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Results for “Radiosensitivity”

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PubMed2005

Unraveling the mechanism of radiosensitization by gemcitabine: the role of TP53.

Gemcitabine has excellent radiosensitizing properties, as shown in both preclinical and clinical studies. Radiosensitization correlated with the early S-phase block of gemcitabine. In the present study, we investigated the role of TP53 in the radiosensitizing effect of gemcitabine. Isogenic A549 cells differing in TP53 status were treated with gemcitabine during the 24 h prior to irradiation. Cell survival was determined 7 days after irradiation by the sulforhodamine B test. In addition, cell cycle perturbation was determined by flow cytometry and TP53 expression by Western blot analysis. Gemcitabine caused a concentration-dependent radiosensitizing effect in all cell lines. Transformed A549 cells were less sensitive to the cytotoxic effect of gemcitabine. The cell cycle arrest early in the S phase was dependent on the drug dose but was comparable in the different cell lines and was not related to functional TP53. Using isogenic cell lines, we have shown that neither TP53 status nor the transfection procedure influenced the radiosensitizing effect of gemcitabine. Since both the radiosensitizing effect at equitoxic concentrations and the cell cycle effect of gemcitabine were independent of TP53 expression, it is likely that TP53 protein does not play a crucial role in the radiosensitizing mechanism of gemcitabine.

Cell Cycle↗

PubMed1992

Chemical radiosensitizers in cancer therapy.

The development of effective low-LET radiation therapy for cancer has been hindered by the lack of consistent differential responses to radiation between tumor and normal tissues. One major difference between many solid tumors and the surrounding normal stroma is the presence of hypoxic foci in solid tumors due to the inadequate supply of nutritional needs as a result of the breakdown of microvasculature. Consequently, failure of conventional radiotherapy and local recurrences are in part attributed to the radioresistant hypoxic cell populations, present in the tumor. Local cure/control rates of a tumor can be increased only by an effective increase in the radiation dose. At the same time, an increase in such a dose would damage the oxic normal stroma, more than the hypoxic tumor cells. Hence, specific modification of tumor radiosensitivity by the use of chemical radiosensitizers, in combination with conventional radiotherapy, is an attractive alternative. Many clinicians and radiotherapists are skeptical about the outcome of using radiosensitizers in patients. Nevertheless, a vast amount of information is currently available regarding the first- and second-generation radiosensitizers both in murine and in human tumors. As a result, it is hoped that eventually a radiosensitizing drug would be discovered/synthesized that will overcome the drawbacks so far encountered in their use in the clinic. In this article, the development of chemical radiosensitizers since the early sixties, the basis for their selection, their mechanism(s) of action, and the results obtained with the various groups of radiosensitizers are reviewed.

Animals↗

PubMedDate not supplied

The immunopotentiation effects of the bifunctional radiosensitizer KIN-806 in comparison with its analogs KIN-804 and KIN-844.

KIN-806 is one of the 2-nitroimidazole derivative hypoxic cell radiosensitizers. Its radiosensitizing effects and the degree of lung metastasis detected were evaluated and compared with its analogs KIN-804 and KIN-844. The immune reactions induced by these radiosensitizers were also analyzed. Female C3H/He mice and SCCVII tumor cells were used. Seventeen days after inoculation of SCCVII tumor cells into the animals, 0.4 g/kg of KIN-806, KIN-804, and KIN-844 was administered to each radiosensitizer group 30 min before 40 Gy was delivered as local irradiation. In each group, KIN-806, KIN-804, and KIN-844 markedly suppressed tumor regrowth in comparison with animals that received irradiation alone. There was no significant difference in the radiosensitizing effects among these three radiosensitizers. A marked suppression of lung metastasis and macrophage/T-lymphocyte infiltration into the tumor were observed only in the KIN-806-administered groups, regardless of the presence or absence of radiation therapy. It therefore appears likely that the lung metastasis suppression was caused by the immune reaction elicited by KIN-806, which is an excellent immunopotentiator as well as an effective radiosensitizer.

Animals↗

PubMed1999

Tumor radiosensitization by sustained intratumoral release of bromodeoxyuridine.

