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J H Hendry

Publications and source records attributed to J H Hendry.

At least 109 records · Page 6Linked to original sources
PubMed1993

Dose-fractionation sensitivity of mouse kidney clonogens measured using different interfraction intervals and postirradiation assay times.

The fractionation sensitivity of kidney clonogenic epithelial cells (X-irradiation in vivo, assay in vitro) was quantified using the linear-quadratic model. The cells were assayed either immediately after the fractionation schedule or after a time delay in order to compare the relative amounts of dose sparing due to fractionation (conventionally sublethal damage repair) and to post-irradiation delay intervals before assay (conventionally potentially-lethal damage repair). As the delay before assay was increased, there was a tendency for both alpha and beta to decrease, and as a consequence the alpha/beta ratio stayed virtually unchanged (3.3-4.4 Gy) regardless of delay time before assay. No change in survival was observed from 12 h to 6 weeks after neutron irradiation (62 MeVp-->Be), suggesting that the change observed after X-rays was due to repair rather than repopulation. As the interfraction intervals in an 8-fraction X-irradiation schedule were increased in steps from 6 h to 5 days, there was improved survival, consistent with the presence of long-term repair. These studies provide further evidence for the potential importance of long-term repair in late reacting tissues not only during but also after multifraction irradiation schedules.

Animals↗
PubMed1993

The delay before onset of accelerated tumour cell repopulation during radiotherapy: a direct maximum-likelihood analysis of a collection of worldwide tumour-control data.

The worldwide collection of control data for head and neck tumours presented by Withers et al. (Withers, H.R., Taylor, J.M.G. and Maciejewski, B. Acta Oncol. 27: 131-146, 1988) was reanalysed using a model which includes an explicit lag phase before the onset of tumour clonogen repopulation. A direct maximum-likelihood approach was used and the methodology extended to include the computation of profile-likelihood confidence limits. A statistically significant (p = 0.02) lag of 29 days was obtained with 95% confidence limits covering the range 17-31 days. However, the confidence interval was disconnected, and excluded the period 21-23 days. The analysis gave a time factor of 0.66 Gy/day. The mean values confirm the conclusions drawn by the original authors using a two-stage (indirect) method, and the values are similar to those calculated here for another data set comprising 496 patients (lag period = 26 (19-33) days). However, the data set itself is retrospective, and potentially subject to a number of biases. Therefore any clinical conclusions can only be tentative. A new feature of the methodology is the computation of profile-likelihood confidence limits and this will be useful in future direct analyses of clinical data of this type. The more usually computed normal approximation to the confidence limits have been shown to be inadequate in this analysis, and either profile-likelihood limits or likelihood ratio tests must be employed to determine the significance of the model parameters.

Head and Neck Neoplasms↗
PubMed1993

The distribution of colony-forming cells in the kidney.

A method is described for producing outgrowths of small nephron segments (average 24 cells) in culture. The method was used to estimate an overall colony-forming efficiency of 4.6% for cells constituting the segments. Efficiency was found to be lower for thick segments (1%) than for thin segments (6%) from Henle's loop. The latter higher level indicates that precursor cells are concentrated near the middle of the nephron. For comparison, a two-dose irradiation technique was used to calculate a mean number of 5 +/- 2 (SE) clonogens per segment producing outgrowths. This tended to be higher than the value of about 1 calculated from the 65% of segments producing outgrowths, as expected if the remaining segments contained no clonogens.

Animals↗
PubMed1993

The dose-fractionation sensitivity of the kidney; assessment of viable tubule cross-sections at 19 months after X irradiation.

