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Biomedical subjects

J H Hendry

Publications and source records attributed to J H Hendry.

At least 91 records · Page 5Linked to original sources
PubMed1995

Differential sensitivity of two predominant stromal progenitor cell subpopulations in bone marrow to single and fractionated radiation doses.

The sensitivity of fibroblastoid precursor cells in rat bone marrow to single and fractionated doses of gamma rays delivered in vivo was measured. In vitro colonies were classified as being compact or diffuse, and the progenitor cells for both types were slowly cycling in vivo (survival levels after exposure to hydroxyurea were 90 +/- 6% and 93 +/- 11%, respectively). The progenitor cells forming diffuse colonies were more resistant (D0 = 1.39 Gy) than those forming compact colonies (D0 = 0.76 Gy). The fractionation sensitivities were characterized by an alpha/beta ratio of 12.7 +/- 5.5 Gy for diffuse colonies and 4.5 +/- 3.0 Gy for compact colonies, respectively. The progenitor cells forming diffuse colonies may contribute more to long-term regeneration after high doses in vivo.

Animals↗
PubMed1995

Deduction of the clonogen content of intestinal crypts: a direct comparison of two-dose and multiple-dose methodologies.

A microcolony assay was used in conjunction with fractionated gamma irradiation to determine the number of clonogens in murine intestinal crypts with varying doses of irradiation used in the determination. The experimental design allows direct comparison between two-dose methodologies, employing one and two (or two or four) equal dose fractions, and multiple-dose methodologies involving determination of the crypt survival curves for a number of fractionation regimens using equal doses per fraction. The two-dose methodology yielded estimates of clonogen number of between 3 and 4 at low delivered dose (single and double fractions each of 6.5-7.5 Gy), rising to around 40 at high biological doses (two and four fractions each of 5.75 or 6.5 Gy). The multifraction methodology yielded estimates of clonogen number which increased from 13 after a single fraction to values of 26 and 22 after three and four fractions. However, the latter values were reduced to 11 and 9, and showed little evidence of any dependence on fraction number, when data pertaining to high biologically effective doses were excluded. Hence it is concluded that the high values for clonogen number typically deduced from such multiple-dose protocols, compared with the generally lower (but dose-dependent) values obtained from two-dose protocols, may be explained at least partially by the higher biological doses generally employed in the multiple-dose protocols.

Animals↗
PubMed1995

Gamma irradiation of the fetus damages the developing hemopoietic microenvironment rather than the hemopoietic progenitor cells.

Hemopoiesis is the product of two components: the hemopoietic tissue and the regulatory stromal microenvironment in which it resides. Plutonium-239, incorporated during fetal development, is known to cause deficient hemopoiesis. A predetermined equivalent gamma-ray dose has now been used in combination with cross-transplantation experiments to separate these two components and define where the damage arises. It was confirmed that 1.8 Gy gamma irradiation at midterm gestation caused a 40% reduction in the hemopoietic stem (spleen colony-forming) cell population of their offspring which persisted to at least 24 weeks of age. Spleen colony formation after sublethal doses of gamma rays reflected this reduced complement of endogenous stem cells. The regulatory hemopoietic microenvironment, measured as fibroblastoid colony-forming cells, was similarly depleted. Normal growth of the CFU-S population after transplantation into standard recipients showed that the quality of the stem cell population in the offspring of irradiated mothers was not affected. By contrast, when used as recipients of a bone marrow transplant from either normal or irradiated offspring, the offspring of irradiated mothers were unable to support normal growth: there was a twofold difference in the number of CFU-S per femur for at least 100 days after transplantation. There were 70% fewer CFU-F in the femur 1 month after bone marrow transplantation when the offspring of irradiated mothers were used as transplant recipients compared to when normal offspring were used. This not only confirmed their reduced capacity to host normal stem cells but also indicated that CFU-F in the transplant were unable to compensate for the poor microenvironment in the irradiated offspring hosts. It is concluded that irradiation at midterm gestation damages the developing regulatory microenvironment but not the hemopoietic stem cell population that it hosts.

Animals↗
PubMed1995

Apoptosis in bone marrow cells of mice with different p53 genotypes after gamma-rays irradiation in vitro.

