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PubMed1997

A correlation between residual DNA double-strand breaks and clonogenic measurements of radiosensitivity in fibroblasts from preradiotherapy cervix cancer patients.

PURPOSE: To study the relationship between residual DNA damage and clonogenic measurements of radiosensitivity in fibroblasts from pretreatment cervix cancer patients. METHODS AND MATERIALS: Early passage vaginal fibroblasts from nine preradiotherapy cervix cancer patients and two radiosensitive skin fibroblast cell strains were studied. Cell survival was measured by clonogenic assay following both high and low dose rate irradiation. Residual DNA damage was measured using pulsed-field gel electrophoresis (PFGE) after irradiating radiolabeled, plateau-phase cells at 37 degrees C and allowing 24 h for repair. DNA damage was expressed both in terms of the residual damage slope (fitted to data from 60 to 150 Gy) and the fraction of activity released (FAR) following 150 Gy. RESULTS: The surviving fraction at 2 Gy (SF2) values after high dose rate irradiation for the vaginal fibroblasts ranged from 0.15 to 0.32 (a 2.2-fold difference). When the two radiosensitive cell strains were included, residual damage, expressed as the residual damage slope, correlated with alpha (r = 0.82, p = 0.002), D bar (r = -0.91, p < 0.001) and SF2 (p = -0.79, p = 0.004), and when the vaginal fibroblasts alone were studied, the residual damage slope again correlated with clonogenic survival, although less strongly [alpha (r = 0.66, p = 0.053), D bar (r = -0.83, p = 0.006), and SF2 (r = -0.63, p = 0.07)]. Within the group of vaginal fibroblasts there was a 4.0-fold difference in residual DNA damage slope. When residual damage was expressed as FAR at 150 Gy, then for all cell strains the correlations were alpha: r = 0.78, p = 0.004, D bar: r = -0.86, p = 0.001, and SF2: r = -0.78, p = 0.004, and for the vaginal fibroblast strains alone the correlations were alpha: r = 0.60, p = 0.088, D bar: r = -0.75, p = 0.02, and SF2: r = 0.62, p = 0.077. CONCLUSION: This study confirms previous findings that residual DNA damage correlates with clonogenic survival in fibroblasts. In addition, it demonstrates a correlation for fibroblasts from pretreatment cervix cancer patients demonstrating a relatively small range of SF2 values.

Cell Survival↗

PubMed1998

In vitro radiosensitization of human cervical carcinoma cells by combined use of 13-cis-retinoic acid and interferon-alpha2a.

BACKGROUND: Significant antitumor activity has been reported with the combined use of 13-cis-retinoic acid (cRA) and interferon-alpha2a (IFN-alpha) in the treatment of advanced-stage cervical cancers and skin cancers. Since IFN-alpha has been shown to be a modest radiation enhancer for selected malignant tumor cells and the cytotoxic activity is more enhanced by combining cRA and IFN-alpha, we hypothesized that the exposure of selected human carcinoma cells to combined cRA and IFN-alpha would render the cells highly radiosensitive. METHODS AND MATERIALS: Two human cervical carcinoma cell lines, ME-180 and HeLa-S3, were chosen for the present study because of the different characteristics of the retinoic acid receptor status of the cell lines. To demonstrate the effects of combined cRA and IFN-alpha treatment on radiation response, we exposed the cells to cRA, IFN-alpha, or a combination of the drugs for 72 h before radiation. Experiments were carried out at minimally cytotoxic concentrations of the drug for radiation studies. End points of the study were cell growth inhibition and clonogenic ability of the single-plated cells. Effects of cRA and IFN-alpha on radiation response were quantitatively analyzed by constructing the radiation cell survival curves of ME-180 and HeLa cells. RESULTS: ME-180 cells exhibited varying degrees of cytotoxicity with cRA and IFN-alpha, while HeLa cells showed no toxic effects with the same treatment. Combined treatment of cRA and IFN-alpha produced an additive cytotoxic effect in ME-180 cells. Radiosensitization was minimal when ME-180 cells were treated with either cRA or IFN-alpha before radiation. When ME-180 cells were exposed to 10 microM cRA for 48 h and 1000 U/ml IFN-alpha for 24 h prior to radiation, there was a significant enhancement in radiation-induced cell killing; the dose modification factor was 2.1 +/- 0.9 at the 1% cell-survival level. On the other hand, HeLa-S3 cells exhibited no increased cytotoxicity or radiation enhancement under the same experimental conditions. CONCLUSION: The present data provide a radiobiological basis for using cRA and IFN-alpha as a combination radiosensitizer in selected human carcinoma cells.

