was calculated. The parameter values of the epidermal cell kinetics of the nude mouse are largely similar to those of the hairless mouse.

Animals↗
PubMed1978

Epidermal chalones and squamous cell carcinomas. The growth inhibitory effects of aqueous epidermal extracts (G1 and G2 chalones) on the epidermis and on a transplantable keratinizing carcinoman in nude mice.

Balb/c/nu nude mice that had been transplanted with a moderately differentiated squamous cell carcinoma were injected i.p. with different doses of epidermal chalone, and control animals were injected with saline. The labelling indices (H3TdR) and the mitotic rate (stathmokinetic method with vinblastine sulphate) were determined. In the untreated animals, both the labelling index and the mitotic rate of the tumor were considerably higher than in the epidermis, and the rate of cell birth was almost twice that of the epidermis. Higher doses of chalone were needed to reduce the labelling index for the tumour than for the epidermis, and there was generally a less pronounced dose/response relationship in the tumours than in the epidermis. The same was true of the mitotic rate but here the results were not as obvious as for the labelling index. A possible explanation of the results may be that the tumour cells are less sensitive than epidermal cells to the injected chalones, or that reduced vascularization of the transplanted tumour may lead to reduced access of chalone, or that tumour necrosis may pay a role. However, it is evident that the tumour cells react less than the epidermis to both the G1 and the G2 chalone, and thus the findings of this study do not provide any evidence against the theory that epidermoid transplanted tumours are less sensitive to epidermal chalones than normal tissue of the same histogenetic origin.

Animals↗
PubMed1978

Specificity of epidermal chalone extracts for human epidermoid tumour cells in vitro: a preliminary report.

In order to test the mitosis-inhibiting effect and the tissue specificity of the epidermal G2 chalone for tumour cells, extracts from hairless mouse epidermis were tested in short-term tissue cultures of cells from human respiratory tract epidermoid carcinomas and adenocarcinomas. The chalone inhibited strongly the mitotic activity in two cases of histologically proven epidermoid carcinoma, and had no effect in two cases of adenocarcinoma. In one case of a supposed epidermoid carcinoma, the chalone had no effect. Revision of the histology, and the result of autopsy 11 months later, showed that in this case the lesion in the lung had been a poorly differentiated metastasis from an adenocarcinoma of the ovary. Liver extracts produced in the same way as the epidermal extracts showed no mitotic inhibition in any of the cultures. These results indicate that epidermal G2 chalone produced from mouse skin is tissue specific for human epidermoid tumour cells, and also indicate that a chalone test might be used as a diagnostic tool for poorly differentiated carcinomas to see whether they are of epidermoid origin or not.

Adenocarcinoma↗
PubMed1977

Partial purification of epidermal G2 chalone.

A partial purification of epidermal G2 chalone from crude epidermal cell extracts from hairless mice is described. The procedure involved the sequential use of ammonium sulphate precipitation, affinity chromatography and gel filtration. Mitosis-inhibiting activity at each stage in the purification was tested in an in vitro assay system employing human epidermoid carcinoma cells in exponential growth phase and Colcemid (Ciba) for arresting mitoses. This assay system is much more rapid and convenient than conventional in vivo systems. By the procedure described, a 10,000-fold material purification of the active component has been obtained. This corresponds to a 3,000-fold purification measured by protein content, and a 300-fold increase in mitosis-inhibiting activity per unit we;ght. The active component is acidic, contains sugar residues and has gel chromatographic properties characteristic of a substance with molecular weight of approximately 20,000. On SDS polyacrylamide gel electrophoresis, however, three weak bands were found. The active component is resistant to trypsin and protease and stable between pH 6.0 and 8.5. It is easily inactivated at pH values below 6.0. At the present stage of purification, several components other than the active one still remain in our material and further purification steps must be eventually employed.

Animals↗
PubMed1977

[Species-non-specific and reversible growth inhibition by chalones in human epidermoid carcinomas in vitro].