We have previously reported that the use of the polymer bis(p-carboxyphenoxy)propane-sebacic acid (20:80) for intratumoral delivery of cis-platinum in a mouse tumor model (RIF-1) potentiated the effects of acute and fractionated radiation. This mode of drug delivery seems particularly applicable to the administration of radiosensitizing drugs because an optimum concentration of radiosensitizer can be maintained in the tumor over the prolonged period required for fractionated radiation treatment. We have now investigated, in the same tumor model, radiosensitization by the thymidine analogue bromodeoxyuridine (BrdUrd). BrdUrd (20%, w/w) was incorporated into bis(p-carboxyphenoxy)propane-sebacic acid (20:80) and polymer rods containing the drug implanted in the RIF-1 tumor. Preliminary in vitro studies of the rate of release of BrdUrd from the polymer showed an initial rapid loss over 24 h, followed by a slower release extending over the next 5 days. In experiments in which tumor cells, which had incorporated BrdUrd in vivo from implanted polymer, were excised and a single cell suspension irradiated in vitro radiosensitization indicative of BrdUrd incorporation was associated mainly with an increase in the alpha constant for the linear quadratic model of cell survival. Radiosensitization was seen for tumor cells harvested between 5 and 10 days after polymer implant, a finding that is consistent with results of experiments in which the percentage of cells that had incorporated BrdUrd were measured by flow cytometry at various times after polymer/BrdUrd implant. The proportion of tumor cells positive for BrdUrd was 40-50% between 3 and 8 days after polymer implant. When tumors were irradiated in situ and response measured in terms of tumor growth delay (TGD), radiosensitization was not seen for an acute dose of 16.5 Gy. In contrast, significant radiosensitization was seen for fractionated treatments when polymer/BrdUrd was implanted 3 days before the first radiation dose. For a dose of 5 x 6 Gy, TGD was increased from 22 days for radiation alone to 27 days for radiation plus polymer implant. For 10 x 6 Gy fractions, TGD increased from 45-77 days for those mice in whom the tumor eventually regrew, whereas for 25% of the mice in this group the tumor volume was reduced to a point where it was no longer detectable and there was no recurrence for at least 120 days after treatment.

Animals↗

PubMed1999

Apoptosis as a predictor of paclitaxel-induced radiosensitization in human tumor cell lines.

Paclitaxel is a deterpene with antitumor activity against a variety of human neoplasms. Paclitaxel cytotoxicity is thought to derive mainly from a stabilization of microtubules as a result of enhanced tubulin polymerization that leads to an accumulation of cells in the mitotic (M) phase of the cell cycle. Because cells in this phase of the cell cycle are known to be radiosensitive, it was thought that paclitaxel, in addition to its direct toxicity, may also sensitize tumor cell populations to radiation. Studies evaluating the radiosensitizing potential of paclitaxel in cultured cells have been equivocal, with only approximately 50% of the tested cell lines showing radiosensitization. To explain this variability, we advanced the hypothesis that the ability of paclitaxel to radiosensitize cells may be inversely correlated to the efficiency with which it induces apoptosis. To test this hypothesis, we studied paclitaxel-induced apoptosis and radiosensitization in seven human tumor cell lines. Approximately one-half of these cell lines showed radiosensitization that was associated with a low apoptotic index (<20% after a 48-h treatment with 10 or 20 nM paclitaxel). The results suggest that the level of apoptosis, after paclitaxel treatment, may predict for paclitaxel-induced radiosensitization, and that it could be introduced as a parameter for the optimization of combined treatment protocols.

Antineoplastic Agents, Phytogenic↗

PubMed2000

Radiation-induced apoptosis and cell cycle alterations in human carcinoma cell lines with different radiosensitivities.

Radiosensitivity of examined human neoplastic cell lines was assessed with the aid of MTT assay. Differences between radiosensitive and radioresistant human neoplastic cell lines were as follow: a) radiation-induced apoptosis detected by flow cytometry was apparent in the most radiosensitive (i.e. CH-1 ovarian carcinoma cell line), but not in the radioresistant (i.e. SKOV-3 ovarian carcinoma) cell lines, b) radiation-induced G2/M arrest appeared early after irradiation (6 hours) in both the radioresistant SKOV-3 cells and in the radiosensitive CH-1 human ovarian carcinoma cell line, but a different pattern was observed 24 hours after irradiation with 2 Gy dose with G2/M arrest only in radiosensitive cell line. The radiosensitivity and resistance to radiation-induced apoptosis in the radioresistant human breast carcinoma MDA-MB-231 cell line were similar to those observed in SKOV-3 cells. These data suggest that radiation-induced apoptosis and cell cycle alterations can predict radiosensitivity at least in some examined human malignant cells in vitro.

