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Biomedical subjects

K A Mason

Publications and source records attributed to K A Mason.

At least 55 records · Page 3Linked to original sources
PubMed1994

Enhancement of tumor radioresponse of a murine mammary carcinoma by paclitaxel.

Paclitaxel is a chemotherapeutic agent with potent microtubule stabilizing activity that arrests cells in G2-M. Because G2 and M are the most radiosensitive phases of the cell cycle, paclitaxel has potential as a cell cycle-specific radiosensitizer. In this study, we investigated the ability of paclitaxel to increase tumor radioresponse in vivo using a murine mammary carcinoma and the dependency of this response on accumulation of tumor cells in mitosis. Mice bearing 8-mm tumors were treated with paclitaxel (60 mg/kg i.v.), 9, 15, or 21 Gy of single-dose radiation, or with a regimen of both agents in which radiation was given 1, 9, or 24 h after paclitaxel. The effect of the treatments was determined by tumor growth delay. Microscopically, the percentage of mitotically arrested cells was only 4% 1 h after treatment with paclitaxel, increased to a maximum value of 30% at 9 h, and decreased to 12% 24 h after paclitaxel. Paclitaxel enhanced tumor radioresponse by factors of 1.21 to 2.49. The degree of enhancement increased with increases in both the dose of radiation and the time between paclitaxel administration and radiation delivery. Radiation efficiently destroyed mitotically arrested cells by apoptosis. The greatest enhancement of radiation response was not at the time of the highest mitotic arrest but at 1 day after paclitaxel treatment, showing that paclitaxel potentiates tumor radioresponse by mechanisms in addition to blocking the cell cycle in mitosis, possibly by tumor reoxygenation. Thus, these results show that paclitaxel is a potent in vivo radiopotentiating agent and has the potential to be usefully combined with radiotherapy.

Animals↗
PubMed1994

Comparison of continuous and pulsed low dose rate brachytherapy: biological equivalence in vivo.

PURPOSE: Recent studies of human cell lines cultured in vitro and mathematical modeling of the response of acute and late responding tissues have predicted conditions for the equivalence in terms of cell killing of continuous and pulsed dose rate brachytherapy. The aim of this study was to test these predictions in vivo using an acutely responding normal tissue. METHODS AND MATERIALS: The microcolony assay was used to quantify the survival of jejunal stem cells in vivo. Mice were exposed to graded doses of 60Co delivered continuously or as 1- or 10-min pulses given once-per-hour at an average dose rate of 0.7 Gy/hr. In both cases the total dose-per-hour was 0.7 Gy. Overall exposure times ranged between about 30 and 60 h. Mice were sacrificed 3.5 days after exposure, the bowel removed for routine histological preparation, and number of surviving crypts quantified microscopically. RESULTS: An average dose-per-hour of 0.7 Gy, a pulse width of 10 min, and a pulse frequency of 1 h resulted in biological equivalence of pulsed to continuous treatment. Delivering the pulse in a period of 1 min at a dose rate 10-fold higher resulted in a modest 3-4% shift in the survival curve to lower isoeffective doses. The slopes of the survival curves as described by D(o) values were similar for all treatment regimens tested. CONCLUSION: This in vivo study validates the prediction of biological equivalence between pulsed and continuous brachytherapy at a clinically relevant average dose rate and may generate further interest in this new treatment modality because of its advantages in radiation protection, dose optimization, and cost relative to standard low dose rate brachytherapy techniques.

Animals↗
PubMed1994

Unexpected radiation protection with 13-cis-retinoic acid plus interferon alpha-2a.

