Multiple tritylation: a convenient route to polysubstituted derivatives of cyclomaltohexaose.
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Carbohydrate Conformation↗
Biomedical subjects
C C Ling
Publications and source records attributed to C C Ling.
High dose rate gynecological applications--radiobiological considerations based on the alpha-beta model.
We compare the relative efficacy of high dose rate (HDR) and low dose rate (LDR) irradiation in gynecological implants, using formulations based on the linear-quadratic (alpha-beta) model. We consider both acute reaction and late effect as endpoints in evaluating equivalence for HDR and LDR treatments, at Point A (as defined in the text) and at other locations. We define a therapeutic factor gamma as an index for relative efficacy, with gamma > 1 indicating a gain in substituting HDR for LDR. It is found that gamma < 1 for most clinical situations, although a modest decrease (of about 15%) in dose to critical organs for HDR would raise gamma above unity.
Brachytherapy↗
Permanent implants using Au-198, Pd-103 and I-125: radiobiological considerations based on the linear quadratic model.
Based on the linear-quadratic model, we perform calculations to compare the possible radiobiologic results achieved with permanent implants using Au-198, Pd-103, and I-125. We examine the influence of the radiobiophysical parameters (i.e. alpha, beta, SLD repair kinetics, tumor doubling time (Tp), tumor growth delay, and prescribed dose) on the calculated radiobiologic indices or endpoints. The radiobiologic indices or endpoints include the effective treatment time (Teff) (beyond which the additional dose delivered is wasted), the biologically effective dose (BED), and cell surviving fractions. Within the range of reported values of the various parameters, Tp is the most significant in affecting Teff, BED, and the degree of cell inactivation. The effect of Tp and Teff and BED is larger for isotopes with longer half-lives, for which the rate of tumor regrowth is more important. For Tp of 5 to 30 days, the Teff are 14 to 21 days for Au-198, 58 to 102 days for Pd-103, and 120 to 275 days for I-125. For this range of Tp, the wasted doses are less than 5% for Au-198, 15 to 3% for Pd-103, and 30 to 5% for I-125. For reference prescription doses of 60, 120, and 160 Gy for implants using Au-198, Pd-103, and I-125, respectively, the BED and the associated cell-kill is the lowest for Au-198, whereas Pd-103 and I-125 implants are more effective for fast-growth (Tp less than 10 days) and slow-growth (Tp greater than 10 days) tumors, respectively.
Brachytherapy↗
Rat embryo cells immortalized with transfected oncogenes are transformed by gamma irradiation.
Cesium-137 gamma rays were used to transform rat embryo cells (REC) which were first transfected with activated c-myc or c-Ha-ras oncogenes to produce immortal cell lines (REC:myc and REC:ras). When exposed to 6 Gy of 137Cs gamma rays, some cells became morphologically transformed with focus formation frequencies of approximately 3 x 10(-4) for REC:myc and approximately 1 x 10(-4) for REC:ras, respectively. Cells isolated from foci of gamma-ray-transformed REC:myc (REC:myc:gamma) formed anchorage-independent colonies and were tumorigenic in nude mice, but foci from gamma-ray-transformed REC:ras (REC:ras:gamma) did not exhibit either of these criteria of transformation. Similar to the results with gamma irradiation, we observed a sequence-dependent phenomenon when myc and ras were transfected into REC, one at a time. REC immortalized by ras transfection were not converted to a tumorigenic phenotype by secondary transfection with myc, but REC transfected with myc were very susceptible to transformation by subsequent ras transfection. This suggests that myc-immortalized cells are more permissive to transformation via secondary treatments. In sequentially transfected REC, myc expression was high whether it was transfected first or second, whereas ras expression was highest when the ras gene was transfected secondarily into myc-containing REC. Molecular analysis of REC:ras:gamma transformants showed no alterations in structure of the transfected ras or of the endogenous ras, myc, p53, or fos genes. The expression of ras and p53 was increased in some isolates of REC:ras:gamma, but myc and fos expression were not affected. Similarly, REC:myc:gamma transformants did not demonstrate rearrangement or amplification of the transfected or the endogenous myc genes, or of the potentially cooperating Ha-, Ki-, or N-ras genes. Northern hybridization analysis revealed increased expression of N-ras in two isolates, REC:myc:gamma 33 and gamma 41, but no alterations in the expression of myc, raf, Ha-ras, or Ki-ras genes in any REC:myc transformant. DNA from several transformed REC:myc:gamma cell lines induced focus formation in recipient C3H 10T1/2 and NIH 3T3 cells. The NIH 3T3 foci tested positive when hybridized to a probe for rat repetitive DNA. A detailed analysis of the NIH 3T3 transformants generated from REC:myc:gamma 33 and gamma 41 DNA failed to detect Ha-ras, Ki-ras, raf, neu, trk, abl, fms, or src oncogenes of rat origin.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Improved dose distributions for 3D conformal boost treatments in carcinoma of the nasopharynx.
