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J Denekamp

Publications and source records attributed to J Denekamp.

At least 145 records · Page 8Linked to original sources
PubMed1983

The RBE for mouse skin irradiated with 3-MeV neutrons: single and fractionated doses.

Early skin reactions on the feet of mice were measured after irradiation with 240-kVp X rays or with neutrons from a 4-MV Van de Graaff accelerator. The results are compared with previous experiments using cyclotron-produced neutrons. Single doses, or 2, 5, or 9 equal fractions, were given to measure the RBE and repair capacity for neutrons and X rays over the neutron dose per fraction range from 1.0 to 13.0 Gy. The RBE increased with decreasing dose per fraction, and these data could be fitted with a straight line on a log-log plot. The RBE was 4.6 at 1.0 Gy and fell to 2.1 at 13.0 Gy. These RBE values are significantly higher than those from cyclotron-produced 7.5-MeV neutrons, especially at low doses per fraction. The repair capacity was calculated from a comparison of the single-dose and fractionated data over a skin reaction range from 0.6 to 2.4. The D2 - D1 value was 5-10 Gy for X-ray doses up to 18 Gy and less than 1.5 Gy for 7 Gy of neutrons. This reduced repair capacity after neutrons was even more apparent with further fractionation, becoming close to zero for neutron doses below 3 Gy. These data were used to construct quasi-survival curves for epidermal cells. The X-ray data conform to an alpha D + beta D2 model, whereas the neutron data indicate a predominant alpha component, with the initial response appearing linear from zero to 5.0 Gy. Beyond this dose, however, a potentially reparable beta component of neutron damage is detectable, with the same value of beta as for X rays. Thus it is the greatly increased efficiency of the alpha component relative to X rays, rather than an absence of a shoulder after neutrons, that gives rise to the low D2 - D1 values at low doses and to the high RBE. The ratio of alpha components for X rays and neutrons would indicate a limiting RBE of 7.2 at X-ray doses below 1.0 Gy.

Animals↗
PubMed1982

Early and late effects in mouse lung and rectum.

No higher RBE's were found for late than for early damage in mouse rectum up to 70 weeks or mouse lungs up to 48 weeks after irradiation with 3.0 MeV neutrons (4 MeV deuterons on Be). The smallest neutron doses per fraction were 1.5 and 0.6 Gy for rectal and lung irradiation, respectively. There was a suggestion of higher late RBE's for small doses per fraction in the lung. Slow repair after 2 neutron doses split by 31 days was unequivocally demonstrated in the lung, of magnitude about 1 Gy, possibly decreasing after about 40 weeks.

Animals↗
PubMed1982

Interaction of radiosensitizers and WR-2721. I. Modification of skin radioprotection.

We have studied the radiomodifying action in mouse skin of WR-2721 and misonidazole (MISO) when used alone or in combination. The radioprotection with WR-2721 was drug-dose dependent and highly influenced by the O2 concentration at the time of irradiation. Significant sensitizaton was observed with MISO, especially in air-breathing mice. The combination of WR-2721 and MISO produced a radiation response intermediate between the resistant and sensitive responses to either drug alone. The precise degree of sensitivity was dependent on the relative doses of protector and sensitizer. We have also studied the interaction of both drugs in terms of drug-induced lethality, which showed a clear toxic interaction. The WR-2721 LD50 was reduced by a factor of 1.4 with only 200 mg/kg of MISO. We conclude that the combination of WR-2721 and MISO shows an interaction in terms of drug toxicity and radiation response, such that the radioprotection of skin is reduced or even abolished with low doses of MISO.

Amifostine↗
PubMed1982

Skin sensitization by misonidazole: a demonstration of uniform mild hypoxia.

Skin reactions on irradiated mouse feet were used to measure the radiosensitization of normal tissues by misonidazole (MISO). Fractionation schedules of 1, 2, 5 and 10 daily doses of X-rays were combined with either 100 mg/kg or 670 mg/kg MISO. When unanaesthetized mice were irradiated in air, significant sensitization was observed with both the high and low drug doses, in all fractionation schedules. There was no decrease in sensitization with fractionation, even using fractions as small as 5 Gy. This indicates that many of the cells in mouse skin may be marginally hypoxic, and that sensitization at low doses is possible. Irradiation in O2 without MISO rendered the skin more sensitive to X-rays than in air. MISO given 30 min before single doses of radiation further sensitized the skin, but for 10 fractions in O2 no MISO sensitization was detected. There was little evidence for cytotoxic killing in skin by MISO. Repair of radiation damage was slightly reduced when MISO was present, during or after irradiation.

Air↗
PubMed1982

In vivo assessment of basic 2-nitroimidazole radiosensitizers.

