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H D Thames

Publications and source records attributed to H D Thames.

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

A dose-surviving fraction curve for mouse colonic mucosa.

A dose-surviving fraction curve representing the response of the mouse colonic mucosa to single doses of 137Cs gamma radiation was obtained from the results of a multifraction in vivo colony assay. Construction of the curve required an estimate of the average number of clonogens initially present per colonic crypt. The estimated clonogen count (88) was determined by a statistical method based on the use of doses per fraction common to different fractionation protocols. Parameters for the LQ and TC models of cell survival were obtained by weighted least-squares fits to the data. A comparison of the survival characteristics of cells from the mouse colonic and jejunal crypts suggested that the epithelium of the colon is less radiosensitive than that of the jejunum.

Animals↗
PubMed1983

Accelerated fractionation vs hyperfractionation: rationales for several treatments per day.

Treatment with several doses per day offers the prospect of a significant therapeutic gain using readily available low LET beams. These regimens can be classified as either accelerated fractionation or hyperfractionation according to their rationales. With accelerated fractionation a conventional number of dose fractions is delivered in a significantly shortened overall treatment time in order to reduce the opportunity for tumor cell regeneration during treatment. With hyperfractionation, on the other hand, a large number of significantly reduced dose fractions is used to give a greater total dose in a conventional overall treatment time. The rationale for this strategy is threefold: 1) increased opportunity for tumor cell redistribution and reoxygenation between dose fractions: 2) a possibly lower oxygen enhancement ratio with small incremental doses; and 3) different sparing of late reacting normal tissues with small dose fractions. A review of the published clinical experience with multiple fractions per day treatment reveals few studies of either pure accelerated fractionation or hyperfractionation since both are limited by acute normal tissue reactions. This has led to a variety of hybrid regimens, some of which have no clear rationale. The choice between accelerated fractionation and hyperfractionation is determined by the regenerative capability of tumor clonogens during treatment. A method of selection based on potential doubling times is presented.

Clone Cells↗
PubMed1983

Response of fibrosarcoma cell subpopulations to small doses of radiation delivered in situ.

The survival of cells from 2 tumor subpopulations after gamma-ray doses ranging from 1 to 19 Gy was determined using a lung colony assay. Methylcholanthrene-induced fibrosarcomas grown in the hind legs of C3H/Kam pathogen-free mice were irradiated in situ when the tumors were 8-10 mm in diameter. Single cell suspensions prepared from excised tumors were separated on a linear density gradient, and the clonogenicity of predominantly oxic Band 2 (density 1.08 g/cm3) and predominantly hypoxic Band 4 (density 1.14 gm/cm3) cells was measured. The surviving fraction of cells after doses of 1, 2, and 3 Gy was estimated from that measured after total doses of 5 Gy = 5 X 1 Gy, 10 Gy = 5 X 2 Gy, and 15 Gy = 5 X 3 Gy, under the assumption of equal effect per fraction (checked by estimating survival at 3 Gy after different numbers of fractions). Very little curvature was evident in the survival curves of Band 2 and Band 4 cells (beta/alpha = .013-.034 Gy-1). The initial segment of the survival curve of the predominantly oxic Band 2 cells was steeper (1Do = 3.6 Gy) than that of the predominantly hypoxic Band 4 cells (1Do = 5.2 Gy); both remained linear over a large range, to doses in excess of 3 Gy. These results imply that these tumor subpopulations will be insensitive, in their response to multifractionated regimens, to changes in size of dose per fraction in the range 0 to 3 Gy, a trait shared by two acutely responding normal tissues (murine testis and jejunum).

Animals↗
PubMed1983

Flexure dose: the low-dose limit of effective fractionation.

Total radiation dose often can be increased without subsequent increases in the severity of tissue injury by using reduced doses per fraction. The flexure dose, df, is defined as the largest fractional dose for which further fractionation produces no significant change in the total dose required to reach a specified effect level. Thus, df is clinically relevant in that it represents the limit of effective dose fractionation. For those tissues in which injury reflects depletion of a critical proportion of target cells, the flexure dose is a measure of the extent of the initial, nearly linear portion of the dose-survival curve. More generally, the flexure dose is a measure of the extent of the initial, nearly linear portion of a dose-response curve in organized tissue, whatever its relationship to clonogenic target cells might be. Several quantitative expressions for df are derived. The characteristic common to these is that each defines the flexure dose as a multiple of the ratio alpha/beta of the parameters of the linear-quadratic model of cell survival or dose response, where the multiple is a measure of experimental or statistical resolution. These multiples tend to fall within a limited range, thereby defining the "region of flexure" via the inequality 0.05 (alpha/beta) less than or equal to df less than or equal to 0.15 (alpha/beta). Estimates of the region of flexure are presented for a variety of normal and neoplastic tissues.

