Pulsed dose rate brachytherapy: can we take advantage of new technology?
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Brachytherapy↗
Biomedical subjects
E J Hall
Publications and source records attributed to E J Hall.
Fused pyrazine mono-n-oxides as bioreductive drugs. II Cytotoxicity in human cells and oncogenicity in a rodent transformation assay.
PURPOSE: To determine what structural moieties of the fused pyrazine mono-N-oxides are determining factors in their in vitro cytotoxicity and oncogenicity. METHODS AND MATERIALS: A new series of experimental bioreductive drugs, fused pyrazine mono-N-oxides, was evaluated in vitro for aerobic and hypoxic cytotoxicity in the HT29 human colon adenocarcinoma cell line by using clonogenic assays. The relative oncogenicities of these compounds were also determined in aerobic cultures of C3H 10T1/2 mouse embryo fibroblasts by using a standard transformation assay. RESULTS: Removal of the 4-methyl piperazine side chain from the parent compound, RB 90740, reduced the potency of the hypoxic cytotoxin. Reduction of the N-oxide function increased the aerobic cytotoxicity and eliminated most of the hypoxic/aerobic cytotoxic differential. The reduced N-oxide also had significant oncogenicity, consistent with a mechanism of genotoxicity following bioreduction of RB 90740. CONCLUSION: This new series of bioreductive compounds may be effective in cancer therapy, particularly the lead compound RB 90740. The oncogenic potential of these compounds is similar to that for other cancer therapies. Further studies should include evaluation of these compounds in vivo and the development of analogs with reduced oncogenic potential and retention of the hypoxic/aerobic cytotoxicity differential.
Animals↗
Neutrons and carcinogenesis: a cautionary tale.
The best estimates for radiation induced cancer and leukemia are based on the Japanese survivors of Hiroshima and Nagasaki. With the earlier dosimetry systems of the 1960s, it was possible to drive an RBE (relative biological effectiveness) for neutrons from the Japanese data, because it was thought that there was a significant neutron dose at Hiroshima compared with Nagasaki. The estimated RBE of about 20 was consistent with laboratory estimates for oncogenic transformation in vitro and tumors in animals. The revised dosimetry of the 1980s [DS 86] essentially eliminated the neutron component at Hiroshima, and consequently removed the only neutron RBE estimate based on human data. However, recent neutron activation measurements indicate that there may indeed have been thermal neutrons at Hiroshima, and measurements of the ratio of inter- to intra-chromosomal aberrations in peripheral lymphocytes of survivors also tend to indicate that the biologically effective dose was dominated by neutrons. Another area in which the large biological effectiveness of neutrons assumes importance is the production of photoneutrons in high energy medical linear accelerators (Linacs). An increasing number of accelerators operating in the 18 to 20 MV range are coming into routine clinical use and at this energy, photoneutrons generated largely in the collimators result in a total body dose to the patient. The increased risk of second malignancies must be balanced against the slight improvement in percentage depth doses compared with more conventional machines operating at 6 to 10 MV, below the threshold for photoneutron production.
Cell Transformation, Neoplastic↗
Urinary excretion by dogs of intravenously administered simple sugars.
Seven simple sugars, commonly used in intestinal function tests, were simultaneously administered intravenously to dogs and their urinary excretion was measured to assess their potential for metabolic degradation. Lactose, lactulose and 3-O-methyl-D-glucose were excreted unchanged, but small proportions of palatinose and sucrose were not, and were assumed to have been metabolised. More than half of the administered D-xylose and a quarter of L-rhamnose was not excreted and was assumed to have been metabolised. These findings may be significant for the interpretation of differential sugar absorption tests and the D-xylose tolerance test.
3-O-Methylglucose↗
The biological effectiveness of radon-progeny alpha particles. V. Comparison of oncogenic transformation by accelerator-produced monoenergetic alpha particles and by polyenergetic alpha particles from radon progeny.