A recent clinical protocol combining retinoic acid, interferon, and radiotherapy for advanced cervical cancer produced proctitis severe enough to necessitate dose reductions. In an attempt to model this biological response to multimodality therapy, we used a murine model to study the response of the colonic epithelium. Mice were treated with retinoic acid (100 micrograms/day) and interferon (3 x 10(4) units/day) for 5 days before undergoing whole-body irradiation. The functional response of the bowel was assessed by the ability to maintain body weight, and reproductive cell survival was quantified by the colon crypt assay. Both assays indicated a moderate protective effect of treatment with retinoic acid and interferon prior to irradiation. Protection factors in the range of 1.1-1.4 were observed.

Animals↗
PubMed1994

Changes in the radiation sensitivity of mouse skin during fractionated and prolonged treatments.

Reactions of the skin of the right thigh of mice were used as an experimental model to test possible changes in the radiosensitivity of mouse skin, as represented by changes in the linear-quadratic (LQ) model parameters alpha and beta, as a function of fractionation interval and overall treatment time. In the first series of experiments, variable numbers of 3-Gy fractions with intervals of 6, 24 or 48 h were applied, followed by top-up doses to increase the skin damage to a level that could be scored. The results showed that mouse skin is more sensitive to 3-Gy fractions applied with 48-h intervals than to 3-Gy fractions applied with 6- or 24-h intervals. In the second series of experiments we used single-dose or fractionated test treatments for previously unirradiated mice and mice treated with priming doses of 10, 20 or 30 Gy given 1-18 days before the test treatment. The sensitivity appeared to be higher after intervals of 14-18 days than after 1-10 days after priming treatments of 20 and 30 Gy. The increased sensitivity 18 days after 20 Gy was mainly the result of an increase in the beta component of the LQ model; higher values of alpha were also determined. We conclude that the radiosensitivity of mouse skin is higher during a radiation-induced proliferative response.

Animals↗
PubMed1993

Late effects of radiation on the lumbar spinal cord of guinea pigs: re-treatment tolerance.

PURPOSE: Using a guinea pig model of lumbar myelopathy, various factors affecting the tolerance of spinal cord to irradiation were assessed: (a) extent of initial injury (b) time interval between priming and test doses (c) animal age at the time of initial radiation treatment. METHODS AND MATERIALS: A 3 cm section of lumbar spinal cord of guinea pigs was irradiated with fractionated doses of 4.5 Gy gamma rays given as 9 fractions per week. Guinea pigs were primed with 9 x 4.5 Gy in 7 days which is 60% of the ED50 for a continuous course of treatment. After 28 or 40 weeks, animals were retreated with 6-14 fractions of 4.5 Gy. Animals were observed for 2 years following the priming dose and both the incidence and latency of myelopathy recorded. RESULTS: Young adult guinea pigs (8 wk old) showed both a decreased radiation tolerance and latency compared to old individuals (40 wk old). At 28 or 40 wk after 9 x 4.5 Gy, only about 8% of the initial injury was remembered in young adult guinea pigs. CONCLUSION: The amount of residual injury was dependent on the initial damage as a proportion of the tolerance dose. The spinal cord shows a greater capacity for long-term recovery than generally appreciated and re-treatment doses clinically prescribed may be lower than necessary.

Age Factors↗
PubMed1993

The number of clonogenic cells in a mouse jejunal crypt.

The near linearity of cellular dose-survival curves for neutrons facilities back-extrapolation to their origin at zero dose. This zero dose intercept is the number of clonogenic cells per circumference, from which the average number of clonogenic cells per crypt can be calculated. The average estimate of clonogenic cell number per crypt (k) from back-extrapolation of 11 single dose neutron survival curves to a common intercept was 100. Multifraction experiments provide an even better estimate of k because more complete dose survival curves can be constructed on the assumption of an equal effect per equal dose fraction. The short back-extrapolation of five such curves to a common intercept yields an estimated k value of 123 (108-140, 95% confidence interval) cells per crypt. These k values were higher than those estimated by Hendry's two-dose gamma-ray method.

Animals↗
PubMed1993

Stimulation of hematopoietic cell recovery by tetrachlorodecaoxide in sublethally irradiated mice.