Apoptosis↗

PubMed2000

Potential role of microvessel density in predicting radiosensitivity of T1 and T2 stage laryngeal squamous cell carcinoma treated with radiotherapy.

Curative radiotherapy is the first choice of therapy for T1 and T2 stage laryngeal squamous cell carcinoma (LSCC) patients to preserve their phonation. Patients with recurrent tumors who undergo salvage surgery require prolonged nasal feeding. Therefore, clinical interest has been focused on elucidating a predictive factor indicating which tumors are likely to be radiosensitive before radiotherapy. We analyzed the relations between radiosensitivity and clinicopathological factors (gender, tumor location, histological factors, and clinical tumor-node-metastasis stage), expression of apoptosis-related proteins (p53, bax, bcl-2), apoptotic index using the terminal deoxynucleotidyltransferase-mediated nick end labeling method, expression of cell proliferation-related proteins (Ki-67-labeling index and epidermal growth factor receptor overexpression) and microvessel density (MVD, vessels/field = 0.391 mm2) in biopsy specimens from 31 LSCC patients given radiotherapy (total radiotherapy dose of 52-70 Gy over 4-6.5 weeks). Univariate analysis revealed that tumors with a high MVD (> or =35 vessels/field) showed better radiosensitivity than those with a low MVD (<35 vessels/field, P = 0.008) and that a high Ki-67-labeling index (> or =40%) was weakly associated with radiosensitivity (P = 0.056). Multivariate analysis and Kaplan-Meier analysis showed that MVD alone had significant predictive power for radiosensitivity in T1 and T2 stage LSCCs after radiotherapy (P = 0.012, 0.0003, respectively). No significant association between clinicopathological factors, or of overexpression of p53, bax, bcl-2, epidermal growth factor receptor, or apoptotic index, with radiosensitivity was found. These results indicate that MVD is a potentially useful clinical factor predicting radiosensitivity for patients with early stage LSCCs before treatment.

Aged↗

PubMed2003

Inhibition of base excision repair potentiates iododeoxyuridine-induced cytotoxicity and radiosensitization.

5-Iodo-2'-deoxyuridine (IdUrd) is a halogenated thymidine analogue recognized as an effective in vitro and in vivo radiosensitizer in human cancers. IdUrd-related cytotoxicity and/or radiosensitization are correlated with the extent of IdUrd-DNA incorporation replacing thymidine. IdUrd cytotoxicity and radiosensitization result, in part, from induction of DNA single-strand breaks (SSB) with subsequent enhanced DNA double-strand breaks leading to cell death. Because base excision repair (BER) is a major DNA repair pathway for SSB induced by chemical agents and ionizing radiation, we initially assessed the role of BER in modulating IdUrd cytotoxicity and radiosensitization using genetically matched Chinese hamster ovary cells, with (AA8 cells) and without (EM9 cells) XRCC1 expression. XRCC1 plays a central role in processing and repairing SSBs and double-strand breaks. We found that EM9 cells were significantly more sensitive than parental AA8 cells to IdUrd alone and to IdUrd + ionizing radiation. The EM9 cells also demonstrate increased DNA damage after IdUrd treatment as evaluated by pulse field gel electrophoresis and single cell gel electrophoresis (Comet Assay). BER-competent EM9 cells, which were stably transfected with a cosmid vector carrying the human XRCC1 gene, showed responses to IdUrd similar to AA8 cells. We also assessed the role of methoxyamine, a small molecule inhibitor of BER, in the response of human colon cancer cells (HCT116) to IdUrd cytotoxicity and radiosensitization. Methoxyamine not only was able to increase IdUrd cytotoxicity but also increased the incorporation of IdUrd into DNA of HCT116 human colon cancer cells leading to greater radiosensitization. Thus, a genetic or biochemical impairment of BER results in increased IdUrd-induced cytotoxicity and radiosensitization in mammalian cells.