Generation of estimates of risk caused by exposure to radon in the home, either from miner data or from A-bomb data, requires several scaling factors such as for dose, dose rate and radiation quality, and possible synergisms. Such scaling factors are best developed from laboratory-based studies. Two possible sources of alpha particles for such studies are (1) a polyenergetic spectrum, generated directly by radon and its progeny, or (2) a series of monoenergetic alpha particles. We compare here the results of oncogenic transformation from studies using both systems. At the Columbia University Radiological Research Accelerator Facility (RARAF), C3H 10T1/2 cells were irradiated with alpha particles of various energies, with defined LETs from 70 to 200 keV/mum. At Pacific Northwest Laboratory, cells from the same stock were exposed to alpha particles from radon gas and its progeny, which were in equilibrium with the culture medium. There was good agreement between the results of oncogenic transformation experiments using the two different exposure systems. Apart from the experimental transformation frequencies themselves, such a comparison requires (1) reliable dosimetry at both facilities and (2) estimated LET distributions for the polyenergetic alpha-particle irradiator. Thus this good agreement gives some confirmation to the technique which is used to fold together oncogenic transformation rates from monoenergetic alpha particles to yield a predicted rate for a spectrum of alpha particles.
Alpha Particles↗
Oncogenic potential of bifunctional bioreductive drugs.
Potential oncogenicity must be a factor of concern in the design and development of novel bioreductive drugs. In the present studies, the cytotoxicity and oncogenic transforming potential of a series of heterocyclic mono-N-oxides, designed to be used as bioreductive drugs, were examined using the mouse C3H 10T1/2 cell system. Exponential phase cultures of 10T1/2 cells were treated with graded doses of the bioreductive drugs for a 4 h period, either in air or hypoxia, at 37 degrees C. After treatment, cultures were replated for both survival and transformation assays. The fused pyrazine mono-N-oxide RB 90740 and its N-deoxy analogue, RB 92816, demonstrated a dose-dependent cytotoxicity and oncogenic transforming potency under aerobic conditions. Similarly, the indoloquinone E09 and the structurally related mitomycin C demonstrated dose dependence in both toxicity and oncogenic transforming potential. The most cytotoxic aromatic-N-oxides tested, RB 92816, also demonstrated the highest oncogenic transformation incidence. In hypoxia, the bioreductive metabolites of RB 90740 were substantially more cytotoxic and induced a higher oncogenic transformation yield than the drug in air. These data are consistent with the structure-activity relationship for bioreductive drugs in that heterocyclic-N-oxides with reactive side chains such as RB 92816 are cytotoxic and potentially carcinogenic.
Animals↗
Photoneutrons from medical linear accelerators--radiobiological measurements and risk estimates.
PURPOSE: To assess the oncogenic potential of the photoneutrons produced by high energy medical linear accelerators. METHODS AND MATERIALS: An established line of cells of rodent origin (C3H 10T1/2) was used to assess the oncogenic potential of the radiation dose received in the breast of an anthropomorphic "randoman" phanton, while the cervix received a dose of 70 Gy. Experiments were performed at 6 MV, below the threshold for the production of photoneutrons, and at 20 MV where the dose includes about 0.01 Gy of photoneutrons as well as scattered x-rays. RESULTS: A significantly higher transformation incidence was observed for the 20-MV machine, consistent with the measured neutron dose of about 0.01 Gy and a quality factor of 20. CONCLUSION: An estimate can be made of the additional deaths from second malignancies that might result from the photoneutrons generated by higher energy linear accelerators (Linacs), which must be offset against the possible improvements in survival that might result from the higher tumor doses made possible by the increased percentage depth doses.
Animals↗
A convenient extension of the linear-quadratic model to include redistribution and reoxygenation.
PURPOSE: At present, the linear-quadratic model for cellular response to radiation can incorporate sublethal damage repair and repopulation. We suggest an extension, termed LQR, to include also the other two "Rs" of radiobiology, cell cycle redistribution, and reoxygenation. METHODS AND MATERIALS: In this approach, redistribution and reoxygenation are both regarded as aspects of a single phenomenon, which we term resensitization. After the first portion of a radiation exposure has decreased the average radiosensitivity of a diverse cell population by preferentially sparing less sensitive cells, resensitization gradually restores the average sensitivity of the population towards its previous value. The proposed LQR formula is of the same form as the original LQ formula, but with two extra parameters, an overall resensitization magnitude and a characteristic resensitization time. The LQR model assumes that resensitization is monotonic rather than oscillatory in time, i.e., always tends to increase average cellular sensitivity as overall time increases. We argue that this monotonicity assumption is likely to hold in clinical situations, though a possible extension is discussed to account for oscillatory decay of resensitization effects. RESULTS: The LQR model gives reasonable fits to relevant experimental data in the literature, reproducing an initial rise in cell survival, due to repair, as the treatment time is increased, followed by a resensitization-related decrease in survival due to redistribution and/or reoxygenation for treatment times of the order of the cell cycle time, and a final survival increase due to repopulation as the treatment time is increased still further. CONCLUSION: The LQR model is a simple and potentially useful extension of the LQ model for computing more realistic isoeffect relations for early responding tissues, including tumors, when comparing different radiotherapeutic protocols.
