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Biomedical subjects

J H Hendry

Publications and source records attributed to J H Hendry.

At least 127 records · Page 7Linked to original sources
PubMed1991

Clonogen number and radiosensitivity in rat thyroid follicles.

A technique has been developed for transplanting whole thyroid follicles into the fat pads of recipient thyroidectomized rats to assess the ability of the follicular cells to proliferate and form colonies, i.e., clusters of new follicles. Of the transplanted follicles, 80-90% formed follicle clusters, indicative of the presence of transplanted follicles not containing colony-forming cells (clonogens) or some reproducible degree of transplantation trauma. The initial number of clonogens per regenerative follicle was calculated from data from split-dose experiments to be 3.3 +/- 1.5, and their sensitivity was characterized by a D0 value of 350 +/- 95 cGy. Three clonogens among about 80 epithelial cells per regenerative follicle and the 10-20% of nonregenerative follicles represent an overall colony-forming efficiency of about 3%. This is similar to the value of 2-3% reported by others using single-cell transplantation techniques.

Animals↗
PubMed1991

Recovery of the proliferative and functional integrity of mouse bone marrow in long-term cultures established after whole-body irradiation at different doses and dose rates.

Injury inflicted upon the bone marrow stroma following whole-body irradiation and its repair over a 1-year period has been assessed in murine long-term bone marrow cultures established at increasing time intervals after irradiation. Different doses at different dose rates (10 Gy at 0.05 cGy/min, 4.5 Gy and 10 Gy at 1.6 cGy/min, and 4 x 4.5 Gy [3 weeks between doses] at 60 cGy/min) were chosen so as to maximize differences in effect in the stroma. The cellularity of the adherent layer in long-term cultures established 1 month after irradiation was reduced by 40%-90% depending on the dose and dose rate. Simultaneous with the poor ability of the marrow to form adherent layers, the cumulative spleen colony-forming unit (CFU-S) and granulocyte-macrophage colony-forming cell (GM-CFC) production over a 7-week period was reduced to 0% and 30% of control cultures, respectively. The slow recovery of the adherent layer was paralleled by an increase in the numbers of CFU-S and GM-CFC in the supernatant. Cultures established from repeatedly irradiated mice performed poorly over the entire 1-year period. Whereas the regeneration of the stroma was near complete 1 year after irradiation, the CFU-S and GM-CFC levels reached only between 50% and 80% of control cultures, respectively. Also, the concentration of CFU-S and GM-CFC in the supernatant remained persistently lower in cultures established from irradiated mice as compared to control cultures. The levels of sulfated glycosaminoglycans, which have been implicated in the establishment of the functional integrity of the microenvironment, were not reduced in the adherent layers at any time after irradiation. These results indicate that the regeneration of the stroma is accompanied by an incomplete recovery of active hemopoiesis in vitro. However, no evidence was found for persistent functional defects in the stroma after irradiation, using the present endpoints.

Animals↗
PubMed1991

The radiosensitivity of populations of murine hemopoietic colony-forming cells that respond to combinations of growth factors.

Combinations of murine recombinant interleukin 3 (IL-3), purified murine macrophage colony-stimulating factor (M-CSF), and human recombinant interleukin 1 alpha (IL-1 alpha) were used to determine the effects of growth factors on the measured radiosensitivity of different populations of murine colony-forming cells (CFC). The data showed that combinations of growth factors resulted in different values of CFC radiosensitivity, being less than values observed when colony growth was stimulated using a single factor. For various combinations of growth factors, Do values ranged from 106 +/- 8 to 175 +/- 24 cGy for progenitor cells in normal bone marrow; 74 +/- 3 to 171 +/- 18 cGy for primitive multipotent CFC enriched using fluorescence-activated cell sorting; and from 46 +/- 4 to 131 +/- 10 cGy for more mature granulocyte-macrophage CFC, enriched by counterflow centrifugal elutriation. Only combinations of three factors produced the high values of Do reported in experiments using unpurified conditioned medium as a stimulus for colony formation.

Animals↗
PubMed1990

Radiosensitivity testing of primary cervical carcinoma: evaluation of intra- and inter-tumour heterogeneity.