This study investigated whether tetrachlorodecaoxide (TCDO), a potent wound-healing agent, promotes recovery of hematopoietic tissue of mice depleted by sublethal X irradiation. Mice were exposed to 3 Gy total-body irradiation and were given 1 ml/kg TCDO intravenously daily from day 1 to 5 or day 4 to 8 after irradiation. The effect was assessed by the change in the total number of nucleated cells in bone marrow and spleen, endogenous spleen colony formation, and 30-day mouse lethality. In the spleen there were profound effects on spleen weight, total organ cellularity, and endogenous colony formation. The TCDO produced radiation dose-modifying factors between 1.4 and 1.5 for endogenous spleen colony formation in mice primed with 3 Gy and reirradiated 4 days after treatment. This stimulated cellular recovery resulted in an increased protection of mice from lethality caused by subsequent total-body irradiation by factors of 1.12-1.18. The results show that TCDO is a potent stimulator of cellular recovery in the spleen of sublethally irradiated mice.

Animals↗
PubMed1993

Dose-survival curves, alpha/beta ratios, RBE values, and equal effect per fraction for neutron irradiation of jejunal crypt cells.

Jejunal crypt cell survival after regimens of one, two, three and five fractions was used to reconstruct composite single-dose survival curves for neutrons of five different energies. There is no obvious shoulder, but there is a gradual divergence from linearity that is most evident at low levels of cell survival (high doses). The effect of dose fractionation is relatively small, especially at the low doses characteristic of each treatment session in neutron radiotherapy. The alpha/beta values for the linear-quadratic survival curves range from 27 to 40 Gy. The curves for neutrons are different from the curves for gamma rays mainly in their alpha coefficients, as predicted by Kellerer and Rossi's theory of dual radiation action, but both alpha and beta values are higher the lower the mean neutron energy, which is not consistent with the theory. The ratio of alpha coefficients reported here for various neutron beams to those for gamma rays reported elsewhere ranges between 3.2 and 4.6. This range of values represents the maximum limits for RBEn/gamma values (at very low doses), and is sometimes referred to as RBEm. These values increase with decreasing neutron energy. The ratios of beta coefficients for neutron and gamma-ray survival curves were lower than the alpha ratios, ranging between 0.9 and 1.9, although not reliably distinguished from 1.0. Each of a series of equal dose fractions given at 3-h intervals produced a constant (logarithmic) decrease in cell survival as evidenced by the consistency of the estimate of cell survival from a certain single dose fraction, regardless of the level of cell survival (number of dose fractions) from which the estimate was made. Even more significant than the overlap of individual data points is the excellent fit of all the data to survival curves reconstructed on the assumption of an equal effect per fraction. An implication of these results is that, with neutrons, too little unrepaired injury persists at 3 h to influence the response to a subsequent exposure measurably.

Animals↗
PubMed1992

Alteration in myelin-associated proteins following spinal cord irradiation in guinea pigs.

The aim of this study was to investigate the pathological and cellular basis for radiation-induced myelopathy in guinea pigs by monitoring biochemical alterations in levels of myelin basic protein and 2',3'-cyclic nucleotide phosphohydrolase. Guinea pigs were irradiated to the lumbar region with various doses of neutrons or cobalt gamma irradiation. The ED50s for paralysis were 17.2 Gy and 67.5 Gy for neutron and cobalt irradiation, respectively, and was histologically associated with demyelination. In spinal cords taken from animals at the onset of paralysis myelin basic protein levels were decreased in direct relationship to the radiation dose. The lowest doses to cause paralysis led to a 25% decrease in MBP levels. In a separate experiment, alterations in MBP were measured in the spinal cords over the time period leading up to paralysis. Surprisingly, decreases in MBP were found immediately after the end of the 4 week irradiation period. These early changes in MBP were not markedly dose dependent and occurred with nonparalyzing doses. Dose-dependent decreases were found only just before the onset of paralysis. CNPase activity measured in the same specimens showed changes that were essentially similar to those for MBP. In the CSF, MBP levels were essentially constant until onset of paralysis. This study showed that demyelination, as assessed by the levels of the myelin-associated proteins MBP and CNPase, can occur soon after spinal cord irradiation but that profound dose-dependent changes are seen only immediately preceding the onset of paralysis. Although increases in MBP in the CSF were associated with the onset of radiation-induced myelopathy, its assay is unlikely to predict this complication of irradiation.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗
PubMed1991