Animals↗
Potential reduced late effects for pulsed brachytherapy compared with conventional LDR.
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Brachytherapy↗
A stable isotope study of zinc kinetics in Irish setters with gluten-sensitive enteropathy.
The short-term kinetics of Zn turnover were studied in Irish setters with gluten-sensitive enteropathy and control dogs following intravenous injection of 0.25 mg 96.5% enriched 70ZnCl2. The 70Zn enrichment of serum was found closely to obey two-compartment kinetics and the derived two-compartment decay equation was used to calculate the size and turnover of the two initial rapidly exchanging pools of body Zn. In normal Irish setters isotopic Zn initially equilibrates with a pool (a) of size 1.27 (SD 0.46) mumol/kg and then with a second pool (b) of size 6.83 (SD 1.72) mumol/kg. The fractional turnover of pool (b) was approximately one eighth that of pool (a). Enteropathic dogs showed no reduction in the size of either rapidly exchangeable Zn pool, reduction in serum Zn concentration or abnormality in Zn balance and hence these results do not support the possibility of an underlying Zn deficiency in this disorder.
Animals↗
Intestinal permeability testing in dogs with diet-responsive intestinal disease.
Fifteen dogs with signs of small and, or, large bowel disease that responded clinically to an exclusion diet were studied, using differential sugar absorption as an objective parameter of the mucosal response to the diet. Intestinal permeability and function were assessed by determining the urinary excretion ratios of lactulose/rhamnose and xylose/3-O-methylglucose, respectively, following oral administration of a mixture of these four sugars. Five dogs, all retrievers, were tentatively diagnosed as having dietary hypersensitivity, based upon resolution of clinical signs and normalisation of high intestinal permeability following an exclusion diet and recurrence of signs (in four of five dogs) upon challenge with the original diet. The fifth dog did not become symptomatic when challenged, but intestinal permeability increased. The remaining 10 dogs were diagnosed as having food intolerance, based upon clinical improvement on an exclusion diet, relapse on challenge with their original diet, but lack of improvement in intestinal permeability. These findings suggest that a differential sugar absorption test may be useful to determine the reasons for clinical response to exclusion diets. Demonstration of increased intestinal permeability with subsequent normalisation following an exclusion diet may be useful in the diagnosis of dietary hypersensitivity, while persistent abnormalities in intestinal permeability are suggestive of underlying intestinal disease and food intolerance.
Analysis of Variance↗
Neutron-induced cell cycle-dependent oncogenic transformation of C3H 10T1/2 cells.
Exposure of synchronized populations of mouse C3H 10T1/2 cells to a single dose (0.6 Gy) of 5.9 MeV neutrons at intervals after mitotic shake-off results in a distinctive variation in the oncogenic transformation frequency through the cell cycle. Previous findings show a sensitive window for X-ray-induced oncogenic transformants at late times after mitotic shake-off (14-16 h). Optimal sensitivity to neutrons was observed for cell populations irradiated soon after mitotic shake-off (4-6 h), where the majority of cells would be in the G1 phase of the cell cycle. Additionally, enhanced sensitivity was also found for that period after shake-off (14-16 h) which was maximally sensitive to X rays corresponding to cell populations with a high proportion of G2-phase cells. That is, low-LET radiation (250 kVp X rays) largely appears to produce oncogenic transformants in G2-phase cells, while intermediate-LET radiation (5.9 MeV neutrons) is effective principally on G1- and, to a somewhat lesser extent, G2-phase cells. Cells irradiated with neutrons showed less variation for lethality through the cell cycle than those irradiated with X rays, in agreement with previous findings. The mechanistic basis for the difference in the response of cells in the different phases of the cell cycle to radiations of different quality is unknown but is suggestive of distinct ("signature") molecular changes leading to the observed oncogenic transformation response.