Antineoplastic Agents↗

PubMed1998

Selective in vivo radiosensitization by 5-fluorocytosine of human colorectal carcinoma cells transduced with the E. coli cytosine deaminase (CD) gene.

PURPOSE: The E. coli cytosine deaminase (CD) gene encodes an enzyme capable of converting the nontoxic prodrug 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU), a known radiosensitizer. Having previously shown that combined CD suicide gene therapy and radiation (RT) results in pronounced radiosensitization in vitro, we progressed to in vivo studies of combined therapy. METHODS AND MATERIALS: WiDr human colon cancer cells were transduced in vitro with the CD gene and cells expressing CD were selected for use as xenografts in a nude mouse model. After administration of 5-FC, tumors received 10-30 Gy local field radiation (RT) and tumor growth delay was compared to control animals receiving either 5-FU, 5-FC, or RT alone. RESULTS: Maximal growth delay was seen in mice treated with 5-FC for 6 consecutive days prior to RT. Combined treatment with 15 Gy radiation resulted in a dose-modifying factor (DMF) of 1.50, and a greater DMF was observed with higher doses of radiation. There was no appreciable toxicity using this new approach. In contrast, a similar treatment of combined 5-FU and radiation resulted in considerable toxicity and no appreciable radiosensitization. CONCLUSION: The present results show that combined suicide gene therapy and RT results in pronounced antitumor effect without any notable toxicity. This indicates that the CD gene may be useful in the development of novel treatment strategies combining radiation and gene therapy in the treatment of locally advanced cancers.

Animals↗

PubMed1999

The immunohistochemical expression of DNA-PKCS and Ku (p70/p80) in head and neck cancers: relationships with radiosensitivity.

PURPOSE: The DNA-PK complex is one of the major pathways by which mammalian cells respond to DNA double-strand breaks induced by ionizing radiation. This study evaluated the relationship between the immunohistochemical expression of the individual components of DNA-PK and cellular radiosensitivity in head and neck cancers. METHODS AND MATERIALS: Biopsies from patients with previously untreated squamous cell carcinomas of the head and neck were assessed for inherent tumor radiosensitivity measured as the surviving fraction at 2 Gy (SF2) using a soft agar clonogenic assay. Paraffin-embedded tumor material from 64 successfully grown specimens was immunohistochemically stained for expression of DNA-PKcs and Ku (p70/p80). The same tumor material was previously analyzed for the immunohistochemical expression of p53. RESULTS: A significant correlation was found between the degree of expression of DNA-PKcs and Ku (p70/p80) (r = 0.55, p<0.001). There were no overall significant differences in the levels of expression of DNA-PKcs and Ku (p70/p80) in tumors from patients of either sex, different sites, histologies, and stages. No relationship was found between SF2 and the expression of either DNA-PKcs (r = 0.22, p = 0.081) or Ku (p70/p80) (r = 0.064, p = 0.62). Comparison with previous immunohistochemical characterization showed no significant correlations between the expression levels of p53 and either DNA-PKcs (r = 0.093, p = 0.46) or Ku (p70/p80) (r = -0.17, p = 0.17). CONCLUSIONS: This study suggests that determining the immunohistochemical expression of DNA-PK in head and neck cancers from multiple sites does not have a role as a predictive assay of tumor in vitro radiosensitivity.

Antigens, Nuclear↗

PubMed1997

Rejoining of DNA double-strand breaks after the introduction of chromosome 11 into a radiosensitive bladder carcinoma cell line.