The radiosensitizing efficiencies of 4 structural analogues of misonidazole (MISO) have been compared with that of the parent compound. Three of these were charged basic compounds, previously shown in vitro to be 10 times more efficient. Enhancement ratios were measured from pairs of tumour growth-delay curves for the mouse fibrosarcoma SA Fab. Two routes of administration and ranges of drug dose and intervals between injection and irradiation were tested. Drug concentrations in blood, brain and tumor were measured using high-performance liquid chromatography. The peak concentration in tumours coincided with the peak in radiosensitization: 20 min after i.v. injection and 40 min after i.p. injection. The concentration in tumours was similar for either route. Comparison of radiosensitizing efficiency on the basic of equal administered dose showed no difference between the 5 compounds, but after equimolar doses the charged compounds achieved lower tumour concentrations. Comparison of sensitizing efficiency on the basis of tumour concentration showed that they were 3 times more potent than MISO, as predicted from their higher electron-affinity. The resultant improvement in radiosensitization at low, clinically relevant, concentrations is so slight that any therapeutic benefit would depend on reduced drug toxicity in man.

Animals↗
PubMed1982

Endothelial-cell proliferation in experimental tumours.

The proliferation characteristics of vascular endothelium have been studied in 131 individual experimental tumours, representing 18 transplanted tumour lines. The labelling index (LI) is high in most tumours, with a mean value of 0.9%, regardless of the growth rate of the tumours, or whether different tumour types are considered or individual tumours from within one line are studied in detail. A similar high LI value has been found by others for a human tumour. These high LI values may even underestimate the proliferation in new capillary buds. The high proliferative index of tumour endothelium is in marked contrast with the previously reported low 3HTdR uptake into normal tissue blood vessels. It seems likely that it is the type of new vessels formed that will influence tumour growth rates more than the simple rate of endothelial-cell proliferation. The large difference between the proliferation characteristics of tumour endothelium and normal tissue endothelium, recently identified as a possible approach for tumour therapy, has now been confirmed for a range of animal tumours and a human tumour.

Animals↗
PubMed1982

Comparative studies of hypoxic-cell radiosensitization using artificially hypoxic skin in vivo.

The survival of epidermal cells in vivo has been used to assess potential radiosensitizers. Mouse skin was made acutely hypoxic for the irradiations, to give radioprotection by a factor of 2.7-3.0. Several concentrations of each drug were used to determine whether any of them were more effective sensitizers than misonidazole. The SER at each concentration was determined from radiobiological dose-response curves. The blood concentration and toxicity of the compounds were also determined. The sensitizing efficiency, assessed in several ways, indicated that only Ro 03-8799 gave significantly greater sensitization than misonidazole, and then only when assessed by comparing the compounds on the basis of equimolar blood concentrations. If the comparison of efficiency was made in terms of LD50 the ranking order change. The need for a more clinically relevant test of peripheral neurotoxicity is stressed.

Animals↗
PubMed1982

Proliferation kinetics of endothelial and tumour cells in three mouse mammary carcinomas.

An autoradiographic study of three corded mouse tumours is reported. The proliferation characteristics of both tumour cells and endothelial cells were studied. The doubling time of these three tumours differed by a factor of 2.6 but there was only a small difference in the intermitotic time. All three tumours showed a very high cell loss factor (approximately 0.80) and the differences in growth rate resulted mainly from differences in the growth fraction. The endothelial cell proliferation rates differed markedly in the three tumours, with labelling indices ranging from 18% in the faster tumours to 4.5% in the slowest. The potential doubling times for endothelium, calculated from these values, were much slower than the tumour cell cycle time or the tumour potential doubling time, but were two to four times faster than the volume doubling time of the tumour. It appears likely that the endothelial proliferation rate influences the growth fraction, but similar high cell loss factors can occur in tumours with a four-fold difference in endothelial cell production rates. Inadequate branching of blood vessels seems likely to be at least as important as inadequate production of endothelial cells. It is not possible to determine whether slow tumour cell production evokes a slower endothelial growth or vice versa.

Animals↗
PubMed1982

Does local tumour heating im mice influence metastatic spread?

Experimental studies are reported on the effect of local tumour hyperthermia, combined with radiation, on the incidence of distant metastases. Two types of study were performed: a retrospective analysis of data obtained incidentally from regrowth delay experiments, and prospective studies designed specifically to investigate the effect of heat on the spread of disease. In the first case, tumours were treated with a range of palliative doses of X rays given either alone or in combination with heat (42.8 degrees C/h). Only one tumour out of 5 showed a significantly increased incidence of metastases, and then only when heated immediately before radiation. The prospective studies were designed so that primary tumours were locally controlled. Neither heat applied immediately before nor after irradiation resulted in a significant change in incidence of metastases. However, whole body heating did produce a marginally significant increase. Fractionated hyperthermia (4 heat doses plus curative radiation) did not result in any significant change in frequency of metastasis. These data suggest that local heating combined with radiation does not result in an increased risk of metastatic spread.