3T3 Cells↗
The biological effectiveness of radon-progeny alpha particles. II. Oncogenic transformation as a function of linear energy transfer.
Epidemiological studies have established an association between exposure to radon and carcinoma of the lung. However, based on data for either lung cancer in uranium miners exposed to radon or bronchial epithelial carcinomas in Japanese A-bomb survivors, it has not been possible to assign estimates of risk of lung cancer for the general population exposed to radon in their homes. Based on past success with the excellent quantitative properties of the C3H 10T1/2 in vitro oncogenic transformation assay system, the relative biological effectiveness (RBE) for radiation-induced transformation for charged particles of defined LET has been determined. As the LET of the radiation was increased, the rate of induction of oncogenic transformation increased and the RBEm approached 20. At higher LETs, RBE dropped precipitously. The rapid drop in effectiveness for alpha particles with LETs between 120 and 265 keV/microns implies a lower quality factor than the 20-25 currently considered appropriate when estimating lung cancer mortality.
Alpha Particles↗
The biological effectiveness of radon-progeny alpha particles. III. Quality factors.
Domestic radon risk estimates are typically based either on data for uranium miners or on data derived from A-bomb survivors; comparison of domestic radon risk estimates derived from these two disparate sources represents an important test of their reliability. There is currently a significant discrepancy of about a factor of three between domestic radon risk estimates generated with these two independent methods. To base such risk estimates on the data for A-bomb survivors, who were exposed mainly to low-LET radiation, requires a quality factor for alpha particles from random progeny; the final risk estimate is then directly proportional to this quality factor. We have used the most extensive quantitative in vitro data set currently available at high LET for an oncogenic end point, to make the best estimate we can that could be used as a basis for a quality factor. Our best estimates of values appropriate for the quality factor for radom progeny are significantly lower than those currently used (20-25) in estimating lung cancer mortality due to randon. Specifically, our best estimate for home dwellers is around 10. In addition, because of the different geometry in the bronchial epithelia of nonsmokers compared to smokers, our best estimate of an appropriate quality factor for home dwellers is about 18% greater than that for miners; thus our best estimate of the "effective K factor" to convert to effective dose/WLM in home dwellers from effective dose/WLM in miners would be increased by this factor. Based on a quality factor of approximately 10, the dosimetrically based estimate of radon-induced mortality would be approximately 35,000 per year in the U.S. rather than the value of approximately 70,000 obtained using a quality factor of 20. The value of 35,000, while larger than the values based on data for miners (approximately 20,000), is much smaller than previous estimates of approximately 70,000 based on dosimetric methods; thus risk estimates based on the two approaches, dosimetric and epidemiological, may be partially reconciled. Finally, a quality factor of 10 would reduce the proportion of the collective effective dose caused by radon progeny from the currently accepted value of 55% down to about 38%.
Alpha Particles↗
The biological effectiveness of radon-progeny alpha particles. IV. Morphological transformation of Syrian hamster embryo cells at low doses.
Primary explants of Syrian hamster embryo (SHE) cells were exposed to either low-LET 250 kVp X rays or graded single doses of defined high-LET alpha particles (90, 100, 120, 150, 180 and 200 keV/microns), simulating those produced by radon progeny, and monitored for cell inactivation and oncogenic transformation. For the alpha particles the doses delivered ranged from 1 cGy to 1 Gy with an emphasis on doses less than 20 cGy, while for the X rays the doses ranged from 20 cGy to 4 Gy. The dose-response curves for cell killing by alpha particles approximated an exponential function of dose, whereas the X rays produced a curve with a shoulder characteristic of linear-quadratic relationships seen for low-LET radiations. The RBE at 10% survival varied between 3.6-7.0 depending on the LET of the alpha particles, with the RBEm ranging between 7-12. The most effective alpha particles were those with an LET of 120 keV/microns. All radiations produced initial increases in the frequency of morphological transformants, as a function of dose, with a rise to a maximum followed by a plateau in the response which was relatively constant at approximately 2-6 x 10(-3) transformants frequency, expressed per initial cell at risk, had a tendency to decline to parallel the cell survival response. Both the dose at which the maximum frequency of transformants was expressed and the initial slope of the dose-response relationship differed substantially between the different radiation qualities. Maximal transformation per initial cell at risk occurred at doses as low as 1-4 cGy for the 90 and 100 keV/microns particles with the maximum occurring at higher doses (to 16 cGy) as the LET increased toward 200 keV/microns. In contrast, the maximal transformation for 250 kVp X rays was at 50 cGy. The 90 and 100 keV/microns particles, with an RBEm of 60 and 37, respectively, based on the ratios of the initial slopes of the dose-response curves, were the most effective LETs in terms of the ability to induce morphological transformation of SHE cells. When expressed in terms of particle fluence, it appears that in the LET range of radon progeny approximately two to four particle traversals per nucleus are required per killing event, whereas it is at doses corresponding to less than one particle per nucleus that maximal oncogenic transformation is expressed.(ABSTRACT TRUNCATED AT 400 WORDS)
Alpha Particles↗
Molecular biology in radiation therapy: the potential impact of recombinant technology on clinical practice.