This study was designed to demonstrate the feasibility of 3-dimensional (3D) treatment planning in patients with carcinoma of the nasopharynx, and to explore its potential therapeutic advantage over the traditional 2-dimensional (2D) approach in this disease. Qualitative and quantitative comparisons between the two techniques were made for the boost portion of the treatment (19.8 Gy of a total 70.2 Gy treatment schedule) in 10 previously untreated patients and for the entire treatment in 5 patients with locally recurrent disease. The 2D and 3D plans were compared in each patient using dose-volume histograms (DVH's), tumor control probabilities (TCP's), normal tissue complication probabilities (NTCP's), and a new biologic figure of merit that describes the probability of uncomplicated control. Although there was no attempt to optimize the 3D treatment approach by using this method throughout the total treatment course (rather than for the boost only), it was still found that for each of the endpoints examined the 3D approach resulted in improved plans. An average of 22% of the target volume was underdosed at the 95% isodose level with the 2D plans compared to 7% with the 3D plans. The improved treatment planning by 3D increased the mean dose to the tumor volume by an average of 13% over 2D planning. The dose to normal structures such as the mandible and parotid glands was reduced with the 3D plans while the brain stem and spinal cord remained within tolerance limits. The probability of uncomplicated tumor control was increased by an average of 15% with 3D treatment planning compared to the 2D approach. Our findings demonstrate the potential of 3D planning for improving the treatment of carcinoma of the nasopharynx, but prospective studies are required to define the true clinical advantages of this methodology.
Humans↗
Clinical implications of I-125 dosimetry of bone and bone-soft tissue interfaces.
The dose to bone from I-125 photon interactions is expected to be approximately five times greater than the dose to soft tissue for the same photon fluence because of the dominance of the photoelectric effect. However, adverse clinical effects are not observed for I-125 implants near bone. Both the strong absorption of I-125 photons in bone and the narrowness (about 10 mu) of the high dose transition zone at a bone-soft tissue interface act to limit the volume of radiation sensitive tissue in the high dose region. Examples of calculated implant dose distributions in bone and in soft tissue cavities in bone are presented. Radiobiological measurements are consistent with the theoretical interface calculations. Calculation of the macroscopic dose distribution uses a recently measured radial dose function, while at the bone-soft tissue interface an analytic theory of the transition zone that is applicable to regular shaped cavities is used. Radiobiological experiments comparing cell survival for cells irradiated with 70 kvP X rays at Al-water and polystyrene-water interfaces are consistent with the transition zone calculations.
Bone and Bones↗
The biological basis for conformal three-dimensional radiation therapy.