Animals↗

PubMed2003

2-Deoxy-D-glucose-induced cytotoxicity and radiosensitization in tumor cells is mediated via disruptions in thiol metabolism.

Exposure to ionizing radiation is believed to cause cell injury via the production of free radicals that are thought to induce oxidative damage. It has been proposed that exposure to agents that enhance oxidative stress-induced injury by disrupting thiol metabolism may sensitize cells to the cytotoxic effects of ionizing radiation. Recently, it has been shown that glucose deprivation selectively induces cell injury in transformed human cells via metabolic oxidative stress (J. Biol. Chem., 273: 5294-5299; Ann. N.Y. Acad. Sci., 899: 349-362), resulting in profound disruptions in thiol metabolism. Because 2-deoxy-D-glucose (2DG) is a potent inhibitor of glucose metabolism thought to mimic glucose deprivation in vivo, the hypothesis that exposure to 2DG might be capable of inducing radiosensitization in transformed cells via perturbations in thiol metabolism was tested. When HeLa cells were exposed to 2DG (4-10 mM) for 4-72 h, cell survival decreased (20-90%) in a dose- and time-dependent fashion. When HeLa cells were treated with 6 mM 2DG for 16 h before ionizing radiation exposure, radiosensitization was observed with a sensitizer enhancement ratio of 1.4 at 10% isosurvival. Treatment with 2DG was also found to cause decreases in intracellular total glutathione content (50%). Simultaneous treatment with the thiol antioxidant N-acetylcysteine (NAC; 30 mM) protected HeLa cells against the cytotoxicity and radiosensitizing effects of 2DG, without altering radiosensitivity in the absence of 2DG. Furthermore, treatment with NAC partially reversed the 2DG-induced decreases in total glutathione content, as well as augmented intracellular cysteine content. Finally, the cytotoxicity and radiosensitizing effects of 2DG were more pronounced in v-Fos-transformed versus nontransformed immortalized rat cells, and this radiosensitization was also inhibited by treatment with NAC. These results support the hypothesis that exposure to 2DG causes cytotoxicity and radiosensitization via a mechanism involving perturbations in thiol metabolism and allows for the speculation that these effects may be more pronounced in transformed versus normal cells.

Acetylcysteine↗

PubMed2003

Prediction of tumor radiosensitivity in rectal carcinoma based on p53 and Ku70 expression.

The identification of predictive indicators of radiosensitivity is extremely useful in selecting patients suited for preoperative radiotherapy and avoiding unnecessary preoperative treatment. In this study, we evaluated the possible role of the immunohistochemical expression pattern of p53 and Ku70 protein in determining tumor radiosensitivity in rectal cancer before preoperative irradiation. We examined pretreatment biopsy materials from 111 patients by immunohistochemistry. The expression pattern of p53 and Ku70 was evaluated for association with tumor radiosensitivity, which was defined according to the criteria of the Japanese Research Society for Cancer of the Colon and Rectum. There was a significant correlation between the expression pattern of p53 and tumor radiosensitivity (P = 0.045); Ku70 and tumor radiosensitivity (P < 0.001); and the combination of p53 and Ku70, and tumor radiosensitivity (P < 0.001). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy in both p53 and Ku70-positive cases for radioresistance were all superior to those of the group positive for p53 alone. In conclusion the examination of the combination of p53 and Ku70 may predict the radiosensitivity of rectal cancer before preoperative irradiation.

Adult↗

PubMed1992

Intrinsic radiosensitivity of normal human fibroblasts and lymphocytes after high- and low-dose-rate irradiation.