Insertion of a normal chromosome 11 into tumour cell lines can protect against a sensitivity to irradiation and oxidative stress. A possible mechanism underlying this effect is that there is a correction of a defect in the rejoining of double-strand breaks (dsb) by the chromosome insertion. In order to explore this hypothesis, three cell lines were evaluated for their ability to rejoin dsb: (1) a bladder carcinoma cell line ('parent') previously shown to be sensitive to irradiation and radical generating species; (2) a derivative of this cell line into which a normal chromosome 11 had been inserted by microcell fusion ('hybrid') showing corrected radiosensitivity; and (3) a 'revertant' cell line that had spontaneously lost the insert and reverted to the radiosensitive phenotype. Nuclear extracts from the 3 lines were isolated and evaluated for their capacity to rejoin plasmid (pUC18) DNA broken at defined restriction sites (SalI, EcoRI, KpnI, SmaI) in the lacZ gene. The extent of rejoining was determined by gel electrophoresis and the fidelity of rejoining determined by expression of the lacZ gene in E. coli DH5 alpha bacteria. Results suggest there is no difference between the 'parent', 'hybrid' and 'revertant' nuclear extracts in the fidelity and the total extent of rejoining, regardless of the type of break. However, there is an alteration in the distribution of rejoined products. Nuclear extracts from 'hybrid' cells tend to rejoin linear DNA into circular monomers with a greater efficiency than extracts from both 'parent' and 'revertant' cells. This alteration in distribution is observed when 3'- or 5'-protruding ends are rejoined but not in the rejoining of blunt ends. The results suggest that loci on chromosome 11 are involved in the rejoining of dsb, affecting the relative amount of the different rejoined products. Whether this alteration plays a role in the 'parent' cell's radiosensitivity is yet to be determined.

Cell Fusion↗

PubMed1995

Thrombocytopenia with absent radii (TAR) syndrome: a new increased cellular radiosensitivity syndrome.

A 70-year-old woman with congenital absence of both radii but preservation of the thumb developed a marked pancytopenia after two i.v. injections of 1 g of 5-fluorouracil (5-FU) 1 week apart. She developed bloody diarrhoea after nine fractions of 2 Gy to parallel opposed 16 x 15 cm abdominal fields. This unusual response prompted an investigation of the radiosensitivity of the patient's cells by the sensitive G2 assay of transformed lymphocytes. The radiosensitivity of the patient's lymphoblastoid line appeared to be intermediate between that of normal individuals and an ataxia telangiectasia line. The clinical response and in vitro radiosensitivity testing suggest that the thrombocytopenia with absent radii (TAR) syndrome appears to be one of the inherited impaired DNA repair syndromes and is a very newly described radiation sensitivity syndrome. The development of three separate primary cancers in this patient (small bowel, ovary and bladder) suggests there is an increased risk of neoplasia in this condition.

Aged↗

PubMed1991

Synthesis of a series of nitrothiophenes with basic or electrophilic substituents and evaluation as radiosensitizers and as bioreductively activated cytotoxins.

A series of 2- and 3-nitrothiophene-5-carboxamides bearing N-(omega-aminoalkyl) side chains has been prepared by treatment of the thiophenecarbonyl chloride with the appropriate (protected) omega-aminoalkylamine. Analogous N-(oxiranylmethyl)nitrothiophene-5-carboxamides have been synthesized by epoxidation of the corresponding N-allylamide. Compounds in both classes were evaluated in vitro both as radiosensitizers of hypoxic mammalian cells and as selective bioreductively activated cytotoxins. The most potent radiosensitizers were those agents with strong tertiary amine bases or oxiranes in the side chain. Studies in vivo showed that 2-methyl-N-[2-(dimethyl-amino)ethyl]-3-nitrothiophene-5- carboxamide caused slight radiosensitization of the KHT sarcoma in mice given 0.34 mmol kg-1. However, administration of this and related tertiary amines at higher doses was precluded by systemic toxicity.

Animals↗

PubMed1981

Potential radiosensitizing agents. 2. Synthesis and biological activity of derivatives of dinitroimidazole with oxiranes.