Animals↗
PubMed1983

A new isoeffect curve for change in dose per fraction.

A method is proposed for using survival curve parameters for calculating the change in total dose necessary to achieve an equal response in a tissue when the dose per fraction is varied. The method uses the ratio alpha/beta of the coefficients of the linear quadratic survival formula and accounts only for the effect of repair of cellular injury. Absolute values for alpha and beta are not required. The isoeffect curves vary for different tissues. A dose adjustment to account for differences in the regeneration of surviving cells that might result from changing a treatment regimen must be made separately and will also vary from tissue to tissue. Examples of the use of the curves are given. At present, the curves, particularly those for late effects, are uncertain and caution should be observed in using them until they are defined more accurately with additional data.

Cell Survival↗
PubMed1983

Optimal design of multifraction assays of colony survival in vivo.

Certain fractionation protocols for multifraction in vivo colony assays permit the use of a statistical method to test the hypothesis that equal dose fractions produce equal decrements in cell survival and to obtain an estimate of the number of clonogens initially capable of structure regeneration. The essential requirement is that common doses per fraction be given in two or more regimens consisting of different fraction numbers. It is shown that the accuracy of the method is dependent upon the particular selection of common-dose regimens used in the assay. Calculations with theoretical data were used to determine guidelines for selecting the optimal experimental design. It was found that the fraction number pairs (n, m) which result in observable levels of survival tend to lie in a triangular region when plotted in the plane. Use of regimens corresponding to points along the lower edge of this triangle can substantially improve the results of the statistical method. It was also found to be optimal to use a minimal dose for each regimen, subject to the constraint that survival levels lie in the observable range. An application of the main ideas to data from assays of mouse jejunal crypt cell survival illustrates that use of a near-optimal design would have produced better results with 80 mice than were obtained with 140 mice.

Animals↗
PubMed1983

Repair in mouse lung between multiple small doses of X rays.

Multiple fraction experiments have been carried out to determine the response of mouse lung to repeated small doses of 240 kV X rays down to 150 rad/fraction using breathing rate and lethality to assess damage. Two experimental approaches were used to measure the effect of small doses in vivo: (1) multiple equal doses and (2) multiple priming doses followed by a large test dose. Analysis was performed using the multitarget two-component model and the linear quadratic model of cell survival. The amount of repair was calculated as a function of either dose per fraction (FR) or total dose (Frec). Both FR and Frec increased with decreasing dose per fraction but the change in FR was small. The advantage of Frec was that it varied more rapidly with dose per fraction than FR, so that possible differences between tissue repair capabilities are more visible on plots of repair as a function of dose per fraction. FR and Frec both decreased with the level of single-dose isoeffect injury; thus neither parameter is acceptable for comparing repair capability of different normal tissues with widely differing single-dose end point levels. Beta/alpha values were calculated and found to be a more acceptable index of repair capability than either FR or Frec because unlike those two parameters, beta/alpha varied little with level of damage. Beta/alpha values of 1.7 to 4.2 krad-1 were obtained for both lung death and increased breathing rate and are clearly intermediate between the lower beta/alpha ratios for acute reactions, i.e., skin and intestine, and the higher values for late reactions in kidney and spinal cord.

Animals↗
PubMed1982

Tumor radioresistance in clinical radiotherapy.

Tumor radioresistance in clinical radiotherapy implies failure to achieve loco-regional disease control with radiation doses producing an acceptable degree of morbidity. Such radioresistance may be a result of many different causes (biological and technical) which are reviewed in terms of possible remedial actions. Dose response relationships for human cancers suggest that in many sites, tumors are heterogenous with respect to their cure-limiting characteristics. The case is developed that unless the predominant cure-limiting factor can be predicted, little benefit may be seen in trails of new treatment strategies using heterogeneous tumor populations. The fundamental problem of clinical radioresistance is therefore perceived as the inability to predictively identify its cause in the individual patient.

Cell Line↗
PubMed1982

Changes in early and late radiation responses with altered dose fractionation: implications for dose-survival relationships.

Clinical and experimental evidence for divergent changes in early and late radiation responses in normal tissues after changes in dose fractionation indicate a greater sensitivity of late responses to changes in dose per fraction. In experimental studies of the effect of dose per fraction on early and late isoeffects, a larger number-of-fractions exponent for the late responses is the rule. These findings imply that the shape of the dose-survival curve for the target cells whose depletion results in late effects is different from that for target cells for acute effects: as the dose increases the contribution to cell killing from accumulated sublethal injury, relative to killing from single hit events, increases more rapidly in the target cells for late effects. In other words, the survival curve for the target cells for late injury must be "curvier" than that for acute effects. Although such survival curve characteristics are independent of the survival curve model chosen to describe them, they would represent, in terms of the parameters of the linear quadratic model, S = e -alphaD-beta D2, a higher beta/alpha ratio for late effects. If the dose survival characteristics of tumor clonogens resemble those of the target cells in acutely responding normal tissues, and if late injury in normal tissues is dose-limiting, then a therapeutic gain would result from reducing the size of dose per fraction by hyperfractionation. Conversely, increasing the size of dose per fraction should reduce the therapeutic differential.

