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Biomedical subjects

J Denekamp

Publications and source records attributed to J Denekamp.

At least 163 records · Page 9Linked to original sources
PubMed1980

Proliferation kinetics of the mouse bladder after irradiation.

The proliferation response of the mouse bladder was investigated, using continuous labelling with tritiated thymidine, at various times after a single dose of radiation. Bladder epithelial and vascular endothelial cells were studied. The cell turnover rate in unirradiated epithelium and endothelium was found to be extremely slow (in excess of 1 year). Irradiation with a single dose of 25 Gy resulted in compensatory proliferation of the epithelium but the response was not initiated for many months. At 3 months after irradiation there was little difference from the control proliferation rate, but from 6 to 22 months after irradiation (the end of the study) there was a period of sustained rapid proliferation with the cell turnover time reduced to approximately 1 week. The increase in proliferative activity observed at 22 months was found to be dose-dependent. Endothelial cells in the blood vessels of the submucosa also showed an increased turnover rate after irradiation and the timing this response was found to be similar to that of the epithelium. The onset of compensatory proliferation in both cell types was found to coincide with marked histological and functional changes in the bladder. In this slowly proliferating tissue, the onset of rapid compensatory proliferation after irradiation is delayed and occurs at the time that functional impairment is observed. This supports the postulate that proliferation is unlikely to contribute much to the sparing effect of prolonged fractionated radiotherapy in slowly dividing tissues.

Animals↗
PubMed1980

Proliferation studies of the endothelial and smooth muscle cells of the mouse mesentery after irradiation.

A continuous labelling technique was employed to study the effects of external beta-radiation on the proliferation of endothelial cells and smooth muscle cells in the mesenteric arterioles of mice. Labelled and non-labelled cells of either type were determined by autoradiographic techniques in control animals and at different times (3, 12 and 48 weeks) after single doses of 20 and 45 Gy (2000 and 4500 rads). The fraction of cells labelled, even after 7 days of repeated injections was very low in all instances. Calculations showed very long turnover times for the two cell populations in control animals (greater than 2 years for endothelium and greater than 3 years for smooth muscle). After 20 and 45 Gy, no significant increase in endothelial proliferation was seen except at 3 weeks. No significant increase in labelling was observed in smooth muscle at any time after irradiation. These labelling data have been compared with the pattern of cell depletion of the irradiated endothelium. It was concluded that the depletion was much earlier than expected for a slowly proliferating tissue, if all the cells were cycling very slowly. Such an early depletion is, however, consistent with cell death resulting from a small proportion of the cells having a short cell cycle. The recovery of the endothelial cell numbers between 9 and 12 months was not accompanied by a rise in the fraction of labelled cells. Its is suggested that repopulation may occur from outside the treated area.

Animals↗
PubMed1980

Fractionation studies with combined X rays and hyperthermia in vivo.

The combined effects of single and fractionated doses of X rays and local heat were investigated using an experimental fibrosarcoma and normal mouse skin. Thermal enhancement ratios were measured from pairs of dose-response curves for both tumour and skin, and the therapeutic advantage of each treatment was then assessed by comparing the enhancement for tumour and skin. For single doses there was a therapeutic advantage when heat was applied three hours after X rays but not with heat applied immediately after irradiation. For two and five daily fractions with heat immediately after irradiation there was significantly less thermal sensitization in tumour than in skin; hence there was a therapeutic loss. When heat was applied at three hours after each fraction there was no thermal sensitization in either skin or tumour; the therapeutic ratio was therefore 1.0. The repair capacity of skin after fractionated X rays alone, or in combination with heat, was also investigated. Heat immediately after X rays caused a small decrease in the repair capacity between two fractions but no decreased repair capacity was observed with five fractions.

Animals↗
PubMed1980

Misonidazole in fractionated radiotherapy: are many small fractions best?

Computer simulations have been made of four radiotherapy fractionation regimes either in current use or proposed for clinical trials of misonidazole. A variety of cell-survival parameters and reoxygenation patterns have been used. The models allow the relative importance of repair capacity, reoxygenation rate, and dose per fraction to be assessed for these four schedules in the presence or absence of misonidazole. Unlike hyperbaric oxygen, the dose of misonidazole and the fractionation scheme to be used are critically interdependent, because the total drug dose is limited to 12 g/m2 by its neurotoxicity, regardless of the extent to which it is fractionated. The largest sensitizing effect is always demonstrated with six fractions, each given with 2 g/m2 of misonidazole. In the absence of reoxygenation a sensitizer enhancement ratio of 1.7 is predicted, but this falls to 1.1--1.2 if extensive reoxy-generation occurs. Less sensitization is observed with 30 fractions, each with 0.4 g/m2 of drug. However, for clinical use, the important question is which treatment kills the maximum number of tumour cells. Many of the simulations predict a marked disadvantage of reducing the fraction number for X rays alone. The circumstances in which this disadvantage is offset by the large SER values with a six-fraction schedule are few. The model calculations suggest that many small fractions, each with a low drug dose, are safest unless the clinician has some prior knowledge that a change in fraction number is not disadvantageous.

Animals↗
PubMed1980

Is any single in situ assay of tumour response adequate?