A series of 1-substituted 2,4-dinitroimidazole analogues have been synthesized and tested for their radiosensitizing ability for selectively sensitizing hypoxic mammalian cells to the lethal effect of radiation. The reaction of 2,4-(5)-dinitroimidazole (1) with a variety of oxiranes upon heating in absolute ethanol yielded the expected 1-substituted 2,4-dinitroimidazoles (2) and also resulted in the formation of a novel class of isomeric nitroimidazo[2,1-b]oxazoles 3 and 4) by intramolecular cyclization. The results of radiosensitizing activity of these agents against hypoxic Chinese hamster cells (V-79) indicated that 2,4-dinitroimidazoles were better sensitizers than the nitroimidazo[2,1-b]oxazoles, suggesting the necessity of the 2-nitro function in the molecule. The 1-(2-hydroxy-3-methoxypropyl)-2,4-dinitroimidazole (2d) was found to be the most effective radiosensitizer of this series.

Animals↗

PubMed1982

Potential radiosensitizing agents. 4. 2-Nitroimidazole nucleosides.

A series of 2-nitroimidazole nucleoside analogues has been synthesized as potential radiosensitizers in an effort to reduce neurotoxicity and increase therapeutic efficacy. The 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl and glucothiopyranosyl analogues of 2-nitroimidazole were synthesized by condensation in the presence of stannic chloride and mercuric cyanide. The deacetylation of these esters was carried out with sodium methoxide at 0 degree C. Condensation of the trimethylsilyl derivative of 2-nitroimidazole with methyl 2-deoxy-2-chloro-4,7,8,9-tetra-O-acetyl-N-acetyl-alpha-D-neuraminate was achieved in the presence of mercuric bromide. These agents were tested for cytotoxicity and radiosensitization in vitro against Chinese hamster (V-79) cells under oxic and hypoxic conditions. The thioglucose and sialic acid analogues were found to be active radiosensitizers.

Animals↗

PubMed1983

Potential radiosensitizing agents. 6. 2-Nitroimidazole nucleosides: arabinofuranosyl and hexopyranosyl analogues.

New 2-nitroimidazole nucleosides have been synthesized as radiosensitizers of hypoxic mammalian cells in an attempt to reduce the neurotoxicity and to increase the therapeutic efficacy of this class of agents. The trimethylsilyl derivative of 2-nitroimidazole was condensed with 1-bromo-2,3,5-tri-O-benzoylarabinofuranose in the presence of mercuric cyanide to yield anomeric isomers of arabinofuranosides, which were separated by preparative thin-layer chromatography. Reaction of 2-deoxy-1,3,4,6-tetra-O-acetyl-D-glucose or 3,4,6-tri-O-acetyl-D-glucal with 2-nitroimidazole in the presence of an acid catalyst produced alpha and beta isomers of 2',3'-dideoxy-D-erythro-hex-2'-enopyranosides and an isomeric 3-substituted 1,2,3-trideoxy-D-erythro-hex-1-enopyranose. Hydrolysis of the esters was accomplished with sodium methoxide in methanol at 0 degrees C. The radiosensitizing efficacy of these agents was determined against Chinese hamster (V-79) cells in vitro. The 1-(2',3'-dideoxy-alpha-D-erythro-hex-2'-enopyranosyl)-2-nitroimidazole was the most active agent of this series and was found to be superior to misonidazole as a radiosensitizer.

Animals↗

PubMed2000

PR-000350, a novel hypoxic radiosensitizer, enhances tumor cell killing by promoting apoptosis preferentially in the S-phase fraction.

PR-000350, a novel hypoxic radiosensitizer, is a 2-nitroimidazole nucleoside analog and has begun to be used for clinical cancer therapy. In this study, using U937 monoblastoid cells we investigated the mechanisms of enhanced cell killing by PR-000350. When cells were irradiated under an extremely hypoxic condition, the apoptotic rate was strongly suppressed. However, a remarkable increase in the DNA fragmentation rate as well as in the ladder formation was observed when hypoxic cells were irradiated in the presence of 5 mM PR-000350. DNA histograms of the PR-000350 treated group showed enhancement of the sub-G1 fraction and simultaneous suppression of the progression of the cell cycle from the S to G2/M phase at 4-8 h after X-irradiation, suggesting the importance of the S phase in the induction of apoptotic cell death. Flow cytometric and immunohistochemical analyses after BrdU labelling revealed that apoptotic cell death is induced mainly in the BrdU-positive cells. In addition, by using cell synchronization technique it was proved that the S phase is the most sensitive fraction to the radiosensitizing effect of PR-000350. These results suggest that PR-000350 strongly enhances tumor cell killing by promoting X-ray induced-apoptosis preferentially in the S-phase fraction. PR-000350 is a new type radiosensitizer and promise to provide an effective anti-cancer activity against hypoxic tumor cells that are resistant to the usual radiotherapy.