The recent introduction of new computer technology for treatment planning and computer-driven treatment delivery systems, such as multi-leaf collimators and on-line verification systems, has accelerated the development of 3-dimensional (3-D) radiation therapy as a modality for curative cancer treatment. The goal of 3-D treatment planning is to conform the spatial distribution of the high radiation dose to the shape of the tumor contour while concomitantly decreasing the volume of the surrounding normal tissues receiving high radiation doses. The improved precision of tumor coverage and the exclusion of normal tissues should permit tumor dose escalation and may enhance local tumor control. It has been suggested that any survival gains derived from improvements in local control may be offset by the subsequent appearance of distant metastases arising from micrometastases already present at the time of initial diagnosis. However, clinical and laboratory studies indicate that failure to control the primary tumor at the time of initial treatment significantly increases the incidence of metastatic dissemination. This phenomenon is consistent with the hypothesis that the enhanced mitotic activity associated with the re-growth process of locally recurring primary tumors promotes the multi-step transformation of non-metastatic tumor cells into clonogens with metastatic potential, leading to increased overall rates of metastatic disease. These biologic considerations provide support for the need to focus attention on the identification of more effective therapeutic strategies designed to eradicate the primary local tumor completely at the time of initial therapy and serve as the rationale for clinical studies using 3-D conformal radiation therapy.
Humans↗
CT-based optimized planning for transperineal prostate implant with customized template.
A computerized planning procedure has been developed for CT-guided transperineal prostate implants. The segment for custom planning of perineal needle orientations allows placement of I-125 seeds in the entire prostate gland while avoiding the pubic bones. Least-squares optimization (LSO) is used to obtain the seed-loading pattern along the needles. The optimized seed distribution produces a better fit between treatment and target volumes than that obtained from our previous manual technique. Also, the present semi-automatic technique reduces planning time by about a factor of 10 compared to that of the manual approach.
Brachytherapy↗
Enhancement of SR 2508 (etanidazole) radiosensitization by buthionine sulphoximine at low-dose-rate irradiation.
SR 2508 (etanidazole) (1 mM) or buthionine sulphoximine (BSO, 50 microM) or both drugs together did not radiosensitize oxic V79 Chinese hamster cells irradiated at either an acute dose rate (2.35 Gy/min) or at a low dose rate (0.117 Gy/min). BSO pretreatment (15 h at 37 degrees C) depleted cellular glutathione (GSH) to less than or equal to 1% of control level and radiosensitized hypoxic cells at both dose rates with an enhancement ratio (ER) of 1.2. SR 2508 alone radiosensitized hypoxic cells equally at both dose rates with an ER of 1.5. However, ER values of 2.2 and 2.5 were obtained with 1 mM SR 2508 in GSH-depleted cells at acute and low dose rate, respectively, with no significant difference between the two, i.e. there is no dose rate dependence for this potentiation. Since BSO increases SR 2508 radiosensitization and the combined BSO + SR 2508 treatment is extremely cytotoxic to hypoxic cells, our results suggest that combining BSO with SR 2508 will be useful in brachytherapy as well as external-beam therapy if the toxicity from both drugs in vivo is less than the gain in radiosensitization achieved.
Animals↗
Three-dimensional conformal treatment: a new frontier in radiation therapy.
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Dose-Response Relationship, Radiation↗
Sensitization of low-dose-rate irradiation by nonlethal hyperthermia.
To assess whether hyperthermia could radiosensitize cells irradiated at a low dose rate, Chinese hamster V79 cells were simultaneously heated and irradiated at 0.86 Gy/h. The data showed that heat treatments at 39 and 40 degrees C, which did not induce heat killing alone or high-dose-rate radiosensitization, resulted in enhanced cell killing with low-dose-rate irradiation. The dose-modification factor (ratio of the slopes of the curves for low dose rate and high dose rate) was reduced to 1.8 at 39 degrees C and 1.4 at 40 degrees C, compared to a value of 2.1 at 37 degrees C. These data indicate that nonlethal heat treatments can cause enhanced radiosensitization under low-dose-rate conditions. The implications of these results for interstitial thermoradiotherapy are discussed.