Dose-Response Relationship, Radiation↗
PubMed1982

Biological bases for high RBE values for late effects of neutron irradiation.

The late effects of fractionated irradiation with neutrons have been relatively more severe than after x-irradiation. Reasons for the RBEn/x being higher for late than for acute effects may include: (1) Late effects are reduced more by fractionation of X ray doses than are acute effects, whereas, with neutrons, the fractionation response is the same in rapidly-and slowly-responding tissues; (2) Late-responding tissues are less "sensitized" (and are, therefore, relatively protected) by redistribution throughout the division cycle during a fractionated regimen than are acutely-responding tissues: since neutron responses are less affected by cell-cycle distribution than are X ray responses, the relative protection of slowly-responding tissues is less; (3) The target cells for late, but not acute injury, may repair potentially lethal damage after X ray, but not after neutron exposure. Thus, the dissociation of RBE values for acute and late injury reflects mainly the dissociation between acute and late responses to conventional fractionated X ray regimens and, from the point of view of complications of radiotherapy, we should not condemn neutrons but praise X rays. Since fractionation of neutron doses into increments equivalent to those used in X ray therapy does not provide a preferential sparing of slowly-responding tissues, it is reasonable to shorten the overall duration of neutron treatment to deliver the total dose tolerated by the relevant "late-effects" tissue(s) in the shortest time consistent with acceptable acute responses.

Animals↗
PubMed1982

Protective effects of S-2-(3-aminopropylamino)ethylphosphorothioic acid against radiation damage of normal tissues and a fibrosarcoma in mice.

S-2-(3-Aminopropylamino)ethylphosphorothioic acid (WR-2721) was investigated for its protective effect against radiation-produced damage of jejunum, testis, lung, hair follicles, and a fibrosarcoma of C3Hf/Kam mice. Most of these tissues were radioprotected, and the degree of radioprotection depended on the dose of WR-2721 and the time interval between administration of WR-2721 and radiation treatment. WR-2721 increased resistance of jejunal epithelial cells and spermatogenic cells to single doses of gamma-rays by factors of 1.64 and 1.54, respectively. Protection against hair loss was less pronounced; the dose-modifying factor here was 1.24. The radiation-induced acute damage of the lung expressed by the increased formation of tumor nodules in the lung was not decreased by treatment of animals with WR-2721 before radiation. In contrast, WR-2721 augmented the radiation-induced enhancement of metastasis formation in the lung. WR-2721 protected fibrosarcoma micrometastases in the lung against therapeutic effect of radiation by a factor of 1.238. In contrast, this compound had no effect on the therapy of an 8-mm fibrosarcoma growing in the legs of mice.

Amifostine↗
PubMed1980

Test of equal effect per fraction and estimation of initial clonogen number in microcolony assays of survival after fractionated irradiation.

In the use of multifraction microcolony assays to infer the low-dose response of in situ renewal systems such as intestinal crypts, the assumption of equal effect per dose fraction is required. Moreover, the construction of a cell-survival curve requires knowledge of the initial count of cells capable of repopulating each renewal structure. We describe a method of designing fractionation protocols which provides a regression estimate of the initial number of clonogens per renewal structure and a test of the hypothesis of equal effect per fraction. The essential factor in the experimental design is the use of common dose fractions (use of the same dose per fraction in series with different numbers of fractions). Applications of the method to data for which the assumption of equal effect per fraction holds (four-hour fractionation interval testis study) and does not hold (one-hour fractionation interval jejunal crypt study) are presented.

Animals↗
PubMed1980

Dose response of squamous cell carcinomas of the upper respiratory and digestive tracts.

Dose-response curves have been computed for 5 tumour sites of the head and neck region, using 2 regression models. In agreement with clinical observation, a significant increase has been found from moderate to high control rates with modest dose increases for exophytic tumours (T1 + T2 retromolar trigone-anterior faucial pillar and T2 + T3 supraglottic larynx). Further significant increases in local control after modest dose increases are not obtained when the control rate is already high and the slope of the dose-response curve consequently diminished. Despite unsatisfactory (50%) control rates for large heterogeneous tumours (T3 + T4 pharyngeal walls), further increases cannot be obtained without excessive doses because the curve flattens at the 50% control rate level.

Carcinoma, Squamous Cell↗