Repopulation of mouse jejunal crypt cells.

The regenerative response to radiation of mouse jejunal crypt cells was investigated using a three fraction experiment. The time between the second and third fraction was varied between 5 and 60 h, and the dose in each of the three fractions was different. The data show that the onset of regeneration is within 14 h of the first dose and possibly earlier. The doubling time of the clonogenic cells during repopulation is estimated to be between 5 and 10 h, with the most likely value approximately 6 to 7 h. The data also show that the time course of repopulation in an acutely responding tissue depended in a complex way on the fractionation scheme. The implications of this for radiotherapy are that simple formulas are unlikely to be accurate predictors of acute effects in altered fractionation schemes. Detailed mathematical modelling of the data is undertaken using a model which consists of a single dose survival curve, a part to incorporate the regenerative response and a part to accommodate the delayed onset of regeneration. The model is shown to give a good, although not perfect, fit to the data. A mathematical derivation is given of the expected number of crypts following the 3 dose radiation schedule. This derivation takes into account the fact that any crypt could be denuded of cells prior to the final dose and hence not repopulate, and thus the formula given is necessarily more complex than previous formulas which were based on simpler models.

Animals↗
PubMed1991

Direct analyses of in vivo colony survival after single and fractionated doses of radiation.

Several methods are described for analysing the results of in vivo colony assays using the statistical procedure called maximum-likelihood analysis. The methods differ in the way in which they take into account possible sources of variability in the data. The methods described here for analysing microcolony data are direct methods, in that they use the observed colony counts rather than transformed (e.g. Poisson-corrected) data. Each method can be used to estimate the average number of surviving cells per tissue structure (e.g. per jejunal crypt) in a single dose group, together with 95% confidence intervals, or to fit cell-survival models to data from a range of dose groups (e.g. to obtain estimates of D0 or of the linear-quadratic parameters alpha and beta). Experimental microcolony data from murine jejunum, colon, and hair follicles irradiated in anagen (proliferative) or telogen (resting) phase have been analysed. Estimates of D0 have been derived from single-dose data and estimates of alpha, beta, and the initial number of clonogenic cells per structure have been derived from fractionation data. For hair follicles, the half-time of repair of sublethal radiation injury has also been derived from fractionation data.

Animals↗
PubMed1990

Alternating zinc-finger motifs in the human male-associated protein ZFY.

ZFY, a putative transcription factor encoded by the human Y chromosome, contains a distinctive two-finger repeat: odd-numbered and even-numbered CC/HH metal-binding motifs exhibit systematic alternation in sequence pattern. Such alternation, which is not generally observed in zinc-finger proteins, has also been described in an extensive family of Kruppel-like genes in Xenopus laevis and in the AIDS-associated human DNA-binding protein HIV-EP1. The strict conservation of a two-finger repeat among ZFY-, Kruppel- and HIV-related zinc-finger proteins suggests distinct mechanisms of protein-nucleic acid recognition. To test whether this sequence pattern reflects an underlying alternation in domain structure, we have synthesized and characterized single-finger peptides from the human ZFY gene. Remarkably, systematic differences in metal-dependent folding are observed in the circular dichroism spectra of even- and odd-numbered domains. Our results suggest the existence of distinct CC/HH finger submotifs, which may play different roles in nucleic acid recognition.

