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Results for “Radiosensitivity”

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PubMed2002

Adenovirus-mediated mda-7 gene expression radiosensitizes non-small cell lung cancer cells via TP53-independent mechanisms.

We examined the ability of adenoviral-mediated expression of the melanoma differentiation associated gene-7 (Ad-mda-7), to radiosensitize non-small cell lung cancer (NSCLC) cell lines (A549 (wt-TP53/wt-RB1) and H1299 (del-TP53/wt-RB1)), and normal human lung fibroblast (NHLF) lines (CCD-16 and MRC-9). Results of clonogenic assays indicated that Ad-mda7 enhanced the radiosensitivity of the NSCLC cells independent of their TP53 gene status. On the other hand, the NHLF cell lines seemed to be relatively resistant to the cytotoxic effects of Ad-mda7 and were not radiosensitized compared with the NSCLC cells. We further examined the basis for this difference in the ability of Ad-mda7 to radiosensitize NSCLC cells compared with normal cells. Radiation-induced apoptosis was restored in the NSCLC lines, but not in the normal lines. Western blot analysis revealed that Ad-mda7 enhances radiosensitivity independently of any ability to upregulate the expression of Fas or Bax in NSCLC cells. Further analysis indicated that phosphorylated c-Jun expression was increased by Ad-mda7 in both A549 and H1299 cells, but not in CCD-16 cells. These results support the use of gene replacement with Ad-mda7 in combination with radiotherapy for the treatment of NSCLC.

Adenoviridae↗

PubMed2003

[Abrogation of radiation-induced G2 arrest and radiosensitization by 7-hydroxystaurosporine (UCN-01) in human nasopharyngeal carcinoma cell line].

BACKGROUND & OBJECTIVE: To enhance the radiosensitivity of cancer cell is one of the most important way to improve the effect of radiotherapy. This study was designed to investigate the radiosensitization of 7-hydroxystaurosporine(UCN-01) by its abrogation of radiation-induced G2 arrest. METHODS: Flow cytometry was used to observe the effect of irradiation and UCN-01 on cell cycle of human nasopharyngeal carcinoma cells (CNE-1) with mutated p53. The effect on radiosensitivity was determined by clonogenic assay and was quantified by calculating the sensitive enhancement ratio (SER). RESULTS: Irradiation resulted in G2 arrest in a dose-dependent manner. The proportion of cells at G2 phase, comparing to the control group (18.4%), was increased to 43.6%, 77.4% and 86.4% after 12 hours with irradiation of 2, 4 and 6 Gy, respectively. Radiation-induced G2 arrest was abrogated by UCN-01 in a concentration-dependent manner. UCN-01 at the concentrations of 50, 100, 200 and 400 nmol/L decreased the proportion of cells in G2 phase from 63.5% in the control group to 28.5%, 25.0%, 16.1% and 13.7%, respectively. UCN-01 resulted in a radiosensitization in CNE-1 cells. The SERs were 2.60 and 3.09, for 100 nmol/L and 200 nmol/L of UCN-01, respectively. CONCLUSION: Radiosensitization of UCN-01 in CNE-1 cells characterized by mutated p53 is associated with its abrogation of radiation-induced G2 arrest.

Carcinoma, Squamous Cell↗

PubMed2003

Adenovirus-mediated heat-activated antisense Ku70 expression radiosensitizes tumor cells in vitro and in vivo.