The formation of viable tubule cross-sections was assessed in histological sections of murine kidneys at 19 months after fractionated bilateral X-ray doses with 12 h intervals between fractions. The data were analysed using the linear-quadratic model which provides values of alpha and beta characterizing the slope of the dose-response curve, and the ratio of alpha and beta indicative of the sparing effect of dose fractionation. The tubule data were characterized by alpha = 0.057 +/- 0.009 Gy-1, beta = 0.011 +/- 0.001 Gy-2, alpha/beta = 5.0 +/- 0.9 Gy. Also, the number of cells (per focus region of the nephron) calculated as being capable of producing a viable focus was 2.5 +/- 0.5, which was confirmed using a separate two-dose approach (2.1 +/- 0.3). Together with other data, of the order of 1000 regenerative cells per nephron (10(4) total cells) can be deduced. The values of the fractionation sensitivity parameters are similar to values measured previously for cells taken from irradiated kidneys up to a year after irradiation and forming colonies in primary culture, and also similar to values assessed using various functional measures of kidney injury.

Animals↗
PubMed1992

The effect of increasing the treatment time beyond three weeks on the control of T2 and T3 laryngeal cancer using radiotherapy.

Local control of cancer by radiotherapy may be prejudiced by accelerated tumour clonogen repopulation particularly during protracted treatment schedules. A series of 496 cases of T2 and T3 larynx cancer treated here by radiotherapy has been studied to examine the impact on local control of treatment durations ranging from 9 to 41 days. Data were analysed using a linear-quadratic formulation describing the fractionation sensitivity, with the incorporation of a parameter relating to treatment time. Using combined T2 and T3 data, the increase in dose required to maintain a constant local control (the time factor) was between 0.5 and 0.6 Gy per day. These values are similar to those reported for 4 weeks or more in the literature. Also, the calculated dose to control 50% of tumours, given over the standard Christie duration of 21 days, was on the line projected back from literature data over 28-66 days. The present data are consistent with the presence of such a time factor following a lag phase of not more than 3 weeks after starting radiotherapy. Hence, further consideration should be given to using shorter overall treatment times in radiotherapy for head and neck cancer.

Carcinoma↗
PubMed1992

Treatment acceleration in radiotherapy: the relative time factors and dose-response slopes for tumours and normal tissues.

A published collation of data for control of head and neck cancer in over 4500 patients has been subjected to direct analysis to deduce dose-response, fractionation, and time parameters. The analysis confirms the presence of a significant time factor of the order of 0.5-0.6 Gy/day, deduced previously using various assumptions and normalisation procedures. In addition, the dose-response curve was characterised by Da = 29 Gy which contributed to long "effective" doubling times being deduced for tumour clonogens in the patient population as a whole. Some late-reacting normal tissues also show significant time factors, and furthermore, their dose-response curves are in general steeper than for tumours. Hence, care should be taken in accelerating treatments to improve local control, if the treatments are truly at tolerance regarding late-appearing major complications.

Dose-Response Relationship, Radiation↗
PubMed1992

Can modest escalations of dose be detected as increased tumor control?

Clinically defined groups of tumors are usually characterized by shallow dose-response curves, and this results from heterogeneity among individual dose-response curves, each of which is very likely quite steep. A review of published results for human tumors indicates that a 10% escalation of dose to tumors controlled at the 50% level, where changes in outcome are most likely to be detected, will be detectable in a population of unselected patients only in sizable clinical trials (130-300 patients per dose level). With a few exceptions, a dose escalation of 20% will be detectable in much smaller trials (50-130 patients per dose level). Therefore, clinical trials of improved treatment modalities will be confounded by patient heterogeneity, and modest improvements may go undetected in all but the largest trials. Mathematical modeling was used to study the effect on the steepness of the dose-response curve of selecting patients on the basis of the radiosensitivity measure SF2 (surviving fraction at 2 Gy). If SF2 is a faithful predictor of response in a group of tumors, then heterogeneity could be reduced by excluding the patients with the most sensitive (controlled with near certainty) and most resistant (recurring with near certainty) tumors. The resulting "stochastic fraction" (tumors for which treatment outcome is probabilistic) would be characterized by a steep dose response, and the number of patients required to demonstrate the effect of dose escalation would be substantially reduced (by about 50%).