Amino Acid Sequence↗
PubMed1989

Adhesion formation in experimental chronic radiation enteropathy.

We have studied the late changes associated with radiation enteropathy in mice over a period of 224 days following single or split doses of gamma radiation delivered to the total abdomen (TAI). We focused on the importance of adhesion formation as a cause of strictures and gut-associated deaths following TAI. Gut-associated peritoneal adhesions were found in mice 2-7 months after receiving 13.5-17.5 Gy TAI and appeared to constitute the most consistent serious late effect of irradiation. There was a good correlation between adhesion formation and death for both the single and split-doses of radiation. Adhesions primarily involved the large gut, normally near the cecum. They appeared to result from serosal breakdown and were the major cause of partial gut obstruction. Submucosal fibrosis was present but seemed to be a comparatively minor cause of strictures. Local lymphoid hyperreactivity was also seen following TAI and may have contributed to the late sequelae. The complexity of the pathogenesis of chronic radiation enteropathy was indicated by finding three successive waves of non-scheduled deaths following TAI. The first wave (28-70 days) was not related to adhesion formation and may have been due to localized failure of mucosa to regenerate after irradiation with consequent ulceration. The second wave (98-140 days) occurred over the period when adhesion formation and fibrosis were most marked. In the third wave (168-224 days), the additional complication of fluid exudation was seen. Further experimentation is obviously needed to better define the complex pathogenesis of radiation enteropathy with dose and time after radiation but our data strongly support a multifactorial causation with an important role for adhesion formation in the disease complex.

Animals↗
PubMed1989

Role of the beta 93-100 determinant loop sequence in receptor binding and biological activity of human luteinizing hormone and chorionic gonadotropin.

The intercysteine loop sequence (93-100) in the beta-subunit has been postulated to be important for receptor binding and specificity in the glycoprotein hormones, LH and human CG (hCG). To demonstrate this directly, and to characterize the structural features essential for activity, we prepared a series of synthetic peptides and analogs incorporating this determinant loop region. Peptides were assayed for inhibition of labeled hCG binding to ovarian membrane receptors and stimulation of testosterone production in Leydig cells. Peptides with the native (93-100) sequence from hCG and hLH inhibited hCG binding half maximally at 2.18 and 2.62 x 10(-4) M, respectively, while the sequence from FSH was inactive. Isosteric substitution of Ala for Cys resulted in an inactive peptide, indicating that the (93-100) disulfide bridge is essential for activity. Optimal binding activity requires at least one net positive charge among the side chains, as shown by loss of activity in hybrid analogs with neutral or negative charges conferred by progressive replacement of Arg by Asp at 94 and 95 or by introduction of Asp at 96 and 97. Despite binding to receptors, the native sequence did not promote testosterone production at doses up to 10(-2) M. This contrasts with a second receptor binding sequence, beta (38-57) that activates testosterone production. There are differences between the (93-100) and (38-57) loop sequences in their chemical and physical properties, biological activity and antigenicity. While the cumulative evidence suggests that they associate with counterpart sites in alpha-subunit to form a topographical binding domain in the whole hormone, our results suggest that each sequence may contribute in different ways to activation of postreceptor events.

Amino Acid Sequence↗
PubMed1989

Comparison of the gastrointestinal syndrome after total-body or total-abdominal irradiation.

In pathogen-free mice, but not standard conventionally housed laboratory rodents, two distinctly different modes of early radiation lethality can be identified by modifying the irradiation technique (total-body versus abdominal irradiation) or by therapeutic intervention such as rescue of total-body-irradiated mice with syngeneic bone marrow or spleen. While damage to the gastrointestinal tract is usually designated as the predominant cause of death occurring within 10 days of radiation exposure, it was demonstrated that damage to the hematopoietic/lymphopoietic system can result in animal lethality over the same period as the gastrointestinal syndrome and that this target cell population is more radiation-sensitive than the gastrointestinal epithelium.

Abdomen↗