Biopsies from 89 patients with cervical carcinoma were studied using a clonogenic assay to obtain values for the surviving fraction at 2 Gy (SF2). Heterogeneity in intrinsic radiosensitivity was investigated by independently processing multiple biopsies from 18 tumors. No significant differences between intra-tumour SF2 values were demonstrated (p = 0.30). The results have shown that intra-tumour heterogeneity is not a limitation to radiosensitivity testing using the Courtenay-Mills assay. A wide range of values (0.13-0.97) for SF2 was obtained with a mean value of 0.47 +/- 0.18 (+/- 1 S.D., CV = 38%) for 52 squamous cell carcinomas and 0.59 +/- 0.27 for four adenocarcinomas. There were statistically significant differences between the individual tumours (p less than 0.001). From the analysis-of-variance of all the SF2 results it appears to be the surviving fractions below about 0.40 and those above about 0.7 which show significant differences in radiosensitivity between pairs of tumours (p = 0.05). Also 36% of the values of SF2 show significant differences from the mean SF2 of all tumours. The storage of tumour cell suspensions in liquid nitrogen improved the colony-forming efficiency (CFE) but it did not alter the radiosensitivity.

Analysis of Variance↗
PubMed1990

Predicted dose-latency relationships for early- and late-responding hierarchical tissues.

Theoretical dose-latency relationships for the time to manifestation of radiation injury in a hierarchical (type H) tissue were investigated using mathematical modelling. Observable tissue injury was assumed to correspond to depletion of cells in the functional compartment to a critical level. The results illustrate that the latent times of an early-responding type H tissue can be dose-dependent, although the difference between the maximum and minimum latent times is fairly small; the dose-dependence occurs because the dose affects the rate at which cells enter the functional compartment from the proliferative compartment while the functional cells are initially shed from the tissue at a rate that is independent of dose, resulting in a net dose-dependence of functional cell loss. Dose-dependent latent times were also obtained for a hypothetical late-responding type H tissue, but the dose-dependence was much more pronounced than for the acutely responding tissue; the difference in latent times was nearly 3 months over a dose range of a few Gy. This illustrates that the experimentally observed dose-latency relationships for late-responding normal tissues, which have unknown renewal characteristics, are not inconsistent with the hypothesis that those tissues have a hierarchical tissue structure similar to that of early-responding tissues. The dose-latency relationship for early responses was influenced most strongly by the characteristics of the transit cells, whereas for the late responses it depended mainly on the characteristics of the stem cells. Residual injury in both early and late-responding tissues can be modelled on the basis of permanent depletion of the stem cell compartment, e.g. via depletion of the number of tissue-renewal units.

Dose-Response Relationship, Radiation↗
PubMed1990

The effects of the platinum anti-tumour agents on renal cell kinetics and the response to a second cytotoxic agent.

Following 15 mg kg-1 cisplatin to mice, the labelling index (LI) in the kidney decreased from 0.4% to less than 0.01% at 1-3 d, increased to 1.9% at day 16 and returned to control levels by day 30. Cytotoxicity was assessed by counts of viable tubule cross-sections and recovery was incomplete up to 14 months after treatment. Cisplatin treatment impaired the regeneration response to a dose of 16 mg kg-1 uranyl nitrate (UN) given 14 d after cisplatin when assessed by an increase in LI and sub-capsular tubule count. However, there was recovery with greater time intervals. At nine months after cisplatin there was no difference in response to UN of controls and mice previously treated by cisplatin. Prior treatment with paraplatin or iproplatin at LD50 doses produced not only no histopathological changes but also no impairment of the subsequent responses to UN.

Animals↗
PubMed1990

Lack of late skin necrosis in man after high-dose irradiation using small field sizes: experiences of grid therapy.

Out of a total of 437 patients with superior vena caval syndrome or advanced malignancy, given single-dose grid radiotherapy, four survived to 7 years. The dose to the skin under each of the 77 holes in the grid was approximately 58 Gy. The lack of skin necrosis in the total of 308 skin circles of 1 cm diameter among these survivors, compared with known necrosis rates in larger irradiated areas, implies that there is a marked field-size effect for late necrosis in small areas of irradiated skin.

Adult↗
PubMed1990

Analysis of dose-incidence relationships for marrow failure in different species, in terms of radiosensitivity of tissue-rescuing units.