There is good evidence to believe that the most important lesion induced in deoxyribonucleic acid (DNA) by ionizing radiation is a double strand break. Two double strand breaks may interact and rejoin in three different ways. (a) To form a dicentric, which is a lethal event, and will lead to the death of the cell. (b) To form a symmetrical translocation, which may activate an oncogene, and result in, for example, a leukemia or lymphoma. (c) To result in a deletion, which may remove or inactivate a suppressor gene and result in, for example, a solid tumor. Genes identified in mammalian cells may be conveniently grouped into four families. Genes involved in the repair of radiation damage can greatly influence radiosensitivity. Molecular checkpoint genes hold damaged cells in G2 to check for the integrity of their chromosomes before allowing them to proceed into mitosis; consequently, an inactivated checkpoint gene can also result in increased radiosensitivity. Activated oncogenes are associated with only a small proportion of human cancers, and tend to be found more commonly in leukemias and lymphomas and less frequently with solid tumors. A reciprocal translocation is the most likely mechanism by which radiation may activate an oncogene. An inactivated or deleted suppressor gene is commonly associated with a wide range of human cancers. It is becoming increasingly evident that many common cancers do not arise randomly in the population, but that subgroups of individuals are particularly susceptible. The challenge of recombinant technology is that in the near future it may well be possible to determine at birth the susceptibilities of a given individual by identifying mutations in key genes. This is the revolution and challenge we face in the treatment of cancer.
Amino Acid Sequence↗
Sublethal damage repair rates--a new tool for improving therapeutic ratios?
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Animals↗
Optimizing the time course of brachytherapy and other accelerated radiotherapeutic protocols.
PURPOSE: It is likely that early-responding tissues, such as tumors, repair sublethal damage more rapidly than do late-responding tissues. This difference can be exploited to design protocols with a significantly improved therapeutic advantage for accelerated radiotherapeutic regimens, including brachytherapy. METHODS AND MATERIALS: The time course of potential protocols is computer optimized, maximizing the therapeutic difference between tumor-control probability (TCP), and normal-tissue complication probability (NTCP). These quantities are evaluated with the linear-quadratic model, using clinically derived parameters. The optimization is performed by individually adjusting doses in different parts of the treatment, maximizing the therapeutic advantage. In the main calculations, half times for damage repair were T1/2(late) = 4 h, T1/2(early) = 0.5 h. Two component (fast/slow) repair processes were also investigated. RESULTS: Protocols determined by optimization have significantly greater therapeutic advantage than continuous low-dose rate (CLDR) protocols of the same overall dose and time. The optimized protocols are either (a) acute-dose/gap/CLDR/gap/acute-dose; or (b) a series of acute doses separated by 3-4 h. As a typical example, results are given for 60 Gy/120 h CLDR brachytherapy, which is assumed to give NTCP = 0.2 and TCP = 0.8. Under our assumptions, optimized regimes, with the same overall time and dose, produce an NTCP of approximately 0.11 and TCP of approximately 0.83, a significant therapeutic gain over CLDR. CONCLUSION: Difference in repair rates between early- and late-responding tissues can be exploited to produce clinically practical protocols that are significantly superior to current regimens. Such optimized protocols produce slightly better tumor control than CLDR with the same overall dose and time, significantly less late damage, and similar early normal-tissue sequellae. Temporal optimization, thus, promises to be a powerful tool in designing better treatment protocols.
Animals↗