Anaerobiosis↗

PubMed2002

BCL-2 family proteins modulate radiosensitivity in human malignant glioma cells.

Radiotherapy is the standard treatment for glioblastoma. Here, we assessed the radiosensitivity of 12 human malignant glioma cell lines in vitro and correlated these data with irradiation-induced cell cycle changes, chemosensitivity profiles and BCL-2 family protein expression. Irradiation at 3 Gy failed to cause major cell cycle perturbations. Radioresistance was associated with collateral sensitivity to the topoisomerase II inhibitors, teniposide and doxorubicin. High levels of BCL-XL and low levels of BAX were independently linked to radioresistance. Ectopic expression of a BAX transgene induced radiosensitization in the LN-18 cell line. Thus, BCL-2 family protein expression modulates radiosensitivity in human glioma cells and targeted alterations in BCL-2 family protein expression are a promising strategy to improve the therapeutic efficacy of radiotherapy for gliomas.

Antineoplastic Agents↗

PubMed1975

Human studies with "high dose" metronidazole: a non-toxic radiosensitizer of hypoxic cells.

The serum concentrations of the radiosensitizer metronidazole have been determined in mice for both oral and intraperitoneal doses of the drug and these have been related to radiosensitization studies in murine tumour systems. In preliminary work before a possible clinical trail the serum metronidazole concentration/time curves have been determined in 7 patients using single doses of metronidazole of up to 15 g. The data suggest that a linear relationship exists between the metronidazole dose expressed in mg/kg and the peak serum concentration. The possibility of achieving radiosensitization of tumours in patients after tolerable doses of metronidazole is discussed in relation to enhancement ratios determined for in vitro and in vivo systems. It is concluded that predictions from in vitro systems give values that are probably too optimistic.

Administration, Oral↗

PubMed1977

Further investigations of the effects of the hypoxic-cell radiosensitizer, Ro-07-0582, on local control of a mouse tumour.

The tumour used, designated MT1, is a more radiosensitive form of the anaplastic MT tumour previously described. No explanation for the increased radiosensitivity was found, but it was shown not to be due to infection or to a change in immunological status, growth rate or histology. The sensitivity has remained constant throughout the present work. No cytotoxicity in the tumour was observed when 1 mg/g body weight of Ro-07-0582 was injected immediately after a single dose of X-rays; indeed a small protective effect was seen. A radiosensitization enhancement of 1-5 was achieved with a relatively low drug dose of Ro-07-0582 in a 5F/4d fractionated regime. The interval between the injection of a low dose of Ro-07-0582 and the start of irradiation was found to be critical, the optimum interval being 45-60 min. The subsequent incidence of distant metastases was not increased by the use of Ro-07-0582 at the time of "primary" tumour irradiation.

Animals↗

PubMed1980

Is tumour radiosensitization by misonidazole a general phenomenon?

The response of 14 mouse tumour sub-lines to the radiosensitizing action of a large single dose of misonidazole (MISO) has been assessed by regrowth delay. In 13 of these, significant enhancement of radiation effect occurred under ambient conditions, indicating sensitization of naturally hypoxic cells. The enhancement observed (SER') varied with the radiation dose, as would be predicted for a mixed oxic/hypoxic cell population. The maximum SER' in these 13 tumours did not depend on histology or regrowth rate. The 14th tumour, a slow-growing sarcoma, was not sensitized under ambient conditions, but showed marked sensitization when clamped to produce acutely hypoxic cells. This is consistent with no hypoxic cells occurring naturally in a sarcoma with a slow rate of growth. Faster-growing variants of this tumour showed radiosensitization under ambient conditions. The slow-growing carcinoma, RH, however, appears to contain hypoxic cells and did show sensitization. The cytotoxic action of MISO was compared with the radiosensitization by administering it after irradiation in 8 of the tumour lines. In 2 tumours no cytotoxicity was observed. In the rest cytotoxicity was significant, but much smaller than the sensitization observed when MISO was administered before irradiation. These regrowth-delay data have been used to calculate hypoxic fractions in 3 ways. Estimates of hypoxic fraction ranged from less than 0.1% in the slow sarcoma to greater than or equal to 30% in several tumours. There is considerable variation in the estimate, according to the technique used.