Animals↗
PubMed1982

Histology as a method for determining thermal gradients in heated tumours.

It is proposed that histological assessment of tumours may be a useful biological thermal dosimeter. Assessment of nodules may give information about thermal gradients, and biopsies of treated tumours may serve as a prognostic indicator in clinical hyperthermia. Cell death after hyperthermia occurs rapidly and surviving cells are readily recognizable as small foci within 24 h. This contrasts with the delayed cell death and the more random distribution of survivors amongst killed cells after ionizing radiation. By 24 h, sections of tumours can demonstrate islands of apparently viable cells in a sea of necrosis after 44.8 degrees C/1 h. This technique has been used to identify regions of poor heating in mouse tumours treated by water immersion. Cells surrounding blood vessels and cells adjacent to underlying normal tissue were seen to be protected from thermal damage.

Animals↗
PubMed1982

The potential benefit from a perfect radiosensitizer and its dependence on reoxygenation.

The potential benefit of a perfect radiosensitizer has been assessed by computing the sensitization ratios that would be observed in a mixed population of oxic and hypoxic cells if different reoxygenation rates existed. The sensitizer has been assumed to be as effective as oxygen, completely non-toxic and freely diffusible to all hypoxic cells within the tumour. The calculations have been made for several different clinical fractionation regimes, namely 30, 20, 9 or 6 fractions, all with the same ret dose (NSD = 1700 rets). These calculations have allowed us to deduce how large the observed sensitization would be for differing rates of reoxygenation and for the different fractionation schemes. The size of the extrapolation number is seen to be an important parameter in these calculations. They have allowed us to indicate how much reoxygenation would be needed to abolish the benefit from (and hence the need for) a perfect radiosensitizer.

Animals↗
PubMed1982

Site dependent response of tumours to combined heat and radiation.

In previous experiments, large differences in thermal sensitisation were observed for tumours grown on the tails of the chest of mice. The present work reports the results of experiments to compare the response of tumours in four different sites to the radiosensitising effects of both heat and misonidazole. Factors influencing tumour response, e.g., tumour growth rate, blood flow, temperature uniformity, temperature increase during heating and drug availability, were also studied. Tumour response and most of the parameters measured varied according to the site of tumour implantation. Growth rate, blood flow and natural tumour temperature are all likely to be important. However, there appears to be no simple relationship by which tumour response could be predicted, although heat dose, the product of temperature elevation above the natural level and treatment time, may be the most relevant parameter. Clearly the choice of implant site does influence response to treatment. Tumours grown on the extremities may be poor models for human tumours, because of their low natural temperatures.

Animals↗
PubMed1981

Repair during fractionated irradiation of the mouse bladder.

The capacity for repair of sublethal damage during fractionated irradiation of the mouse bladder has been measured. Graded doses of electrons were given as 1, 2, or 5 equal daily fractions. Two functional end points were used to assess bladder damage: (a) increased urination frequency and b) decreased bladder capacity. Repair of sublethal injury within 24 hours was found to be similar using both assays for bladder damage and was greater than the repair observed in mouse skin for a given dose per fraction. The possibility of a slower repair process occurring in bladder was investigated by giving two fractions in increasing overall times (from 24 hours to one month). No increased repair was observed with the longer time intervals; hence there was no evidence for slow repair in the bladder.

Animals↗
PubMed1980

Is tumour radiosensitization by misonidazole a general phenomenon?

The response of 14 mouse tumour sub-lines to the radiosensitizing action of a large single dose of misonidazole (MISO) has been assessed by regrowth delay. In 13 of these, significant enhancement of radiation effect occurred under ambient conditions, indicating sensitization of naturally hypoxic cells. The enhancement observed (SER') varied with the radiation dose, as would be predicted for a mixed oxic/hypoxic cell population. The maximum SER' in these 13 tumours did not depend on histology or regrowth rate. The 14th tumour, a slow-growing sarcoma, was not sensitized under ambient conditions, but showed marked sensitization when clamped to produce acutely hypoxic cells. This is consistent with no hypoxic cells occurring naturally in a sarcoma with a slow rate of growth. Faster-growing variants of this tumour showed radiosensitization under ambient conditions. The slow-growing carcinoma, RH, however, appears to contain hypoxic cells and did show sensitization. The cytotoxic action of MISO was compared with the radiosensitization by administering it after irradiation in 8 of the tumour lines. In 2 tumours no cytotoxicity was observed. In the rest cytotoxicity was significant, but much smaller than the sensitization observed when MISO was administered before irradiation. These regrowth-delay data have been used to calculate hypoxic fractions in 3 ways. Estimates of hypoxic fraction ranged from less than 0.1% in the slow sarcoma to greater than or equal to 30% in several tumours. There is considerable variation in the estimate, according to the technique used.

Animals↗