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Biomedical subjects

J H Hendry

Publications and source records attributed to J H Hendry.

At least 55 records · Page 3Linked to original sources
PubMed1998

Loss of atm radiosensitizes multiple p53 null tissues.

An unusual clinical finding in ataxia-telangiectasia, a human disorder caused by mutations in atm, is exquisite sensitivity to gamma irradiation. By contrast, homozygous deletion of p53 is marked by radiation resistance in certain tissue compartments. Previous studies (A. J. Levine, Cell, 88: 323-331, 1997) have shown that, in vitro, p53-deficient bone marrow cells are resistant to gamma irradiation. Furthermore, the gastrointestinal radiosensitization engendered by the loss of atm has recently been shown (C. H. Westphal et al., Nat. Genet., 16: 397-401, 1997) to be independent of p53. Expanding on previous work, we have looked at in vivo bone marrow resistance in p53-deficient mice. Our results indicate that inbred FVB strain p53 null mice survive lethal irradiation doses because of bone marrow resistance. Moreover, the deletion of atm radiosensitizes even p53 null bone marrow and mouse embryonic fibroblast cells. The results presented here argue that the loss of atm radiosensitizes multiple tissues in a p53-independent manner. Hence, functional inhibition of atm in p53 null and p53 wild-type human tumors may be a useful adjunct to gamma irradiation-based antitumor therapy.

Animals↗
PubMed1998

A realistic closed-form radiobiological model of clinical tumor-control data incorporating intertumor heterogeneity.

PURPOSE: To investigate the role of intertumor heterogeneity in clinical tumor control datasets and the relationship to in vitro measurements of tumor biopsy samples. Specifically, to develop a modified linear-quadratic (LQ) model incorporating such heterogeneity that it is practical to fit to clinical tumor-control datasets. METHODS AND MATERIALS: We developed a modified version of the linear-quadratic (LQ) model for tumor control, incorporating a (lagged) time factor to allow for tumor cell repopulation. We explicitly took into account the interpatient heterogeneity in clonogen number, radiosensitivity, and repopulation rate. Using this model, we could generate realistic TCP curves using parameter estimates consistent with those reported from in vitro studies, subject to the inclusion of a radiosensitivity (or dose)-modifying factor. We then demonstrated that the model was dominated by the heterogeneity in alpha (tumor radiosensitivity) and derived an approximate simplified model incorporating this heterogeneity. This simplified model is expressible in a compact closed form, which it is practical to fit to clinical datasets. Using two previously analysed datasets, we fit the model using direct maximum-likelihood techniques and obtained parameter estimates that were, again, consistent with the experimental data on the radiosensitivity of primary human tumor cells. This heterogeneity model includes the same number of adjustable parameters as the standard LQ model. RESULTS: The modified model provides parameter estimates that can easily be reconciled with the in vitro measurements. The simplified (approximate) form of the heterogeneity model is a compact, closed-form probit function that can readily be fitted to clinical series by conventional maximum-likelihood methodology. This heterogeneity model provides a slightly better fit to the datasets than the conventional LQ model, with the same numbers of fitted parameters. The parameter estimates of the clinically important time factors and lag periods are very similar to those obtained from the conventional LQ model, but with slightly narrower confidence intervals, reflecting the better fit to the clinical data. DISCUSSION: We have demonstrated, as have others, the importance of intertumor heterogeneity in the response of patient populations to radiotherapy. With the possible inclusion of a radiosensitivity-modifying factor (in vitro/in vivo) of around 1.7, the in vivo data can be made consistent with the in vitro SF2 and Tpot data. Fitting two previously analyzed multicenter datasets indicated that previous analyses based on conventional LQ models gave results for clinically important time factors and lags periods that were not significantly biased by the failure to include intertumor heterogeneity, with slightly narrower confidence intervals, reflecting the better fit to the clinical data. The simple closed-form model we have developed allows direct estimation of the heterogeneity in radiosensitivity within clinical series, and should prove useful in the analysis of other clinical series.

Dose-Response Relationship, Radiation↗
PubMed1998

Similar decreases in local tumor control are calculated for treatment protraction and for interruptions in the radiotherapy of carcinoma of the larynx in four centers.