Dose-Response Relationship, Radiation↗
PubMed1992

Transfection of the Escherichia coli nth gene into radiosensitive Chinese hamster cells: effects on sensitivity to radiation, hydrogen peroxide, and bleomycin sulfate.

The Escherichia coli nth gene encodes endonuclease III, which catalyses the glycolytic removal of various oxidized thymine residues from DNA. A truncated version of nth, with the prokaryotic regulatory sequences removed, was ligated into the retrovirus-based vector pZipneoSV(X)1 and transfected into the radiosensitive Chinese hamster ovary cell line, xrs7. Following selection with G418, two clones (x7nth1 and x7nth6) were shown by Southern analysis to contain the nth gene. No substantial difference in gamma-ray sensitivity was detected between xrs7, clones x7nth1 and x7nth6, and the parent vector transfected clone (x7neo1). However, clones containing the nth gene were more resistant to hydrogen peroxide cytotoxicity [D0's for x7nth1 and x7nth6 were 0.072 microgram/ml (4 microM) and 0.046 microgram/ml, respectively, compared with D0's of 0.034 and 0.027 microgram/ml for xrs7 and x7neo1, respectively] but markedly more sensitive to bleomycin sulfate cytotoxicity than xrs7 and x7neo1 (e.g., 1D0's for x7nth6 and xrs7 were 0.05 and 0.12 microgram/ml, while 2D0's for x7nth1 and xrs7 were 0.35 and 0.48 microgram/ml, respectively). Alterations in sensitivity to hydrogen peroxide and bleomycin sulfate could not be explained by differences in the distribution of the cell-cycle phases and growth rate of nth-containing clones and control cell lines. These results are consistent with the hypothesis that modified thymine lesions are potentially cytotoxic. Hence, when cells incur a high level of endonuclease III-repairable damage relative to strand breakage, such as after treatment with hydrogen peroxide, increased repair capacity increases survival. Gamma radiation produces a lower level of endonuclease III-repairable damage relative to all the other types of lesions produced; hence increased repair capacity has no measurable effect on cell survival. The increased sensitivity of x7nth1 and x7nth6 to bleomycin sulfate toxicity may indicate that, when thymine damage and single-strand breaks are in close proximity on opposite strands of the DNA, endonuclease III, which incises DNA at the site of damaged residues, can increase the number of double-strand breaks and hence decrease the level of cell survival.

Animals↗
PubMed1992

The clonogen content of murine intestinal crypts: dependence on radiation dose used in its determination.

The number of colony-forming (clonogenic) cells in each of the crypts in mouse small intestine was deduced using a two-dose irradiation technique. The number was 7.5 +/- 0.8 cells using two equal doses each less than 9 Gy and 38 +/- 7 cells using 9 Gy or more per dose. The significant dose dependence could not be accounted for by considerations of intra- or intercrypt variability, or by the factor introduced to correct the sampling frequency for the influence of crypt size. The results suggest that more colony-forming cells may be recruited when the injury is more severe.

Animals↗
PubMed1991

Interactions in recovery and in residual injury from sequential treatments of mouse haemopoietic and stromal marrow cell populations, using X-rays, cyclophosphamide and busulphan.

The acute recovery of populations of day 11 CFU-S, iv-CFC and CFU-F in mouse bone marrow, following a test dose of X-rays, cyclophosphamide (CP) or busulphan (BUS) given to mice previously treated with repeated priming doses of X-rays or CP, was in general predictable from the amount of residual injury after the priming doses. A marked exception was iv-CFC after X-rays, which although amplified to near normal levels during the residual injury phase, recovered after the test irradiation from low levels of CFU-S. The amount of residual injury after sequential treatments of different agents was in general less than expected on the basis of the product of the effects of the individual agents. This was most marked for CP priming treatments, where the long-term recovery of day 11 CFU-S after the test dose remained persistently above control levels. Also, some correlation was found between improved stromal recovery (CFU-F) and the CFU-S content following the sequential treatment protocols.