Animals↗

PubMed1980

Effect of misonidazole and hyperthermia on the radiosensitivity of a C3H mouse mammary carcinoma and its surrounding normal tissue.

Both misonidazole (MISO) and hyperthermia are known to enhance the radiation response of hypoxic cells, and to be selectively cytotoxic against cells in a hypoxic and acidic environment. The ability of these conditions to modify the effect of irradiation and their individual relationship was studied in a C3H mammary carcinoma and its surrounding skin. Simultaneous treatment with MISO, hyperthermia and radiation increased the radiation effect, with enhancement ratios (ER) of up to about 15 (1 mg/g MISO and 43.5 degrees C for 60 min.). However, such treatment also caused a smaller hyperthermic radiosensitization of the normal tissue, so that the therapeutic ratio was only increased by a factor of about 3 compared to radiation alone. Simultaneous MISO and radiation followed by hyperthermia 4 h later gave a moderate enhancement, with ER up to 3 in the tumour, but with no enhancement of the normal tissue, so that there is a similar 3-fold increase in therapeutic gain. The mechanism by which MISO and hyperthermia enhanced the radiation response may be explained as an independent action of the hypoxic radiosensitization of MISO and the selective hyperthermic cytotoxicity against acidic and chronic hypoxic cells; simultaneous hyperthermia added a further heat-induced general radiosensitization. Surprisingly, no MISO cytotoxicity could be detected in this tumour system, with or without simultaneous hyperthermia. The results indicate that in the proper treatment schedule, MISO may be a valuable addition to a combined hyperthermia and radiation treatment.

Animals↗

PubMed1981

Flurbiprofen, a non-steroid anti-inflammatory agent, protects cells against hypoxic cell radiosensitizers in vitro.

Overnight exposure of Chinese hamster cells (V79-753B) to 5 x 10(-5) M flurbiprofen (2-(2-fluoro-4-biphenyl)propionic acid) in vitro reduced the cytotoxic effects of misonidazole, 1-methyl-4-nitro-5-phenoxysulphonylimidazole (NSC 38087) and nitrofurantoin, both in air and in hypoxia at 37 degrees C. Flurbiprofen did not alter the cells' uptake of 14C-misonidazole, nor did it affect the radiosensitivity of aerobic or anaerobic cells, or the degree of hypoxic-cell radiosensitization produced by the sensitizers. When flurbiprofen-treated cells were exposed to melphalan there was no protection against cytotoxicity. These data suggest that flurbiprofen may inhibit the catabolism of radiosensitizers to toxic products and indicate the need to examine whether it will protect against misonidazole-induced toxicity in vivo.

Animals↗

PubMed1986

Growth and radiosensitivity of malignant melanoma multicellular spheroids initiated directly from surgical specimens of tumours in man.

The growth and radiosensitivity of multicellular spheroids initiated directly from disaggregated surgical specimens of four human malignant melanomas were studied. The spheroids were grown in liquid-overlay culture for up to 6 passages. Cell survival following irradiation was measured by using the Courtenay soft agar colony assay. The four melanomas formed spherical, densely packed spheroids. The volumetric growth rate as well as the plating efficiency in soft agar usually increased with increasing passage number. The radiosensitivity differed significantly among the melanomas. The survival curves for single cells from disaggregated spheroids in the first passage were always similar to those for single cells isolated directly from the surgical specimens. Two of the melanomas showed a significant contact effect as spheroids whereas the other two did not. The spheroids of two of the melanomas showed lower D0 in the third and the sixth passage than in the first passage, whereas the spheroids of the other two melanomas showed similar survival curves in the first and the third passage. There was no clear relationship between the changes in radiosensitivity and the changes in growth rate or plating efficiency. It is concluded that spheroids in the first passage, but not spheroids in later passages, may have the potential to identify differences in clinical radioresponsiveness among tumours.

Cell Division↗