PURPOSE: Data on patients with cancer of the larynx are analyzed using statistical models to estimate the effect of gaps in the treatment time on the local control of the tumor. METHODS AND MATERIALS: Patients from four centers, Edinburgh, Glasgow, Manchester, and Toronto, with carcinoma of the larynx and treated by radiotherapy were followed up and the disease-free period recorded. In all centers the end point was control of the primary tumor after irradiation alone. The local control rates at > or = 2 years, Pc, were analyzed by log linear models, and Cox proportional hazard models were used to model the disease-free period. RESULTS: T stage, nodal involvement, and site of the tumor were important determinants of the disease-free interval, as was the radiation schedule used. Elongation of the treatment time by 1 day, or a gap of 1 day, was associated with a decrease in Pc of 0.68% per day for Pc = 0.80, with a 95% confidence interval of (0.28, 1.08)%. An increase of 5 days was associated with a 3.5% reduction in Pc from 0.80 to 0.77. At Pc = 0.60 an increase of 5 days was associated with an 7.9% decrease in Pc. The time factor in the Linear Quadratic model, gamma/alpha, was estimated as 0.89 Gy/day, 95% confidence interval (0.35, 1.43) Gy/day. CONCLUSIONS: Any gaps (public holidays are the majority) in the treatment schedule have the same deleterious effect on the disease free period as an increase in the prescribed treatment time. For a schedule, where dose and fraction number are specified, any gap in treatment is potentially damaging.

Carcinoma↗
PubMed1998

The radiosensitivity of human fibroblast cell lines correlates with residual levels of DNA double-strand breaks.

PURPOSE: To study the correlation of residual DNA double-strand breakage after irradiation and cellular radiosensitivity in cells showing marked differences in radiosensitivity. MATERIALS AND METHODS: The levels of DNA double-strand breaks remaining at 4 h after irradiation were measured by graded-voltage gel electrophoresis in fibroblast cell strains derived from seven individuals either with normal radiosensitivity (n = 2), or with genetic abnormalities known to show increased (two ataxia telangiectasia, one scid) or possibly decreased (two Li-Fraumeni family members) sensitivity. RESULTS: The slope of the dose-response curve for DNA breaks remaining unrepaired at 4 h showed a highly significant correlation with cellular radiosensitivity characterized by SF2, alpha, or D (r > or = 0.91, P < 0.001). Hence, this measure of genotoxic damage was predictive of radiation sensitivity for cells affected by a variety of mutations in different damage signalling/repair components. DISCUSSION: This correlation confirms another published study and extends it to cell lines with other genetic defects. The technique may be useful in the development of rapid assays to predict the sensitivity of normal tissues in patients receiving radiotherapy.

Blotting, Southern↗
PubMed1998

Levels of the DNA repair enzyme human apurinic/apyrimidinic endonuclease (APE1, APEX, Ref-1) are associated with the intrinsic radiosensitivity of cervical cancers.

A study was made of the relationship between the intrinsic radiosensitivity of human cervical tumours and the expression of the DNA repair enzyme human apurinic/apyrimidinic endonuclease (HAP1). The radiosensitivity of clonogenic cells in tumour biopsies was measured as surviving fraction at 2 Gy (SF2) using a soft agar assay. HAP1 expression levels were determined after staining of formalin-fixed paraffin-embedded tumour sections with a rabbit antiserum raised against recombinant HAP1. Both measurements were obtained on pretreatment biopsy material. All 25 tumours examined showed positive staining for HAP1, but there was heterogeneity in the level of expression both within and between tumours. The average coefficients of variation for intra- and intertumour heterogeneity were 62% and 82% respectively. There was a moderate but significant positive correlation between the levels of HAP1 expression and SF2 (r = 0.60, P = 0.002). Hence, this study shows that there is some relationship between intrinsic radiosensitivity and expression of a DNA repair enzyme in cervical carcinomas. The results suggest that this type of approach may be useful in the development of rapid predictive tests of tumour radiosensitivity.

Animals↗
PubMed1998

Repair of radiation-induced DNA double-strand breaks in human fibroblasts is consistent with a continuous spectrum of repair probability.