Human epidermoid carcinomas and adenocarcinomas from the respiratory tract were established as cell cultures and grown on Cell finder film slides (Microlab, Holland). The cultures showed lack of contact inhibition, and cytogenetical analyses revealed both numerical and structural karyotype anomalies, with various abnormal chromosome stemlines. Pig and mouse skin extracts supposed to contain the epidermal G2 chalone and mouse liver extracts prepared in a similar way were added to the cell cultures, which were then assayed for mitotic inhibition by means of the Colcemid technique, i.e. the number of Colcemid-arrested mitoses per 1000 cells during 4 h was counted. The results indicate that the species-non-specificity and the reversibility of the epidermal G2 chalone activity, previously demonstrated in both malignant and non-malignant animal tissues and in human epidermis, is to be found even in human epidermoid carcinomas in vitro. The reversibility of the chalone-induced mitotic depression could be demonstrated by repeated counts of the number of proliferating cells in the cultures before and after addition of chalone extrcts. Whether this hold true for malignant human tumours in general remains, however, to be seen.

Adenocarcinoma↗
PubMed1977

Effects of cellophane tape stripping of mouse skin on epidermal growth regulators (chalones).

Variations in epidermal chalones after a single surface application of methylcholanthrene and croton oil have been described in previous papers. This paper reports a study of the effect of adhesive tape stripping of the skin on epidermal growth regulators (G1 and G2 chalones). Pieces of adhesive tape were applied 6 times to the same area of skin in groups of mice. The short-term effects of tape stripping on epidermal DNA synthesis and on mitotic rate were studied at different intervals after stripping. Other groups of mice were killed at similar time intervals after stripping, and the treated area of skin was homogenized and extracted with water. The inhibitory effect of these extracts on normal epidermal DNA synthesis and mitotic rate was assayed in normal hairless mice. The resulting inhibitions were interpreted as an expression of the concentration of G1 or G2 chalone in the skin extracts. The first experiment confirmed that cellophane tape stripping gives rise to a short block in epidermal mitotic activity and probably also in DNA synthesis. This was followed by bimodal peaks of increased activity, the two maxima of labelling index being found on days 2 and 6, and the two maxima of mitotic rate on days 1-2 and 7. The concentrations of the two chalones in the skins of treated animals varied in inverse proportion to the alterations in the DNA synthesis and the mitotic rate, with one exception. Here there was initially a depression of the mitotic rate and a low concentration of G2 chalone. This was interpreted as a short reaction of the basel cells to the stripping trauma. It is concluded that adhesive tape stripping removes the differentiating cells and injures some basel cells, simultaneously altering the content of G1 and G2 chalones. The resulting increase in the rates of DNA synthesis and mitosis lasts only until the number of cells is high enough to produce growth-regulating substances (chalones) again. This theory may explain the changes observed. Since similar reactions are seen after both carcinogenic and co-carcinogenic chemical injury of the epidermis, the reaction pattern seems to be a general response to cell injury or cell removal.

Animals↗
PubMed1977

Growth kinetics of Kaposi's sacroma.

This is a study of cell kinetics in nodular and florid (fungating) Kaposi's sarcomas. One or more tumours from 9 patients were examined at the Uganda Cancer Institute. The very variable clinical doubling time was assessed by direct measurements of tumour diameters, and an average obtained. The mitotic count, rate of entry of cells into mitosis and cell cycle time were measured in biopsy material, and use to estimate the potential doubling time. From the difference between the potential and the actual doubling times, the rate of cell loss and the cell loss factor were calculated. The average actual clinical doubling time was slightly, but not significantly, higher for growing nodular tumours than for florid tumours. Some nodular tumours were similar to those reported in the literature for other human malignacies. Kinetic studies of static and regressing human tumours have not been reported previously. The rate of cell production found in this tumour is lower than the values reported in the literature for other malignancies. The calculated mitotic duration is long, but similar to previously reported values. The cell loss factor is high: in the static tumours it is 1.0, and in the regressing tumours greater than 1.0. In regressing tumours, the rate of cell loss was 30% higher than the rate of cell production. These tumours did not differ histologically from nearly florid tumours which were increasing in size. It is postulated that regression is determined by local vascular or mechanical factors, supplemented possibly by delayed hypersensitivity responses in some patients.

Cell Count↗
PubMed1977

Effects of bleomycin on the epidermal content of growth-regulatory substances (chalones).