Apoptosis is a physiological phenomenon occurring during embryonic development, T and B cell maturation, and endocrine-induced atrophy. It can be initiated by various agents and has been considered to be related to the expression of the oncosuppressor p53 gene. In this review, p53 gene-targeting mice were used to study the effect of p53 gene status on the induction of apoptosis in bone marrow cells by gamma-ray irradiation. The results showed that homozygous null (p53 -/-) murine bone marrow cells were more resistant to the induction of apoptosis by radiation than other genotypes (heterozygous, p53 +/- and wild type, p53 +/+). The percentage of apoptotic cells in p53 +/+ mice was about three times that in p53 -/- mice at 4 hr after 6 Gy gamma-irradiation, and the analysis of the apoptosis-characteristic DNA ladder further supported these findings. We found that the homozygous null mice also can undergo apoptosis after irradiation. This suggested that there is another independent apoptotic p53 gene mechanism in irradiated murine bone marrow cells. Thus, in murine bone marrow cells, both p53 gene-dependent and -independent apoptosis occurred after irradiation. In our previous work, an increase in survival of hemopoietic progenitor cells after irradiation in vitro in p53 gene deletion mice was observed. This increase is closely related to the inhibition of apoptosis in bone marrow cells in p53 gene deletion mice.

Animals↗
PubMed1994

Differential radiosensitising effect of the scid mutation among tissues, studied using high and low dose rates: implications for prognostic indicators in radiotherapy.

To assess whether radiation-sensitive or radiation-resistant individuals should in principle be predicted equally well using different cell types, the effect of the scid mutation on the radiosensitivity of colony-forming cells in different murine tissues was assessed using high and low dose-rates. At high dose-rate, the amount of radiosensitization due to the scid mutation was greater in epithelial cells of the intestine and the kidney than in haemopoietic and fibroblastoid cells in the bone marrow, when expressed as a dose reduction factor. However, this greater radiosensitization in intestine and kidney did not translate into bigger differences in SF2 (surviving fraction at 2 Gy) or SF3.5. This was because of the greater inherent radioresistance of the epithelial cells compared with the marrow cells, resulting in smaller changes in cell survival from a given dose. Reductions in cell survival due to the mutation increased with increasing dose as expected at high dose rate. The changes in SF2 and SF3.5 due to the scid mutation were not significantly increased by using low dose-rates, because of the tendency for the presence of some low dose-rate sparing in the scid cells as well as the marked amount observed in the wild-type cells. The implications for predictive testing in radiotherapy are that for genetic defects resulting in the same type of radiosensitization phenomenon shown here for scid cells, radiosensitive or radioresistant cell types may still give similar differentials in response due to the mutation when SF2 is used as an endpoint.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Influence of radiotherapy treatment time on control of laryngeal cancer: comparisons between centres in Manchester, UK and Toronto, Canada.

A comparison has been made of the influence of treatment time on tumour control rates for 496 (T2 and T3) larynx cancer cases in Manchester, UK and 1001 (T1-T4) cases in Toronto, Canada. Both series of patients were treated in fairly short overall times, commonly 3 weeks in Manchester and 4-5 weeks in Toronto. All the tumour control data were analysed using the same method to obtain values of fitted dose, fractionation and time parameters. The analysis showed the following. (a) Differences between the total combined (T2 + T3) data sets from the two centres, fitted using direct analysis and the LQ model incorporating a parameter for overall treatment time, were not significant (p = 0.17) and close similarity in control rates was observed using treatment regimens common to both series. (b) The Manchester series over 9-41 days and the Toronto series over 14-84 days are both consistent in showing for (T2 + T3) tumours the presence of a mean time factor of 0.6-0.8 Gy/day required to abrogate the decrease in tumour control concomitant with an increase in overall treatment time from the minimum the maximum employed in each series. (c) When a parameter was included in the model to test for the possible presence of a lag period before the time factor became operative, the lag was not significant for the Toronto data, in contrast to a significant lag for the Manchester data alone (T2 + T3 data).(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinoma, Squamous Cell↗
PubMed1994

Two components of repair in irradiated kidney colony forming cells.