PURPOSE: To propose a novel interpretation of DNA double-strand break (dsb) repair based on the distribution of energy micro-deposition. MATERIALS AND METHODS: Double-strand break repair curves were studied either after irradiation at 4 degrees C or at 37 degrees C (low dose rate). Two human fibroblast cell lines were used: a control line, HF19, and an ataxia telangiectasia repair-deficient line, AT5BI. Irradiations were made with gamma-rays or alpha-particles (241Am). Repair data were fitted by the variable repair half-time (VRHT) model. Assuming that each dsb has its own inherent repair half-time (IRHT) and that the VRHT is the average of the IRHT at any time during repair, the distribution of the IRHT was calculated. RESULTS: At the end of the irradiation, the distribution was a continuous asymmetric curve with a maximum of dsb having a short IRHT. After 1 h of repair, the curve became bell-shaped. There is a striking similarity between the distribution of dsb repair half-times and that of energy micro-deposition described by Goodhead et al. (1993). CONCLUSION: This similarity suggests a possible causal relationship between the energy density deposition and the repair rate or the probability of dsb repair.

Americium↗
PubMed1998

The intrinsic radiosensitivity of normal and tumour cells.

PURPOSE: To examine whether in vitro measurements of normal and tumour cell radiosensitivity can be used as prognostic factors in clinical oncology. MATERIALS AND METHODS: Stage I-III cervix carcinoma patients were treated with radical radiotherapy with a minimum of 3 years' follow-up. Lymphocyte and tumour radiosensitivities were assayed using, respectively, a limiting dilution and soft agar clonogenic assay to obtain surviving fraction at 2 Gy (SF2). The results were related, in an actuarial analysis, to late morbidity assessed using the Franco Italian glossary. RESULTS: Patients with radiosensitive lymphocytes had a significantly increased risk of developing late complications (n = 93, p = 0.002). Increasing tumour radiosensitivity was associated with an increased risk of morbidity (n= 113, p=0.032). A significant correlation was found between fibroblast and tumour cell radiosensitivity (r=0.57, p=0.03), but a weak inverse association was found between lymphocyte and tumour cell radiosensitivity (r= -0.32, p=0.03). Patients with radiosensitive lymphocytes and tumour cells had higher levels of late complications than those whose cells were radioresistant. CONCLUSION: The work described highlights the importance of cellular radiosensitivity as a parameter determining the clinical response to radiotherapy.

Carcinoma↗
PubMed1998

Mutation studies in lacI transgenic mice after exposure to radiation or cyclophosphamide.

We have used the Big Blue lacI transgenic mouse reporter system to investigate mutation induction in the testes, spleen and liver after exposure to an internally incorporated radionuclide, 114mIn, whole body irradiation with 60Co gamma-rays and systemically administered cyclophosphamide. Spontaneous mutation frequencies were 6-17x10(-6). No statistically significant mutation induction was observed in testes or spleen at 35 days after exposure to any test agent, although mutation frequencies tended to be increased (by approximately 1.5-fold) after exposure to 1 Gy gamma-rays. However, liver mutation frequencies were doubled after treatment with 100 mg/kg cyclophosphamide and were elevated by approximately 2.5-fold after systemic administration of 114mIn and 4.5-fold after 1 Gy 60Co gamma-rays. When data from all organs were pooled, mutation frequency was doubled after exposure to 1 Gy gamma-rays, but no other significant increases were observed. These findings support the hypothesis that the lacI transgenic mouse may be relatively inefficient at detecting mutations induced by exposure to ionizing radiation or other agents which produce a spectrum of deletion sizes, including those which are larger than the lacI transgene.

Animals↗
PubMed1997

Modelling the optimal radiotherapy regime for the control of T2 laryngeal carcinoma using parameters derived from several datasets.