The existence of heritable radiosensitivity syndromes and clinical observations in radiotherapy patients suggests that human cellular radiosensitivity differs among individuals. We report here an in vitro study of radiosensitivity in 30 fibroblast and 29 lymphocyte cultures obtained from cancer patients and controls. In 25 cases, both fibroblasts and lymphocytes were obtained from the same donors. Fibroblasts were cultured from skin biopsy samples, and peripheral T-cell lymphocytes were cultured from blood. Clonogenic survival assays were performed by using high- and low-dose-rate irradiation; lymphocytes were in G0 phase and fibroblasts in confluent plateau phase. Various end points were calculated and compared (i.e., surviving fraction at 2 Gy, initial slope of the survival curve, and doses resulting in 10 and 1% survival, respectively). Depending on the end point, the coefficient of variation of the survival parameters ranged from 31 to 68% for lymphocytes and 21 to 41% for fibroblasts following high-dose-rate irradiation. Similar ranges were obtained after low-dose-rate irradiation. Variance analysis performed on replicate assays in cultures derived from the same patient showed that variation due to technical or sampling errors was significantly lower than variation between individuals (P = 0.00034 and 0.014 for fibroblasts and lymphocytes, respectively). No correlation was observed between the radiosensitivity of lymphocyte and fibroblast cultures derived from the same donors. We conclude that there is significant variation in normal cell radiosensitivity among individuals. On the other hand, comparisons of lymphocyte and fibroblast radiosensitivities suggest that tissue-specific characteristics, such as differentiation status, may variably modulate radiosensitivity.

Breast Neoplasms↗

PubMedDate not supplied

Evaluating the combination of molecular prognostic factors in tumor radiosensitivity in rectal cancer.

BACKGROUND/AIMS: The local recurrence ratio following surgery alone is higher in patients with rectal cancer than in those with colon cancer. Preoperative radiotherapy reduces the rate of local recurrence and improves the chances of survival in patients with resectable advanced rectal carcinoma. Identification of predictive indicators of radiosensitivity is useful in selecting patients best suited for preoperative radiotherapy and thus helps to avoid unnecessary preoperative treatment. We investigated whether the combination of Ku, p53, p21, and p16 predicted tumor radiosensitivity. METHODOLOGY: We studied 96 cases with advanced rectal carcinoma. In preradiation biopsy specimens of tumor samples, all immunoreactive nuclei of cells stained positive for Ku, p53, p21, and p16 were evaluated by immunohistochemistry. The expression of p53, p21 and p16 in more than 5% of tumor cells were defined as positive, whereas both Ku70 and Ku86 protein in more than 70% of such cells were defined as Ku positive. The expression patterns of Ku, p53, p21, and p16 were examined for association with tumor radiosensitivity, which was determined according to the criteria of histopathologic assessment of radiotherapy effects. RESULTS: Univariate analysis showed a correlation between the expression patterns of Ku, p53, p21, and p16 and tumor radiosensitivity, while multivariate analysis showed that the expression pattern of Ku and p16 significantly correlated with tumor radiosensitivity. The combination of Ku and p16, or Ku, p53, p21 and p16 was therefore a good predictive marker for tumor radiosensitivity. CONCLUSIONS: These findings tend to support the hypothesis that the combination of Ku, p53, p21, and p16 expression after radiotherapy can act as a marker for radiosensitivity. Further investigation is needed, as the number of cases in this study was limited.

Adult↗

PubMedDate not supplied

Gemcitabine as a radiosensitizer in undifferentiated tumors.

BACKGROUND: Gemcitabine (dFdC) may cause radiosensitization by specific interference with homologous recombination-mediated DNA double-strand break repair. The radiosensitizing effect of dFdC might be less in normal healthy tissue and more restricted to undifferentiated tumor cells, making it a tumor-selective radiosensitizer. Whether dFdC acts as a radiosensitizer in undifferentiated and well-differentiated rat tumors and on rat foot skin was tested. MATERIALS AND METHODS: Undifferentiated L44 lung tumors in BN rats, MLL prostate tumors in Copenhagen rats, and well-differentiated L42 lung tumors in WAG/Rij rats were used. The tumors were treated with a single X-ray dose, combined or not with dFdC (30 mg/kg) administered 24 h earlier. Tumor volume growth delay was the end-point used. In addition, rat foot skin was treated with a single dose of 22.5 Gy, with or without dFdC. The degree of skin damage was determined according to a scoring system. RESULTS: For tumor growth delay, the dose-enhancement ratios were 1.37 and 1.23-1.36 for the L44 and MLL tumors, respectively. No radiosensitization was observed for the well-differentiated L42 tumor and foot skin. CONCLUSION: Radiosensitization by dFdC was observed in the undifferentiated tumors, but not in the well-differentiated tumor and skin. Our data support further trials to evaluate the usefulness of dFdC as a radiosensitizer in undifferentiated tumors.