Hairless male mice were given 2 mg Bleomycin i.p. on two successive days. At different time intervals from 1 to 10 days after the last Bleomycin injection, groups of animals were killed and water extracts of hemogenized skin were made. These extracts, supposed to contain the epidermal G1 and G2 chalones, were injected into female hairless mice, and their growth inhibitory potency determined by two methods. 5 mg of lyophilized crude skin extract were injected i.p. together with Colcemid, and the animals killed 4 hr later. The number of Colcemid-arrested mitoses was determined, and was considered to be a measure of the G2 inhibitor present in the skin extracts. 10 mg of the same extracts were injected i.p., and these animals also got 3H-TdR i.p. 12 hr later, and were killed after a subsequent 30 min. The epidermal LI was determined, and was considered to be a measure of the epidermal G1 factor in the skin extracts. The results obtained were compared to the effect of Bleomycin alone and to the effects of skin extracts from non-Bleomycin-treated animals. The results show that Bleomycin provoked slight alterations in the growth-inhibitory potency of the G1 chalone, whereas significant effects were seen in the G2 chalone, There was an increased amount of growth-inhibiting factors on days 2 and 3, and on days 8-10. The results are discussed and it is concluded that the most probable hypothesis is that Bleomycin, in addition to its known inhibition by accumulation of cells with high growth inhibitory potency. An initial, additional direct effect of Bleomycin on the chalone system cammot be excluded.

Animals↗
PubMed1976

Effects of croton oil on epidermal growth regulators (chalones).

Variations in epidermal chalones after a single surface application of methylcholanthrene have been described in previous papers. This paper reports a study of the effect of croton oil on epidermal growth regulators (G1 and G2 chalones). Hairless mice received a single topical application of 0.2 ml 0.25% acetone solution of croton oil. Control mice received only acetone. The short-term effect of croton oil on epidermal DNA synthesis and mitotic rate was studied. Other groups of croton oil-treated and acetone-treated mice were then killed at similar time intervals, and the treated area of skin was homogenized and extracted with water. The inhibitory effect of these extracts on normal epidermal DNA synthesis and mitotic rate was assayed in normal hairless mice. The resulting inhibition was interpreted as an expression of the concentration of G1 and G2 chalones, respectively, in the skin extracts. The first experiment confirmed that a single croton oil application provokes a short block in epidermal mitotic activity and probably also in DNA synthesis. This was followed by bimodal peaks of increased activity, the two maxima of mitotic rate on days 2 and 7. The concentration of the two chalones in the skins of treated animals varied in inverse proportion to the alterations in the DNA synthesis and the mitotic rate, with one exception. There was here initially a depression both of the mitotic rate and a low concentration of G2 chalone. This was interpreted as a short, initial direct effect of croton oil on the G2 chalone present at the time of application. It is concluded that croton oil application injures and kills epidermal cells, with subsequent alterations in the content of G1 and G2 chalones. This theory may explain the changes observed. The effects of croton oil on the amount of G1 and G2 chalones in the skin are probably related to the direct, toxic, cell-killing effect of croton oil, and not to its specific cancer promoting potency.

Animals↗
PubMed1976

Is there a diurnal variation in the susceptibility of mouse skin to the tumorigenic action of methylcholanthrene? A study of tumour yield with special reference to the variation between cages.

Skin tumour development was studied in groups of mice painted once with 125 mug of 3-methylcholanthrene (MCA) either at 12:00 or at 24:00 MET. Eight animals were kept in each box. The animals were observed weekly for 20 months and all tumours were registered. There was no difference between the two groups of mice as regards tumour induction time or number of papilloma-bearing mice. In the groups of mice treated at 24:00 the number of skin tumours to develop was 9 per cent higher than in groups of mice treated at 12:00. This difference in papilloma yields is not statistically significant. Among female mice painted at 24:00 carcinoma-bearing animals were significantly more numerous (50 per cent) than among those painted at 12:00, whereas there was no difference between the groups of male mice. Considering the groups collectively (males + females), the intergroup difference (17 per cent) in advantage of painting at 24:00 was barely significant (0.5 less than p less than 0.10). There was no difference between the groups as regards the total number of carcinomas to occur. When the tumour yields in individual boxes were found to vary greatly. The slight increase in tumour yield after night painting correlates with the circadian variation in proliferative activity of the epidermidis. Previous reports in the literature have shown similar differences. Further investigations and better methods seem necessary before a definite conclusion can be drawn concerning a possible diurnal variation in the susceptibility of mouse skin to chemical carcinogenesis. It is also emphasized that it is necessary to exercise great caution when the results of classical epidermal chemical carcinogenesis experiments are to be interpreted. It seems necessary to observe animals for at least 15 months before any conclusion can be drawn.

Animals↗