PURPOSE: A number of previous studies have used direct maximum-likelihood methods to derive the values of radiobiological parameters of the linear-quadratic model for head and neck tumors from large clinical datasets. Time factors for accelerated repopulation were included, along with a lag period before the start of this repopulation. This study was performed to attempt to utilise these results from clinical datasets to compare treatment regimes in common clinical use in the UK, along with other schedules used historically in a number of clinical series in North America and elsewhere, and to determine if an optimal treatment regime could be derived based on these clinical data. METHODS: The biologically-based linear-quadratic model, applied to local tumor control and late morbidity, has been used to derive theoretical optimum (maximising tumor control whilst not exceeding tolerance for late reactions) radiotherapy schedules based on daily fractions. The specific case of T2 laryngeal carcinoma was considered as this is treated primarily by radiotherapy in many centers. Parameter values for local control were taken from previous analyses of several large single-center and national datasets. A time factor and a lag period were included in the modelling. Values for the alpha/beta ratio for late morbidity were used in the range 1-4 Gy, which is compatible with the limited range of values reported in the literature for particular complications following radiotherapy for head and neck cancer. Early reactions and their consequential late morbidity were not modelled in this study, but assumed to be within tolerance. RESULTS: For treatments using daily fractions there was a broad optimum treatment time of between 3-6 weeks. The theoretical optimum depended to some extent on the value of the alpha/beta ratio for late morbidity, but in many cases was at or just beyond the end of the purported lag period of 3-4 weeks, although small values of alpha/beta between 1-2 Gy favour longer treatment times. Similar results were obtained using a range of parameter values derived from four independent clinical datasets. CONCLUSION: The mathematical modelling of this broad range of once-daily treatments for most of which differences in local control and late morbidity are essentially undetectable (< 5%) has shown how this clinically-recognised phenomenon is interpreted in terms of the combination of dose-response slopes, fractionation sensitivities and time factors for both tumor control and normal tissue morbidity. Although the conclusions are inevitably tempered by a number of caveats concerning confounding factors in different centers; for example, the use of different treatment volumes, the present analysis provides a framework with which to explore the potential value of modifications to conventional treatment schedules, such as the use of multiple fractions per day.

Carcinoma↗
PubMed1997

A correlation between residual DNA double-strand breaks and clonogenic measurements of radiosensitivity in fibroblasts from preradiotherapy cervix cancer patients.

PURPOSE: To study the relationship between residual DNA damage and clonogenic measurements of radiosensitivity in fibroblasts from pretreatment cervix cancer patients. METHODS AND MATERIALS: Early passage vaginal fibroblasts from nine preradiotherapy cervix cancer patients and two radiosensitive skin fibroblast cell strains were studied. Cell survival was measured by clonogenic assay following both high and low dose rate irradiation. Residual DNA damage was measured using pulsed-field gel electrophoresis (PFGE) after irradiating radiolabeled, plateau-phase cells at 37 degrees C and allowing 24 h for repair. DNA damage was expressed both in terms of the residual damage slope (fitted to data from 60 to 150 Gy) and the fraction of activity released (FAR) following 150 Gy. RESULTS: The surviving fraction at 2 Gy (SF2) values after high dose rate irradiation for the vaginal fibroblasts ranged from 0.15 to 0.32 (a 2.2-fold difference). When the two radiosensitive cell strains were included, residual damage, expressed as the residual damage slope, correlated with alpha (r = 0.82, p = 0.002), D bar (r = -0.91, p < 0.001) and SF2 (p = -0.79, p = 0.004), and when the vaginal fibroblasts alone were studied, the residual damage slope again correlated with clonogenic survival, although less strongly [alpha (r = 0.66, p = 0.053), D bar (r = -0.83, p = 0.006), and SF2 (r = -0.63, p = 0.07)]. Within the group of vaginal fibroblasts there was a 4.0-fold difference in residual DNA damage slope. When residual damage was expressed as FAR at 150 Gy, then for all cell strains the correlations were alpha: r = 0.78, p = 0.004, D bar: r = -0.86, p = 0.001, and SF2: r = -0.78, p = 0.004, and for the vaginal fibroblast strains alone the correlations were alpha: r = 0.60, p = 0.088, D bar: r = -0.75, p = 0.02, and SF2: r = 0.62, p = 0.077. CONCLUSION: This study confirms previous findings that residual DNA damage correlates with clonogenic survival in fibroblasts. In addition, it demonstrates a correlation for fibroblasts from pretreatment cervix cancer patients demonstrating a relatively small range of SF2 values.

Cell Survival↗
PubMed1997

Cell proliferation and death in the irradiated pituitary gland and its modification by growth stimulants.