Data describing the response of mouse kidney colony-forming cells to fractionated X-irradiation using different interfraction intervals were analysed in order to detect the presence of one or more components of repair. A two-component repair model gave a superior fit, with reference to a single-repair rate model, giving distinct repair halftimes of 0.15 (approximate 95% confidence limits: 0.0, 0.40) and 5.03 (1.23, 8.84) h. These values are the first reported for normal cells in vivo, and they are similar to values calculated for tissue responses in skin, lung and the spinal cord. The slow component of repair is important in radiotherapy, in particular regarding novel hyperfractionation regimens when interfraction intervals much less than 1 day are employed.

Animals↗
PubMed1994

The influence of radiotherapy treatment time on the control of laryngeal cancer: a direct analysis of data from two British Institute of Radiology trials to calculate the lag period and the time factor.

This study analyses node-negative laryngeal tumour control data from two clinical trials conducted by the British Institute of Radiology in order to determine the time factors and the presence or absence of a lag period before the time factor takes effect. A direct maximum likelihood approach is used to fit a double-logarithmic model including a repopulation term which commences after an initial lag period, Tk. The analysis yields a time factor of 0.8 Gy per day (95% confidence interval 0.5-1.1 Gy per day) as the extra dose required to counteract the reduction in tumour control probability (TCP) with extension of the treatment time. The latter reduction amounted to between 5 and 12% TCP per week, depending on the stage and time period. With this dataset, where few patients were treated for short times, no statistically significant lag phase can be demonstrated. However, the best estimate of Tk is 21 days (95% confidence interval 0-27 days), which is consistent with estimates from other studies on other datasets. If a lag phase exists, this study would indicate that the duration is less than 27 days. Other studies have used retrospective data and are subject to a number of potential biases. The present study, using data from multicentre prospective randomized clinical trials, is free from some of these sources of bias. The fact that very similar estimates of the radiobiological parameters are obtained lends credence to these other studies and suggests that the potential biases may be small in practice.

Clinical Trials as Topic↗
PubMed1994

Changes in normal and abnormal colony formation of thyroid cells in vivo, when transplanted at 1 day or 6 weeks after X-irradiation in situ.

Thyroid cells were given 5.5 Gy X-rays in situ and transplanted after 1 day or after 6 weeks to form colonies in fat pads. The colony-forming efficiency unexpectedly decreased by a factor of about 2 with this increase in delay time before transplantation. In addition, there was a concomitant marked increase above the control levels in the proportion of new structures of thyroid origin containing abnormal follicles. These quantitative and qualitative increases in injury may be related to the gradual expression of thyroid abnormalities following irradiation in situ, and they may have implications for the recovery of functional tissue subunits in other organs.

Animals↗
PubMed1994

Spermatogenic and mutagenic damage after paternal exposure to systemic indium-114m.

The cytotoxic and mutagenic consequences of systemic administration of 114mIn have been examined. Adult male rats were dosed intraperitoneally with 14.8 or 3.7 MBq/kg 114mIn. Approximately 0.25% of the injected radioactivity was localized within the testis by 24 h and was retained with an effective half-life of 49.5 days. Breeding studies were started 3 days after injection, males being housed with two females for seven consecutive mating trials of 19 days, separated by 2 days. Indium-114m caused a reduction in litter size and an increase in the incidence of pre- and postimplantation losses and dominant lethal mutations. These effects became evident from 24 days but were most marked between 87-126 days after treatment and persisted up to 147 days. When animals were mated 200 days after treatment, no significant changes were observed. In a parallel study, administration of 14.8 MBq/kg 114mIn resulted in decreased testis and epididymal weight and sperm reserves. Maximal reduction occurred between 87-108 days after injection followed by recovery toward control values, but neither organ had reached normal levels at 200 days. A single dose of 3.7 MBq/kg, however, had no effect on reproductive organ weight or sperm content. Male F1 progeny from the 14.8 MBq/kg group of the second mating period (commencing at 24 days) displayed decreased testis weights and sperm content and provoked a higher incidence of dominant lethal mutations. This effect was not observed in male progeny from any other time or the alternative dose level.