Animals↗
Thermal response of oncogene-transfected rat cells.
Rat embryo cells or Rat-1 fibroblasts were transfected with either an activated c-myc or a c-Ha-ras from the T24/EJ bladder carcinoma, or they were cotransfected with both. A gene conferring neomycin or hygromycin resistance was also cotransfected so that independent cell lines could be selected by growth in medium containing the antibiotic. Certain isolates from cells transfected with only one type of oncogene were further transformed by exposure to 600 cGy of 250-kVp X-rays. Successful transfection and transformation were characterized by altered morphology, increased plating efficiency, shorter doubling time, longer life span, foci formation, anchorage-independent growth, and Southern and Northern hybridization analysis. The thermal response of these cells at different stages of oncogenic transformation was examined by exposing exponentially growing cells to 45 degrees C for 0 to 45 min and measuring cellular survivals using colony formation assay. We found that cells transfected with myc oncogene, singly or in combination with ras, were more sensitive to thermal stress. Aside from that, the cells' thermal sensitivity was not affected by the degree or the nature of transformation.
Animals↗
Synergistic effect of the v-myc oncogene with H-ras on radioresistance.
Resistance of tumors to irradiation or chemotherapeutic agents is thought to be one of the reasons why patients who present with early malignancies may not be cured. Much is now known about the molecular mechanisms that underlie drug resistance, but until recently little was known about genetic contributions to radiation resistance. Some evidence now links oncogenes, particularly the ras family of oncogenes, to radiation resistance but heterogeneity between tumors and cell lines has complicated this analysis. Primary rat embryo cells have been chosen as a model system in which the effects on radiation resistance of the H-ras oncogene could be studied on a uniform genetic background. These cells offer several useful advantages. The cells prior to transformation are diploid, and because they have been in culture only for a few passages prior to transformation with the oncogene it is unlikely that any preexisting mutation affecting radiation response could be present. Additionally, the use of rat embryo cells permitted the study of the effects of a second oncogene on the appearance of the radioresistant phenotype. The results show that the activated H-ras oncogene is associated with radiation resistance in primary rat cells after transformation but that the effect of the oncogene by itself is small. However, the oncogene v-myc, which has no effect on radiation resistance by itself, has a synergistic effect on radiation resistance with H-ras. There appear to be differences in the phenotype of radiation resistance associated with these two forms of transfectants. Thus, radiation resistance seen with H-ras by itself is characterized by a change in the slope of the radiation survival curve at high radiation doses but little or no change within the should region of the radiation survival curve. Radiation resistance seen in H-ras plus v-myc transformants is also characterized by an increase in the slope of the curve at high doses but there is also a large effect within the shoulder region of the radiation survival curve. These studies led to the following conclusions: (a) the radioresistant phenotype is not due to preexisting genetic heterogeneity in the cells prior to transfection; (b) the radiation resistant phenotype of cells transformed by H-ras is seen to a greater degree in cells which also contain the v-myc oncogene; (c) the v-myc oncogene may play an important role in the phenotype of radiation resistance at low doses that is within the range most critical for clinical practice.
Animals↗
Glutathione depletion and cytotoxicity of buthionine sulphoximine and SR2508 in rodent and human cells.
SR2508 (1 mM) increases the rate of glutathione (GSH) depletion by L-buthionine-S-R-sulphoximine (BSO) in hypoxic V79 rodent and A549 human cells. Specifically, the GSH content for V79 and A549 cells, after incubating for about 6 hr with 50 and 100 microM BSO, respectively, was lower by at least 10-fold when 1 mM SR2508 was present. In addition, 1 mM SR2508 is extremely toxic to hypoxic cells with lower GSH content. Survival probabilities of GSH-depleted V79 and A549 cells are about 10(-3) after 10 hr incubation with 1 mM SR2508. By itself, 1 mM SR2508 or 50-100 microM BSO decreased cellular viability by about 50% with a 10 hr treatment period. Both the phenomena described above are preferential towards hypoxic cells with minimal effect on aerobic cells.