The different assays available for measuring the response of undisturbed tumours in situ after therapy are reviewed. These are: animal survival time, regression rate of tumours, regrowth delay, local tumour control and loss of incorporated radioactivity. The relative advantages and disadvantages of each assay are reviewed in terms of cost-effectiveness and the relevance of the data they yield. For comparisons of different treatment modalities any single assay seems adequate provided a dose-response relationship can be demonstrated. The assay of choice will depend upon: the dose-range to be investigated, the amount of prior information that is required and the skills and apparatus that are available. No single assay is clearly best, but survival time and regression rate studies probably yield the least valuable information. If the main question is the absolute number of cells surviving a particular treatment, or the mechanisms leading to a given response, no single assay will yield as much information as a combination of several in situ techniques, together with excision assays. For clinically oriented questions, however, a single assay may be adequate. The choice of an appropriate tumour model is the most important factor in determining the relevance of the data obtained from mice for man.

Animals↗
PubMed1980

Testing of hypoxic cell radiosensitizers in vivo.

The sensitizing action of misonidazole in a range of animal tumors is reviewed and the conclusion is drawn that all tumor cells are capable of sensitization if they are hypoxic. There is no evidence of drug diffusion problems to distant hypoxic cells. The misonidazole sensitization at low doses enables an estimate of hypoxic fractions to be made in both mouse and human tumors; these mostly fall in the same range of 5-50%. The optimum way of using misonidazole, based on survival curve characteristics, is briefly reviewed. The potential therapeutic gain factor is based on sensitization of tumor cells more than of normal cells. The evidence for sensitization of some normal tissues in mice is reviewed. The search for better radiosensitizers, either based on the same effect for a lower dosage, or a greater effect for the same normal tissue toxicity, is illustrated with two other nitroimidazoles: Ro-03-8799 and Ro-12-5272. These have been studied in the artificially hypoxic skin clone assay and also by regrowth delay in a fibrosarcoma in mice.

Animals↗
PubMed1980

Tumour growth and cancer therapy.

Tumour growth is the result of a complex balance between cell production and cell loss. The different rate of growth in different tumours depends on the extent to which this balance is tipped towards cell production. In some tumours most cells that are born contribute to the net growth, especially in fast-growing sarcomas. In other tumours very few of the tumour cells that are produced contribute to net growth, for example in slow-growing carcinomas. The kinetics of tumour cells is greatly influenced by the proliferation rate and pattern of branching of the capillary network supplying the tumour. These also influence the response to chemotherapy and to radiotherapy. In chemotherapy the kinetics of the tumour relative to the most rapidly growing cells anywhere in the body influences the potential therapeutic benefit that can be achieved. Radiotherapy depends on the relative kinetics and sensitivities of tumour and local normal tissues within the beam, including the tissue of origin.

Animals↗
PubMed1979

Tumour cell proliferation in relation to the vasculature.

The proliferation pattern of a transplantable mouse mammary carcinoma has been studied in relation to its macroscopic and microscopic structure. No significant differences were seen in the labelling or mitotic indices or in the percentage labelled mitoses curves for the peripheral 2.0 mm rim or for the central tumour core. When these parameters were scored for cells classified according to their position in relation to capillaries or to necrotic regions, marked differences were observed in all the parameters. Higher labelling and mitotic indices and higher grain counts were seen adjacent to the capillaries. These appear to result from a shorter cell cycle duration and a higher growth fraction. The variation in cell cycle is mainly due to a change in the duration of G1.

Animals↗
PubMed1979

The response of six mouse tumours to combined heat and X rays: implications for therapy.

The response of six types of mouse tumour to single doses of X rays alone or to X rays in combination with moderate hyperthermia (42.5 degrees C/60 min) has been assessed using delay in tumour regrowth. Thermal sensitization was observed in five of the six tumours. The degree of sensitization varied with the size of the X-ray dose, being larger at higher doses. The degree of sensitization also depended on the sequence and separation of the heat and irradiation. The thermal sensitization has been measured in terms of the X-ray doses to produce the same level of tumour damage with or without heat, i.e. thermal enhancement ratios. These TER values, measured for X-ray doses in excess of 20 Gy, are not greater in any of the tumours than in a range of normal tissues, if the X rays and heat are given in close succession. Separation of the heat and X rays reduces the TER values slightly, but some effect is still apparent at 3--24 hours. In normal tissues the effect of heat is totally lost within four hours. Comparison of these tumour data with published normal tissue data indicates a therapeutic advantage if the heat and X rays are separated by more than one hour. This therapeutic gain is most reliably achieved and heat given after irradiation.

Animals↗
PubMed1978

The therapeutic advantage of combined heat and X rays on a mouse fibrosarcoma.

The response of an experimental fibrosarcoma to combined heat and X rays has been assessed using delay in tumour regrowth. No thermal sensitization was observed for one hour of heating at 41.5 degrees C. A thermal enhancement ratio of 1.4 to 1.5 was seen for one hour of heating at 42.5 or 43.5 degrees C immediately after irradiation. The importance of the sequence and time interval between the two modalities was tested using a constant heat treatment of 42.5 degrees C for one hour. Heating was most effective when given after irradiation, with little change in TER for an interval of a half to six hours. When heat preceded the irradiation the pattern was more complex, with no sensitization at half, one, and six hours, but with a significant effect at two and three hours. The degree of sensitization often depended upon the X-ray dose, being lower below X-ray doses of about 20 Gy. The therapeutic advantage of the combined treatment was assessed by comparison with previously published results for skin reactions. No therapeutic benefit was found for treatments when heat and X-rays were separated by one hour or less. A therapeutic gain factor of about 1.3 was observed for heat given two to six hours after irradiation of this fibrosarcoma.

Animals↗