Animals↗
PubMed1994

Alpha particles are extremely damaging to developing hemopoiesis compared to gamma irradiation.

Estimates of risk of stochastic effects from contamination with alpha-particle-emitting radionuclides are based on equivalent doses which take into account the RBE of the high-LET radiation. ICRP has recommended a dose-weighting factor, wR, of 20 for alpha-particle radiation. It is assumed that the RBEs for deterministic effects are considerably less than those for stochastic effects. However, the offspring of mice injected with 30 Bq g-1 239Pu at 13 days gestation develop a persistent deficit in hemopoietic stem cells which is primarily the result of damage to their regulatory microenvironment. Their spatial distribution in the marrow is also perturbed, and recent observations on those mice suggested a considerably higher factor than 20. To define a more realistic RBE for hemopoiesis, the effects of external gamma irradiation during the fetal development period have been compared directly with those of 239Pu incorporated via placental transfer on the development of hemopoietic tissue. Pregnant mice were irradiated with 60Co gamma rays (a) continuously from day 13 of gestation to birth at 0.15 or 0.6 Gy/day; (b) six repeated acute doses (0.6 Gy/min) at 0.1 or 0.3 Gy from day 13 of gestation; (c) one acute dose of 0.6 or 1.8 Gy on day 15 of gestation. The spatial distribution of hemopoietic stem cells in 8-week-old offspring was then determined and compared to that resulting from alpha-particle irradiation. In each case, the higher dose was required to match the results for alpha particles, suggesting an RBE for developing hemopoiesis of 250-360 compared to a continuous gamma-ray dose and a rather lower value of 130-180 compared to a single acute dose of gamma rays. This contrasts greatly to values for direct irradiation of the stem cells but argues that the effective RBE, measured for long-term effects in vivo, is the more realistic. It is concluded that an all-embracing factor can be grossly misleading in the specification of protection guidelines and can greatly underestimate the risks of exposure to alpha particles.

Alpha Particles↗
PubMed1994

In vivo induction of O6-alkylguanine-DNA-alkyltransferase in response to indium-114m.

The effect of systemic administration of the radionuclide 114mIn on O6-alkylguanine-DNA-alkyltransferase (ATase) activity has been examined in rats. In response to 14.8 MBq/kg 114mIn injected intraperitoneally, hepatic ATase was induced maximally approximately fivefold at 7 days after injection, at which time the cumulative radiation dose to the liver was approximately 2 Gy. At 63 days after injection ATase activity was still approximately twofold elevated and remained so at 126 days after injection. By 200 days after injection ATase activity had returned to control values. The 114mIn content of the liver increased to a maximum of 28.7 kBq/g 48-72 h after injection, after which it began to decrease such that at 126 days only 0.3 kBq/g remained and at 200 days 0.03 kBq/g. In response to 4.44 MBq/kg 114mIn, hepatic ATase was induced twofold by 7 days after injection, when the liver had received a radiation dose of 0.6 Gy, and was still slightly elevated at 63 days. There was no ATase induction after 0.44 MBq/kg 114mIn up to 7 days after injection; however, at 42 days after injection activity was approximately twofold higher. These results suggest that induction of hepatic ATase activity by 114mIn is dependent upon cumulative radiation dose and dose rate; both must be above minimum threshold values for induction to occur. The induction of a DNA repair enzyme by radiation exposure from an internal radionuclide may have important consequences for risk assessments of occupational, medical and environmental exposures.

Animals↗
PubMed1993

Accelerated repopulation of intestine post-irradiation following intraluminal injection of a mucosal cell suspension or its supernatant.

The injection of (1-7) x 10(5) mucosal cells into the intestinal lumen at 4 h after 14 or 18 Gy increased the number of intestinal microcolonies (> or = 10 cell foci) and microclusters (4-9 cell foci) when assayed at day 3. The effects were less when (a) the interval between irradiation and injection was increased to 20 h, (b) the assay time was increased to 4 days or more, (c) a cell supernatant was injected instead. The data indicate that the injections stimulated earlier regeneration. The effect of the supernatant suggests that the stimulation is mediated through a humoral factor.

Animals↗