Ku70 is one component of a protein complex, Ku70 and Ku80, that functions as a heterodimer to bind DNA double-strand breaks and activates DNA-dependent protein kinase. Our previous study with Ku70-/- and Ku80-/- mice, and cell lines has shown that Ku70- and Ku80-deficiency compromises the ability of cells to repair DNA double-strand breaks, increases radiosensitivity of cells, and enhances radiation-induced apoptosis. In this study, we examined the feasibility of using adenovirus-mediated, heat-activated expression of antisense Ku70 RNA as a gene therapy paradigm to sensitize cells and tumors to ionizing radiation. First, we performed experiments to test the heat inducibility of heat shock protein (hsp) 70 promoter and the efficiency of adenovirus-mediated gene transfer in rodent and human cells. Replication-defective adenovirus vectors were used to introduce a recombinant DNA construct, containing the enhanced green fluorescent protein (EGFP) under the control of an inducible hsp70 promoter, into exponentially growing cells. At 24 h after infection, cells were exposed to heat treatment, and heat-induced EGFP expression at different times was determined by flow cytometry. Our data clearly show that heat shock at 42 degrees C, 43 degrees C, or 44 degrees C appears to be equally effective in activating the hsp70 promoter-driven EGFP expression (>300-fold) in various tumor cells. Second, we have generated adenovirus vectors containing antisense Ku70 under the control of an inducible hsp70 promoter. Exponentially growing cells were infected with the adenovirus vector, heat shocked 24 h later, and the radiosensitivity determined 12 h after heat shock. Our data show that heat shock induces antisense Ku70 RNA, reduces the endogenous Ku70 level, and significantly increases the radiosensitivity of the cells. Third, we have performed studies to test whether Ku70 protein level can be down-regulated in a solid mouse tumor (FSa-II), and whether this results in enhanced radiosensitivity in vivo, as assessed by in vivo/in vitro colony formation and by the tumor growth delay. Our data demonstrate that heat-shock-induced expression of antisense Ku70 RNA attenuates Ku70 protein expression in FSa-II tumors, and significantly sensitizes the FSa-II tumors to ionizing radiation. Taken together, our results suggest that adenovirus-mediated, heat-activated antisense Ku70 expression may provide a novel approach to radiosensitize human tumors.

Adenocarcinoma↗

PubMed2003

Gleevec-mediated inhibition of Rad51 expression and enhancement of tumor cell radiosensitivity.

Rad51 is an essential component of the homologous DNA repair pathway and has been implicated as a determinant of cellular radiosensitivity. Gleevec is a relatively specific inhibitor of c-Abl, a tyrosine kinase that can play a role in the regulation Rad51. The aim of this study was to determine the effects of Gleevec on Rad51 levels and the radiosensitivity of two human glioma cell lines and a nonimmortalized normal human fibroblast cell line. Exposure of both glioma cell lines to radiation resulted in an increase in Rad51 expression; Gleevec treatment alone reduced Rad51 expression. When glioma cells were pretreated with Gleevec, radiation-induced Rad51 expression and nuclear foci formation were reduced. Accordingly, pretreatment of the glioma cells with Gleevec resulted in an enhancement in their radiosensitivity. These data indicate that Gleevec enhances radiation-induced tumor cell killing and suggest that the mechanism involves the reduction in Rad51 levels. In contrast to the glioma cell lines, radiation or Gleevec treatments had no effect on Rad51 expression or foci formation in the normal fibroblast cells. Consistent with these observations, Gleevec did not modify the radiosensitivity of the normal cell line. These results suggest that Rad51 expression is subject to different regulatory processes in the glioma and normal cell lines and further suggest that Rad51 may be an appropriate target for selectively enhancing the radiosensitivity of brain tumor cells.

Benzamides↗

PubMed2003

Adenovirus-mediated wild-type p53 radiosensitizes human tumor cells by suppressing DNA repair capacity.

Functional inactivation of the p53 gene and robust DNA repair capacity may be among the salient causes of radioresistance in tumor cells. We expressed the wild-type (wt) p53 gene in a p53-mutant human epidermoid carcinoma cell line, A431, using an adenoviral vector [adenovirus-p53 (Ad-p53), INGN 201], examined its radiosensitivity, and correlated p53 status and radiosensitivity with cellular repair functions. Using clonogenic survival assays and the terminal deoxynucleotidyl transferase-mediated nick end labeling assay for apoptosis, we demonstrated that preirradiation treatment with Ad-p53 significantly increased the radiosensitivity of A431 cells over controls. Induction of p53 expression using a construct where p53 expression was under the control of an inducible promoter also significantly increased radiosensitivity of H1299 lung tumor cells, which are otherwise null for p53. These results did not correlate with radiation-induced apoptosis but did correlate with functional impairment of DNA repair and suppressed expression of several repair-related genes, such as Ku70, DNA-dependent protein kinase, ataxia telangiectasia mutated, and X-ray-sensitive complementation group 4. Normal human fibroblast MRC-9 cells showed no impairment in the repair capability due to Ad-p53 despite the suppression of some repair genes. Expression of Ku70, which is known to mediate diverse cellular functions, correlated with the differential effects of p53 on radiosensitivity in the normal and tumor cells.

Adenoviridae↗

PubMed1992

The experimental and clinical rationale for the use of S-phase-specific radiosensitizers to overcome tumor cell repopulation.