Animals↗

PubMed1991

Mechanism of radiosensitization by halogenated pyrimidines: effect of BrdU on cell killing and interphase chromosome breakage in radiation-sensitive cells.

The effect of BrdU incorporation on cell radiosensitivity as well as on the induction of chromosome damage by radiation was studied in plateau-phase xrs-5 cells using the premature chromosome condensation (PCC) method. It is well known that xrs-5 cells are sensitive to ionizing radiation and defective in the repair of radiation-induced DNA double-strand breaks, chromosome damage, and potentially lethal damage (PLD). Compared to repair-proficient CHO 10B cells, a reduction was observed in the overall BrdU-mediated radiosensitization in plateau-phase xrs-5 cells for the same degree of thymidine replacement. This finding is interpreted with a model for BrdU-induced radiosensitization advanced previously, in which two distinct components act to produce the overall radiosensitization observed. One component involves processes associated with the increase in initial damage (DNA and chromosome) production per unit absorbed dose and causes an increase in the slope of the survival curve, while the second component involves enhanced fixation of radiation-induced damage (PLD) and causes a reduction in the width of the shoulder of the survival curve. It is suggested that in plateau-phase xrs-5 cells, the deficiency in the repair of radiation-induced damage compromises BrdU-mediated radiosensitization by leaving active only the radiosensitization component that is associated with an increase in damage induction. Enhancement of cell killing by BrdU in plateau-phase xrs-5 cells resulted in a decrease in D0, the relative value of which was similar to the relative increase in the production of chromosome damage as measured by the PCC method. The relative values for the change in D0 and the production of chromosome aberrations were similar in plateau-phase CHO 10B and xrs-5 cells, suggesting that the physicochemical and/or biochemical processes associated with this phenomenon are the same in the two cell lines. Radiosensitization of a magnitude similar to that observed in exponentially growing CHO 10B cells was induced by BrdU in exponentially growing xrs-5 cells. This effect is attributed to a partial expression of the repair gene (transiently during S phase in all cells, or throughout the cycle in a fraction of cells) that permits some repair of radiation-induced damage and which is compromised by BrdU.

Animals↗

PubMed1990

Heat radiosensitization and the level of DNA polymerases alpha and beta of human colony-forming unit-granulocyte-macrophage and myeloid leukemias sensitive and resistant to chemotherapeutic agents.

In these studies, heat radiosensitization in normal human colony-forming unit-granulocyte-macrophage (CFU-GM) and several different leukemic cell lines sensitive or resistant to chemotherapeutic agents were measured. Extent of heat radiosensitization was then correlated with the level of DNA polymerases alpha and beta in control and heat-shocked cells in order to examine whether there is a positive correlation between the degree of heat radiosensitization and the level of these enzymes. Our results show that human bone marrow CFU-GM have an x-ray response with D0 of 1.56 Gy and a small amount of heat radiosensitization with a thermal enhancement ratio (TER) of 1.2. K562, a human erythroleukemic cell, showed a D0 of 1.32 +/- 0.2 Gy and TER of 1.4. However, in contrast to normal CFU-GM which showed no shoulder in the X-ray survival curve, K562 cells showed a small shoulder with a quasi-threshold dose, (Dq) of 2 Gy and n of 2. K562 cells resistant to chemotherapeutic drugs such as 1-beta-D-arabinofuranosylcytosine and etoposide (VP-16) showed D0 of 1.47 +/- 0.13, and 1.77 +/- 0.18 Gy; Dq of 4 and 0 Gy; and n of 5 and 1; and TER of 1.6 and 2, respectively. The level of DNA polymerases alpha and beta activity and their respective mRNA levels were approximately the same in all cells. The reduction in the level of DNA polymerase beta after heat treatment however, correlated with the TER obtained for various leukemic cells. These studies indicate that normal CFU-GM and variety of human leukemic cells show only a small amount of heat radiosensitization. However, drug-resistant leukemic cells show a higher amount of heat radiosensitization than their drug-sensitive parent line. This suggests that hyperthermia may be beneficial in eradicating drug-resistant leukemic cells when combined with X-ray. Furthermore, the inactivation of DNA polymerase beta activity results in a higher amount of heat radiosensitization.