PURPOSE: This study was undertaken to show whether the rate of expression of radiation injury in the rat pituitary gland could be accelerated by the use of growth stimulants. METHODS AND MATERIALS: Rat pituitary glands were irradiated in situ with a range of single doses up to 20 Gy. The rats were then given subcutaneous slow-release implants containing 17beta-estradiol (E2) and sulpiride (S) to stimulate lactotroph proliferation. Two sequential cycles were used, each consisting of stimulation (3 weeks) and withdrawal (2 weeks). Measurements were made of gland weight; BrdU-labeled, giant, and apoptotic cells; lactotrophs; as well as pituitary prolactin content, in response to exogenous thyroid-releasing hormone (TRH). RESULTS: The two cycles of stimulation/withdrawal resulted in marked changes in gland weight, BrdU-labeling index, and serum prolactin (PRL) levels in unirradiated rats. The proportion of immunopositive growth-hormone-producing (GH) cells increased after irradiation. Radiation inhibited the hypertrophic response to E2 + S and also inhibited increases in BrdU-labeling index and serum PRL levels. Also, giant lactotrophs were observed in the irradiated pituitaries. However, they were not seen in the unirradiated rats or in the irradiated rats treated with E2 + S. TRH promoted PRL secretion in the unirradiated rat. In contrast, TRH inhibited PRL secretion in the irradiated rat and in all treatment groups receiving E2 + S. Apoptosis was induced by irradiation and was substantially increased in lactotrophs and in other cell types by withdrawal of the E2 and S stimulus, although the highest observed incidence was only 7 per 10,000 cells. CONCLUSION: Both irradiation and E2 + S treatment removed the hypothalamic control of PRL secretion, which reveals this important inhibitory action of TRH upon PRL secretion. This suggests that it is not suitable as a dynamic test of pituitary PRL reserves in such abnormal situations, where there may also be damage to the hypothalamic-pituitary vasculature. The increasing proportion of GH cells after irradiation indicates that lactotrophs respond more rapidly to irradiation. The stimulation by E2 + S somehow prevented the radiation-damaged lactotrophs from becoming giant cells. Also, the ratio of apoptotic cells to BrdU-labeled cells was increased by the E2 + S treatment, indicating that the E2 + S did enhance radiation-induced cell death relative to cell renewal. However, overall, the E2 + S stimulus protocol did not promote a dramatic increase in cell death (apoptosis) nor a marked decrease in residual gland weight after irradiation. Hence, its use would probably not be beneficial in the treatment of slow-responding prolactinomas, if malignant lactotrophs respond similarly to the normal pituitary lactotrophs. However, the observation of induced apoptosis after hormone and drug withdrawal suggests that agents which promote tumor shrinkage may be effective by causing rapid apoptosis of tumor cells in vivo.

Animals↗
PubMed1997

Differential influence of TGFbeta1 and TGFbeta3 isoforms on cell cycle kinetics and postirradiation recovery of normal and malignant colorectal epithelial cells.

PURPOSE: A clonogenic assay was used to determine the effects of the growth factors TGFbeta1 and TGFbeta3 on the radiation responses of a normal rat epithelial cell line (IEC6) and a human colonic carcinoma epithelial cell line (Widr). METHODS AND MATERIALS: The radiation sensitivity and ability to recover from potentially lethal damage (PLD), of preconfluent monolayer cultures, was assessed in the presence of the growth factors for 24 h prior to, during, and after irradiation. RESULTS: The surviving fractions of both cell lines assessed immediately following irradiation were unaffected by TGFbeta1 or TGFbeta3. However, TGFbeta3 (but not TGFbeta1) significantly reduced the amount of PLD recovery in the Widr cells (but not in the IEC6 cells). This was associated with a reduction in the shoulder region of the survival curve, rather than a change in slope. A comparative analysis of the effects of TGFbetas 1 and 3 on cell cycle events in the two cell lines demonstrated significantly more Widr cells in the S phase, in the presence of TGFbeta3 only, compared to the controls. This remained constant both before and immediately following irradiation. In the IEC6 cell line TGFbeta3 produced an increase in the numbers of G1 phase cells, characteristic of a G1 arrest. CONCLUSION: It seems likely that TGFbeta3-induced radiosensitisation in Widr cells, 6 h after a single dose of irradiation, is related to its effects on cell cycle events such that the failure of these cells to arrest in G1, either before or after irradiation, results in significantly reduced recovery from DNA damage. This, however, may not be the only mechanism by which this growth factor produces this effect. Indeed, it will also be necessary to investigate these effects in in vivo models and to determine the response to fractionated irradiation before the potential therapeutic benefit of both the differential effects observed between the two TGFbeta isoforms and also between the malignant and normal cell lines can be fully assessed.

Animals↗