Clinical and laboratory evidence suggests that several common human cancers contain populations of rapidly proliferating clonogens that may have a substantial impact on local control following conventional radiotherapy. Strategies to improve locoregional control include the use of S-phase-specific radiosensitizers, such as the halogenated pyrimidine analogues (5-iododeoxyuridine, 5-bromodeoxyuridine, fluorodeoxyuridine, 5-fluorouracil) and hydroxyurea. These drugs are taken up and metabolized only by cells synthesizing DNA so that increased tumor proliferation should result in increased radiosensitization. Although the initial clinical trials with these agents were inconclusive, several recent reports have rekindled interest in these radiosensitizers. Ongoing laboratory research has provided further insight into the basic mechanisms of radiosensitization. However, many questions remain unanswered. We will review the data that suggest rapid tumor proliferation, experimental studies with the S-phase-specific drugs, and the results of clinical trials. We will also consider the possible design of future trials based on our current understanding of tumor proliferation and the mechanisms of radiosensitization of S-phase-specific agents.

Animals↗

PubMed1992

Radiosensitization by fluorodeoxyuridine: effects of thymidylate synthase inhibition and cell synchronization.

The combination of fluoropyrimidines and radiation has resulted in increased control of colorectal cancer in the clinic, but the basic mechanism of the interaction is not understood clearly. Preliminary work in our laboratory showed that 2-h exposures of HT 29 human colon carcinoma cells to relatively low levels of 5-fluorodeoxyuridine resulted in extended thymidylate synthase inhibition after the drug was removed (up to 30 h after treatment with 0.5 microM 5-fluorodeoxyuridine). The low cytotoxicity associated with this treatment simplified efforts to test the effects of extended thymidylate synthase inhibition on radiosensitivity of HT 29 cells. Although thymidylate synthase was completely inhibited at the end of the 2-h exposure, an increase in the radiosensitivity of the cells was not evident until 16 h after the removal of drug. Flow cytometric analysis showed that cells accumulated in early S phase over time, and the increase in radiation sensitivity of the entire population followed the increase of the proportion of cells in early S, a relatively radiosensitive phase of the cell cycle. This treatment schedule was compared with 24-h continuous exposure, and we found that the same maximum increase in radiosensitivity was achieved by both treatment strategies. However, more cytotoxicity was associated with continuous exposure. This study provides evidence that radiosensitization by 5-fluorodeoxyuridine is in part due to alteration of cell kinetics and redistribution of cells throughout the cycle. This information may be useful in the design of less toxic combined chemo- and radiotherapy treatment strategies by limiting systemic exposure to fluoropyrimidines.

Cell Cycle↗

PubMed2005

[Correlations of telomere length and telomerase activity to radiosensitivity of human laryngeal squamous carcinoma cells].

BACKGROUND & OBJECTIVE: Many studies showed that telomere length and telomerase activity closely correlate with proliferation and malignant degree of tumor cells, and both of them might be involved in the repair of radiation-induced DNA damage. So it was speculated that telomere length and telomerase activity maybe correlate to radiosensitivity of carcinoma cells. This study was designed to investigate the correlations of telomere length and telomerase activity to radiosensitivity of human laryngeal squamous carcinoma cell line Hep-2. METHODS: Hep-2 cells were irradiated with 0, 2, 4, 8, or 12 Gy of gamma-ray for 3 times. Survival cells were subcultured for 20 generations. Radiosensitivity index, survival fraction at 2 Gy (SF(2)), was measured by clone formation assay. Telomere length (mean length of telomere restriction fragments, TRF) was examined by Southern blotû telomerase activity (TA) was detected by polymerase chain reaction-based telomeric repeat amplification protocol (PCR-TRAP) coupled with ELISA. RESULTS: After different doses of irradiation, SF(2) of Hep-2 cells was 0.47-0.64; TRF was 3.76-9.43 kb; TA was 1.761-2.606. Each parameter had significant differences among the survival progenies (P<0.05). SF(2) was positively correlated with TRF (r=0.921, P<0.01), and negatively correlated with TA (r=-0.929, P<0.01); TRF was negatively correlated with TA (r=-0.944, P<0.01). CONCLUSION: Radiosensitivity of Hep-2 cells negatively correlates with telomere length, and positively correlates with telomerase activity, which suggest that both telomere length and telomerase activity may be used to predict cellular radiosensitivity.

Carcinoma, Squamous Cell↗

PubMedDate not supplied

Expression pattern of telomerase reverse transcriptase in rectal carcinoma predicts tumor radiosensitivity, local recurrence and disease-free survival.