Blotting, Northern↗

PubMed1989

[Analysis of tumor curability in terms of cellular radiosensitivity and its application to physico-chemical therapy modes].

Analysis of curability of multicellular spheroids (a model of solid tumor) in terms of cellular radiosensitivity showed that radiosensitivity of spheroids is determined by four factors; total cell number, two parameters (mean lethal dose and extrapolation number) of cellular radiosensitivity and critical cell number. For example, an increase of cell number and two parameters make spheroids more radioresistant, while an increase of critical cell number makes them more radiosensitive. Various therapy modes could be analyzed by this analysis: Increased radioresistant of larger tumors could be attributed mostly to increased cell number and increased cellular radiosensitivity. Radiosensitization by fast neutrons could be due to increased radiosensitivity of composite cells. Hyperthermia showed a critical cell number below 1, indicating a killing mechanism different from X-rays. One of the future areas to be explored for better therapy mode could be how to increase the critical cell number through modification of environmental conditions (e.g., making the irradiated cells more able to survive or easy to die.)

Cell Count↗

PubMed1986

Chromosomal radiosensitivity during the G2 cell cycle period and cytopathology of human normal x tumor cell hybrids.

The relationship between tumorigenicity and enhanced chromosomal radiosensitivity during the G2 cell cycle phase was examined through the use of nontumorigenic human cell hybrids and their nontumorigenic and tumorigenic segregants. The hybrid cells were produced by fusion of a normal and tumor cell. The parental lines, including HeLa and three fibroblast lines, one of skin and two of fetal lung origin, were also examined. The tumorigenic lines, which had cytological features associated with clinical cancer, showed a significantly higher incidence of chromatid breaks and gaps following X-irradiation during G2 than the normal skin line or the nontumorigenic hybrids. The hybrids and their nontumorigenic subclones had cytological features which are predominantly found with a benign clinical course and had the G2 chromosomal radiosensitivity more characteristic of the normal parental cells. Like tumorigenic cells, fetal cells exhibited enhanced G2 chromosomal radiosensitivity which could be suppressed in fetal X tumor cell hybrids. This observation suggests that the molecular basis for radiosensitivity in fetal cells differs from that of tumor cells. The enhanced G2 chromosomal radiosensitivity of a tumor cell, which appears to result from deficient DNA repair, is suppressed by fusion with a normal cell. Thus, the radiosensitivity, like tumorigenicity, behaves as a recessive trait. Although a Mendelian analysis is not possible with this material, the segregation of enhanced G2 chromosomal radiosensitivity with the neoplastic phenotype suggests that the two may be genetically linked.

Cell Line↗

PubMed1994

Radiosensitivity in vitro of clonogenic and non-clonogenic glioblastoma cells obtained from a human brain tumour.

Cells obtained from a human glioblastoma (G5) were characterized and used to develop an assay measuring their radiosensitivity in vitro. Surviving fractions were estimated 12 days after irradiation by image analysis of the total surface occupied by the cells. This report evaluates 4 experimental factors which may influence the radiosensitivity in vitro of G5 cells: passage number, delay between plating and irradiation, cell density and clonal heterogeneity. The radiosensitivity of the G5 cell line was found to be passage-independent at least between passages 12 and 75. Experimental conditions influence the radiosensitivity as surviving fraction at 2 Gy (SF2) range from 90% (5,000 cells/well, irradiation 72 h after seeding) to 49% (2,500 cells per well, irradiation 24 h after seeding). The heterogeneity of the radiosensitivity is large at the clonal level as SF2 of six clones isolated from the G5 line were 45%, 50%, 72%, 74%, 79% and 84%. Finally, when G5 cells were irradiated at low cell density and at the beginning of the growth phase, the radiosensitivity measured with this assay is comparable to that obtained with a standard colony assay. We propose that this assay may be useful to determine the intrinsic radiosensitivity of cells obtained from human tumours.

Brain Neoplasms↗