The analysis of 68 published sets of dose-incidence data for marrow failure in different species, using a double-log mortality function, indicates: (a) There is more heterogeneity, i.e. greater sums-of-squares per degree of freedom, within the data sets for mouse than for larger species (monkey, dog, sheep, goat, pig). (b) For mice the curves for acute doses are characterized by a D0 of about 100 cGy for tissue-rescuing units (or target cells), which are depleted at most to about 3 x 10(-4) at LD50. (c) Larger species are much less tolerant to target-cell depletion, the corresponding level being consistently in the range of 10(-2)-10(-3) at LD50. Also, the D0 is often lower (approximately 55 cGy), which is compatible in the dog with such a value for hemopoietic progenitor cells. (d) With larger species there is an unexpected reduction in heterogeneity when the dose rate is lower, which gives a D0 lower than expected and a higher extrapolate. It is concluded that the position and slope of the dose-incidence curves are compatible with interpretations based primarily on target-cell number and survival characteristics, modified by additional heterogeneity factors.

Animals↗
PubMed1990

Radiosensitivity increases with differentiation status of murine hemopoietic progenitor cells selected using enriched marrow subpopulations and recombinant growth factors.

The radiosensitivity of populations of colony-forming cells (CFC) in murine bone marrow was investigated using different recombinant colony-stimulating factors (CSFs; murine IL-3 and granulocyte-macrophage CSF and human granulocyte CSF), or purified murine macrophage CSF. With unfractionated normal bone marrow the CFC increased in radiosensitivity as they progressed through the granulocyte lineage. The D0 values ranged from 129 +/- 12 cGy for CFC stimulated with GM-CSF down to 42 +/- 2 cGy after stimulation with G-CSF. IL-3 stimulated a CFC population which gave the only survival curve with a shoulder (n = 1.9 +/- 0.3). With semipurified populations of primitive or bipotential CFC, D0 values were generally lower with respect to the equivalent values for unpurified bone marrow (range 62 +/- 7 cGy to 135 +/- 7 cGy). Changes in cluster/colony ratio and colony morphology together possibly with products of accessory cells influence the interpretation of the radiosensitivity parameters.

Animals↗
PubMed1989

Residual haemopoietic damage in the mouse after fractionated gamma-irradiation, down to 0.1 Gy per fraction.

Residual damage in haemopoietic progenitor cell populations, spleen and granulocyte-macrophage colony-forming cells (CFU-S and GM-CFC) was detected in mice after 15 daily fractions where the dose per fraction was as low as 0.1 Gy. The injury was dose-dependent and after higher total fractionated doses of 7.5-10 Gy the CFU-S population recovered to about 50% of control between 2 and 12 months after irradiation. Residual damage was also detected in the stroma, in the form of reduced numbers of fibroblastoid colony-forming cells and of CFU-S in ossicles under the kidney capsule. The response to a second course of 15 fractions, given 3 weeks after the end of the first course, was similar and additive to the response to the first course in the short term. However, in the long term, recovery levels were similar after either one or two courses.

Animals↗
PubMed1989

The high steepness of dose-response curves for late-responding normal tissues.

Values are calculated for the parameters alpha, beta, and the number of tissue-rescuing units (TRU), which together describe the location and the steepness of dose-incidence curves for functional injury in various normal tissues. The analysis is based on a Poisson model of the distribution of surviving TRUs. The steepness of the curves for early-responding tissues has been shown previously to be compatible with values of sensitivity for the target colony-forming cells in these tissues. We now show that the steepness of curves for late responses in spinal cord, lung, and kidney is higher by a factor of up to 3 than the steepness of curves for early responses in other tissues. Although the interpretation of this higher steepness is not fully understood, this observation is likely to be of importance for radiotherapy.

Animals↗
PubMed1989

Response of human organs to single (or fractionated equivalent) doses of irradiation.