BACKGROUND/AIMS: Predictive indicators of radiosensitivity in rectal cancer are required in order to avoid unnecessary preoperative radiotherapy. Telomeres are specialized structures at the ends of chromosomes that protect against that such as irradiation. Lower telomerase activity has been reported to be related to radiosensitivity in vitro or vivo. The aim of this study was to examine the possible role of telomerase reverse transcriptase expression, which is correlated to telomerase activity, in determining tumor radiosensitivity, local recurrence, and disease-free survival in patients with rectal carcinomas. METHODOLOGY: We studied 96 cases with advanced rectal carcinoma. In preradiation biopsy specimens of tumor samples, the number of cells stained positive for telomerase reverse transcriptase protein was evaluated by immunohistochemistry. RESULTS: The expression pattern of telomerase reverse transcriptase protein correlated with tumor radiosensitivity (P=0.0007). All tumors that had a high percentage of telomerase reverse transcriptase positive cells were radioresistant. High telomerase reverse transcriptase expression pattern is a predictive marker for high local recurrence or poor survival in patients with rectal cancer (P=0.011, P=0.0005). Telomerase reverse transcriptase expression and histopathological grade were significant prognostic variables for disease-free survival in the multivariate analysis (P=0.0003, P=0.0091). CONCLUSIONS: Telomerase reverse transcriptase raises the predictive possibility of tumor radiosensitivity in rectal cancer. Telomerase reverse transcriptase might be a useful parameter for patient selection for preoperative radiotherapy in rectal carcinoma.

Adenocarcinoma↗

PubMed1990

[Radiosensitization of Lewis lung tumor by perfluorochemical emulsion comparison between single and fractionated irradiation].

Previously perfluorochemical emulsion (FDAS) was shown to enhance tumor growth delay, when applied together with breathing carbogen (95% O2+5% CO2) before and during irradiation. In the present paper, radiosensitizing effects of FDAS in tumor bearing mice were examined on a single (10 Gy) and fractionated irradiation (4 Gy, 4 times) and on the dose of administration. The results were as follows; 1) All groups of single irradiation with injection of FDAS 10-40 ml/kg could enhance the radiosensitivity of LLC bearing mice. 2) Tumor growth of even fractionated irradiation groups was significantly delayed by administration of FDAS more than 5 ml/kg. 3) In case of fractionated irradiation, the minimum effective dose of FDAS was estimated to be 5 ml/kg per irradiation, which coincided with that of single irradiation. It was concluded that FDAS in fractionated irradiation could increase the radiosensitivity in tumor bearing mice with more than 5 ml/kg injection. Therefore, FDAS may be useful as a radiosensitizer for clinical application in fractionated radiation therapy. Furthermore, since irradiation doses of single (10 Gy) and even fractionated irradiation (4 Gy X 4 times) were approximately iso effective dose, it may be considered that administration of more than 5 ml/kg (minimum effective dose) FDAS at each irradiation gave similar radiosensitizing effects to both single and fractionated irradiation.

Animals↗

PubMed1990

Dual-function 2-nitroimidazoles as hypoxic cell radiosensitizers and bioreductive cytotoxins: in vivo evaluation in KHT murine sarcomas.

The efficacies of a series of potential prodrugs of RSU-1069 and its alkyl-aziridine analogues were assessed. These 1-(2-haloethylamino)-3-(2-nitro-1-imidazolyl)-2-propanol compounds were designed to cyclize in vivo to generate 2-nitro-imidazoles with aziridine (RSU-1069) or alkyl-substituted aziridine (RSU-1164, RB-7040, or RSU-1150) functions. Maximum tolerated single, intraperitoneal doses (MTD) were determined in C3H/He mice bearing subcutaneous KHT sarcomas, and a drug dose-response relationship for radiosensitization was established for each compound administered at the optimum time (45-60 min) before local irradiation of tumors with a 10-Gy dose of X-rays. The potentials of the compounds as bioreductive cytotoxins were studied by administering them immediately after irradiation. Tumor cell survival was measured 18-24 h after treatment in an in vitro soft agar clonogenic assay. Results of toxicity, radiosensitization, and bioreductive cytotoxicity assays for each of the prodrugs (RB-6171, RB-6172, RB-6173, RB-6174, and RB-6175) of the alkyl-substituted aziridines were entirely consistent with complete conversion to their respective target compounds. For example, RB-6171 (the prodrug form of RSU-1164) was only about four times less efficient than RSU-1069 as a radiosensitizer and bioreductive cytotoxin but had an MTD 7.5 times higher. In contrast, prodrugs of RSU-1069 (RB-6144 and RB-6145) were two- to threefold less toxic than their expected product. RB-6144 was a poor radiosensitizer and bioreductive agent compared with RSU-1069 and was similar to RB-6170, a nonalkylating nitroimidazole. This is consistent with the observation that there is limited conversion of RB-6144 to RSU-1069 in vitro. However, radiosensitization and bioreductive cytotoxicity produced by RB-6145 were only slightly less than the effects produced by RSU-1069; thus a therapeutic gain was achieved with RB-6145 in a murine tumor model.