Animals↗
The role of the H-ras oncogene in radiation resistance and metastasis.
The sensitivity of tumor cells to the killing effects of ionizing radiation is thought to be one of the major determinants of curability of tumors in patients treated with radiation therapy. This paper reviews the evidence from our laboratory and other groups which supports a role for oncogenes in the induction of radioresistance in cultured mammalian cells. Primary rat embryo cells (REC) were chosen as a model system in which the effects on radiation resistance of the H-ras oncogene could be studied on a uniform genetic background. These cells offered several useful advantages. The cells prior to transformation are diploid and because they have been in culture only for a few passages prior to transformation with the oncogene it is unlikely that any preexisting mutation affecting radiation response could be present. Additionally, the use of REC permitted the study of the effects of synergism between oncogenes on the induction of the radioresistant phenotype. The results show that the activated H-ras oncogene induces radiation resistance in primary rat cells after transformation, but that the effect of the oncogene itself is small. However, the myc oncogene, which has no effect on radiation resistance by itself, appears to have a synergistic effect on the induction of radiation resistance by H-ras. Radiation resistance induced by H-ras plus myc is characterized by an increase in the slope of the curve at high doses but there is also a large effect within the shoulder region of the radiation survival curve. The AdenoE1A oncogene which will also act synergistically with ras in transformation assays plays a less clear-cut role in assays of radiation resistance. The H-ras oncogene is also known not only to transform cells but also to induce metastatic behavior in the tumors which form after these transformed cells are injected into syngeneic animals or nude mice. We have also shown in our primary rat embryo cell system that the induction of metastatic behavior in transformed cells, like the induction of radioresistance depends on a complex interaction between oncogenes and the cellular background. This evidence will be reviewed to demonstrate some of the analogies between radiation resistance and metastasis as examples of the complex alterations in cellular phenotype which occur after oncogene transfection.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Computer assisted treatment planning for 125I ophthalmic plaque radiotherapy.
This paper describes a computer program for planning the treatment of ocular tumors with 125I plaques. The program permits the input of the tumor configuration into a model eye and facilitates the viewing of the relative geometry of the tumor and various eye structures in different perspectives. Custom-designed 125I plaques can be localized onto the globe, and dose distributions can be calculated and superimposed on the eye structures in any plane or on the inner eye surface. The program allows efficient evaluation of the plaque design in terms of radiation dose distribution relative to the tumor and critical structures.
Brachytherapy↗
Radioresistance induced by oncogenic transformation.
Rat embryo cells at various stages of oncogenic transformation are obtained by a combination of X irradiation and transfection with the ras and the myc oncogenes. Transfection with either the ras or the myc oncogenes can lead to increased radioresistance, relative to the parental cells. X-ray-transformed clones of the transfected cells do not show additional alteration in radioresponse. Incorporation of the two oncogenes appears to lead to a higher degree of radioresistance.
Animals↗
Repair of radiation induced damage--dependence on oxygen and energy status.
Repair of radiation-induced sublethal damage by Chinese hamster V-79 cells is studied under conditions of different pO2 (15 ppm to 21%) and cellular energy status. Cellular ATP content and energy charge are drastically reduced when cells are deprived of both oxygen and nutrient. Both indices are within normal range when cells are provided with nutrients or trace levels of oxygen (300 ppm). When deprived of nutrient, hypoxic (15 ppm O2) cells do not repair SLD, while cells in 300 ppm O2 do. Thus, cellular SLD repair appears to be dependent on cellular energy status which in turn is sensitive to oxygen concentration. Relatedly, nutrient deprived hypoxic cells are sensitized to radiation with storage under 23 degrees C, a phenomenon which may stem from a decrease of endogenous glutathione content.
Animals↗