Characteristics of the kinetics of radiation response of human tissues and organs are exemplified by effects in the testis and the ovary. Also, published dose-incidence curves for specified levels of injury in bone marrow, liver, bladder and lung are characterised in terms of single doses as well as single-dose equivalents calculated from fractionated doses using the alpha/beta equation. It is shown that these curves, analysed using a Poisson model, have slopes characterised by D0-equivalents ranging between 1.25 and 2.5 Gy. These values are higher or within the range of values reported in general for single-dose survival curves of human cells in primary culture (range of D0 values 0.7-1.8 Gy). This indicates that single-cell responses together with other complicating biological and statistical sources of heterogeneity under discussion, could form a basis for explaining the steepness of dose-incidence curves for organ injury after fractionated doses. With local organ irradiation, increase in the single-dose equivalent by 3-10 per cent would increase the complication rate from 5 per cent to 10 per cent. Higher dosage increases (by up to two times) apply to fractionated doses.

Bone Marrow↗
PubMed1989

The development of spatial distributions of CFU-S and in-vitro CFC in femora of mice of different ages.

The radial distributions of spleen colony forming units (CFU-S) and in-vitro colony forming cells (in-vitro-CFC) were measured in the diaphyseal marrow cavity of femora removed from 3-, 5- and 11-week-old mice. The distributions observed in 11-week-old mice confirm earlier findings that the highest concentrations of CFU-S exist near bone surfaces whereas the concentration of in-vitro-CFC increases to a peak value approximately 300 microns from the femoral axis with a low value at the bone surface. The gradients of the distributions in all three age groups are very similar suggesting that spatial organization in marrow is established by 3 weeks at the latest and, as the marrow cavities grow, so the distributions extend into the new space following their respective gradients. The peak of CFU-S concentration at the bone surfaces in all age groups coincides with increased rates of DNA synthesis and a low self-renewal capacity. Conversely, CFU-S nearer the centre of the cavity maintain a low turnover but have a high self-renewal capacity. Measurements made on 1-week-old mice show that the marrow contains a lower average concentration of CFU-S in the femoral cavity compared to older mice. However, these CFU-S have both a high rate of turnover and a high self-renewal capacity. It appears that these better quality CFU-S remain in a central location while the rest of the population ages and expands in association with growing bone regions.

Aging↗
PubMed1989

The radiation response and recovery of bone marrow stroma with particular reference to long-term bone marrow cultures.

There is evidence for long-term haematopoietic dysfunction in some patients treated with radiotherapy. Although the underlying mechanisms are unclear, both stem cell and environmental defects have been implicated. In the present article we review the evidence concerning the role of stromal cells. According to the endpoints used, a wide range of radiosensitivities for the stroma have been reported. Long-term bone marrow cultures provide a system in which both functional and regenerative aspects of the stroma can be studied. A dose of 5 Gy applied prior to the establishment of long-term bone marrow cultures decreases both the formation of a confluent adherent stromal layer and its capacity to support haematopoiesis. In contrast, in its fully established phase, the adherent layer displays a high radioresistance due to the low proliferative stress applied to its stromal populations. A dose of 10 Gy given to a fully established adherent layer does not prevent haematopoietic engraftment and sustained haematopoiesis. At doses above 100 Gy a macrophage-like and epithelioid cell-type become dominant, which preserve their ability of producing growth regulatory molecules at doses as high as 500 Gy. These data suggest that the main effect on the stroma is a delayed expression of irradiation damage due to the slow rate of turnover of stromal cells. So far, there is little evidence for persistent deficiencies in the functional roles of stromal cell populations.

Animals↗
PubMed1989

Ovarian failure following abdominal irradiation in childhood: the radiosensitivity of the human oocyte.

Ovarian function has been studied sequentially since 1975 in 19 patients treated in childhood for an intra-abdominal tumour with surgery and whole abdominal radiotherapy (total dose 30 Gy). Eleven patients received chemotherapeutic agents that are not known to cause gonadal dysfunction. All but one patient have developed ovarian failure with persistently elevated gonadotrophin levels (FSH and LH greater than 32 IU/litre) and low serum oestradiol values (less than 40 pmol/litre) before the age of 16 years. The majority (n = 12) did not progress beyond breast stage 1 without sex steroid replacement therapy. As the number of oocytes within the ovary declines exponentially by atresia from approximately 2,000,000 at birth to approximately 2000 at the menopause, we have been able to estimate that the LD50 for the human oocyte does not exceed 4 Gy.

Abdomen↗