Animals↗

PubMed1990

The relationship between radiosensitivity and repair of potentially lethal damage in human tumor cell lines with implications for radioresponsiveness.

The relationship between intrinsic radiosensitivity and repair capacity was studied for 22 human tumor cell lines in vitro. The experimental material was taken from 19 published papers. Parameters from three radiobiological models were used to assess this relationship: the one-hit multitarget model (D0 and n), the linear-quadratic model (alpha and beta), and the mean inactivation dose (D). Data were obtained for cells in three stages: exponentially growing cells (exp), plateau-phase cells plated immediately after irradiation (ip), and plateau-phase cells plated after completion of PLD repair (dp). No significant difference was found between radiosensitivity of exp and ip cells. There was no correlation between repair capacity and intrinsic radiosensitivity assessed with plateau-phase cells plated immediately after irradiation. The correlation studies between intrinsic radiosensitivity or repair capacity and clinical responsiveness were achieved by assigning cell lines to one of three groups of decreasing in vivo radioresponsiveness: highly, medium, and poorly responsive. There was a significant correlation between radiosensitivity and radioresponsiveness, but no correlation between repair capacity and radioresponsiveness. The average repair capacity was about 0.6 Gy, in terms of D. Three parameters, the mean inactivation dose of exponentially growing cells, of plateau-phase cells plated immediately after irradiation, and of plateau-phase cells plated after completion of PLD repair, could be used equally to assess the relationship between in vitro data and radioresponsiveness. The present results are compared to those obtained in a similar study on a group of 48 nontransformed fibroblast cell strains.

Analysis of Variance↗

PubMed1990

The effect of single versus double-strand substitution on halogenated pyrimidine-induced radiosensitization and DNA strand breakage in human tumor cells.

To better understand the mechanism underlying halogenated pyrimidine-mediated cytotoxicity and radiosensitization in human tumor cells, a study was undertaken to determine the influence of unifilar (one DNA strand) versus bifilar (both DNA strands) substitution of thymidine by the halogenated bases 5-iodo-2'-deoxyuridine (IdUrd) and 5-bromo-2'-deoxyuridine (BrdUrd) in HT29 human colon cancer cells. Unifilar labeling was obtained by incubating cells with IdUrd or BrdUrd for one doubling time. Cells were incubated for at least three doublings to approximate bifilar substitution. Only IdUrd caused significant cytotoxicity, which correlated with incorporation into DNA. Both BrdUrd and IdUrd were potent radiosensitizers. Radiosensitization was linearly correlated with incorporation of both bases regardless of the number of strands in which thymidine was substituted. In contrast, the relationship between radiosensitization and DNA double-strand breakage was critically dependent in the case of IdUrd, but not for BrdUrd, on whether substitution was unifilar or bifilar. These findings suggest that incorporation is the best predictor of radiation sensitivity, and that the induction of DNA double-strand breaks alone does not account for radiosensitization mediated by halogenated pyrimidines in these human tumor cells.

Bromodeoxyuridine↗

PubMed1989

Radiosensitivity test for cancer of the uterine cervix.

In selecting the method of treating uterine cervical cancer, radiosensitivity is one of the most important factors. To know this factor before treatment, we are trying to estimate radiosensitivity with changes of primary tumors before and after the irradiation. Tumors must be irradiated uniformly with small doses, and based on these considerations, we are attempting external test irradiation for estimation of radiosensitivity. Radiosensitivity was determined histopathologically by comparing the results of histological specimens taken before and seven days after test irradiation. Radiosensitivity is closely related to prognosis: of 183 cases with good sensitivity, 146 cases (79.8%) were surviving at five years after radiotherapy. On the other hand, the five-year survival rate of cases with poor sensitivity was only 37.2%. Comparing radiation with operation in operable cases of stage I and II, the five-year survival rate in cases with good sensitivity was about the same (90%). On the contrary, in cases with poor sensitivity, there was a substantial difference: that is, 66.0% of operated cases had a five-year survival compared with 39.7% of radiated cases.