Animals↗
PubMed1991

The lower radiosensitivity of mouse kidney cells irradiated in vivo than in vitro: a cell contact effect phenomenon.

For mouse kidney cells assayed in primary culture, the Do and n values were 1.1 +/- 0.06 Gy and 7 +/- 2 for single cells irradiated in vitro, and 1.3 +/- 0.08 Gy and 25 +/- 11 for in vivo irradiation. The lower radiosensitivity in vivo was shown not to be caused by natural hypoxia, as the average oxygen enhancement ratios were 2.6 +/- 0.3 for in vitro and 2.8 +/- 0.4 for in vivo irradiation. Irradiations of fragments of kidney tubules produced similar survivals as irradiations of kidneys in situ, even for irradiation immediately before the fragments were disaggregated into single cells. The critical point of change in radiosensitivity from in vivo to in vitro values due to this contact effect was the time that the kidney cells were monodispersed.

Animals↗
PubMed1991

The sensitivity of human tissues to changes in dose fractionation: deductions from the RCR survey among UK radiotherapists.

The dosage prescriptions reported in the Royal College of Radiologists' fractionation survey among radiotherapists have been further analysed using model equations in order to deduce estimates of fractionation-sensitivity parameters for each of the six cases under consideration. For example, using the linear-quadratic model, including a (significant) time factor, with radical treatments of a T2 breast carcinoma or a T1N0 squamous carcinoma of the vocal cord, the (alpha/beta) ratios were 26 +/- 20 Gy and 37 +/- 46 Gy, respectively. The values of the time factor, expressed as the maximum extra dose required per day to counteract the decrease in effect with increasing overall time (gamma/alpha), were 0.60 and 0.45 Gy/day respectively. Using the Ellis formula, which provided a significantly better fit to the dosage prescription (P = 0.003), the exponents of N were calculated to be 0.24 +/- 0.05 and 0.27 +/- 0.07, respectively. The corresponding values of the T exponent were 0.16 +/- 0.06 and 0.014 +/- 0.075. About 20% of radiotherapists prescribed doses greater than +/- 10% from the mean fitted values for the breast treatment, and about 6% of them in the case of the vocal cord.

Aged↗
PubMed1991

Acute response of mouse kidney clonogens to fractionated irradiation in situ and then assayed in primary culture.

Although the difference in sensitivity to the changes in dose fraction size between early-responding and late-responding tissues is well established, the underlying mechanisms in terms of target-cell responses are not yet clearly identified for any tissue. The radiosensitivity of mouse kidney cells after in situ single-dose, 2, 8, and 16 fraction X-irradiations was measured in primary culture using a clonogenic assay. The assay was made 12 h after single doses or 12 h after the last dose of the multifraction regimens. When analysed using the linear-quadratic model, as predicted the individual alpha components for all the different fractionation schedules were not significantly different, and the changes in the beta values were consistent with those expected on the basis of the reciprocal fraction numbers. When all four data sets were integrated to derive a common alpha/beta ratio, the result was 4.4 +/- 1.3 (1SE) Gy, or 2.8 +/- 0.9 Gy (a better fit) if the single-dose data set was excluded. These values fall into the range reported for kidney using assays of tissue function at long times after irradiation. Hence, it has been shown for the first time that the fractionation sensitivity of a late-responding organ is mimicked by that of a clonogenic cell population in that organ. The evidence also suggests that the time available prior to fixation of potentially lethal damage does not influence the low alpha/beta ratio observed for the kidney.

Animals↗
PubMed1991

The slower cellular recovery after higher-LET irradiations, including neutrons, focuses on the quality of DNA breaks.

Data for many biological end points reviewed here indicate that the responsible lesions are not only more severe but also are often more slowly repaired as the LET of the ionizing radiation is increased. This is reflected in high RBE values for end points assayed at long (in contrast to short) times after irradiation, for example, residual injury in normal tissues and carcinogenesis.

Animals↗