Female↗

PubMed1978

Profound radiosensitivity in "leukemic" T-cell lines and T-cell-type acute lymphoblastic leukemia demonstrated by sodium [51Cr]chromate labeling.

Radiation sensitivity was determined by measuring spontaneous release from 51Cr-labeled cells in various lymphoid cell populations. Among six leukemia T-cell lines originating from acute lymphoblastic leukemia, four such lines were found to be highly radiosensitive. In contrast, two of the leukemic T-cell lines and four normal control B-cell lines were not radiosensitive. Thymocytes from six patients and leukemia T-cell blasts from three patients with T-cell leukemia were likewise found to be highly radiosensitive, whereas leukemic blasts from six patients with null-cell (non-T, non-B-cell) acute lymphoblastic leukemia were not radiosensitive. Normal peripheral blood lymphocytes and mitogen-induced normal lymphoblasts were found not to be radiosensitive. The results indicate that measurement of the radiation sensitivity of acute leukemic blasts may have a therapeutic significance in coping with the heterogeneous nature of individual leukemia cases.

Animals↗

PubMed1988

Chromatin modifications associated with N-methylformamide-induced radiosensitization of clone A cells.

Exposure of certain cell lines to the differentiation-inducing agent N-methylformamide (NMF) enhances their radiosensitivity. As part of an attempt to elucidate the mechanism of NMF-induced radiosensitization, we examined the effects of NMF on chromatin structure, as reflected by changes in DNA-protein cross-links (DPCs) and the chromatin protein/DNA ratio, in two cell lines, clone A and HCA-1. Both lines form a better-differentiated phenotype upon exposure to NMF, yet only clone A is radiosensitized. Ionizing radiation induced DPCs in a linear manner beginning at about 10 Gy and continuing to at least 50 Gy in both cell types. NMF treatment of HCA-1 cells did not affect the background level of DPCs, but it enhanced the formation of radiation-induced DPCs at each dose tested. In clone A cells, NMF exposure elevated the DPC background level more than two-fold, and modified radiation-induced DPCs. The dose response for radiation-induced DPCs in NMF-treated clone A cells consisted of a linear increase up to 12.5 Gy, which was greater than in untreated cells, followed by a plateau level of DPCs out to 50 Gy, the highest dose tested. NMF treatment of clone A, but not HCA-1, cells also increased the chromatin protein/DNA ratio by about 30-35%. In clone A cells, the increases in DPC background level and chromatin protein/DNA ratio as a function of NMF exposure time followed a pattern similar to that of the enhancement of radiosensitivity. These data suggested that modifications of chromatin structure, not involved in differentiation, may be associated with the radiosensitizing actions of NMF.

Adenocarcinoma↗

PubMed1987

Potentiation of halogenated pyrimidine radiosensitizers in human carcinoma cells by beta-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran- 5,6-dione), a novel DNA repair inhibitor.

3,4-Dihydro-2,2-dimethyl-2H-naptho[1,2,-b]pyran-5,6-dione (beta-lapachone) is a novel DNA repair inhibitor. It was tested for synergistic X-ray-induced lethality in combination with several halogenated pyrimidine radiosensitizers. Logarithmic-phase growing human epidermoid laryngeal carcinoma (HEp-2) cells were allowed to incorporate pyrimidine analogues for 48 h (approximately two cell doublings) and then were X-irradiated and subjected to various posttreatments. beta-Lapachone synergistically increased the dose enhancement ratios (DERs) of all analogues screened, with the exception of the 2'-chloro derivative of 5-bromodeoxyuridine. For example, following 5-bromodeoxycytidine sensitization an X-ray DER value of 1.87 +/- 0.04 at 1% survival was increased to 3.51 +/- 0.42 due to a 4-h post-X-irradiation exposure to 4 microM beta-lapachone. Do and Dq values for halogenated pyrimidine-sensitized human epidermoid laryngeal carcinoma cells were decreased 1.4- to 5.4-fold and 1.4- to 4.0-fold, respectively. beta-Lapachone had little effect upon the cytotoxicities of unirradiated human epidermoid laryngeal carcinoma cells whether or not they were previously exposed to any of the halogenated pyrimidine radiosensitizers. beta-Lapachone treatment following X-irradiation of cells that had not incorporated a pyrimidine analogue exhibited DER values of 1.38 +/- 0.05 and 1.40 +/- 0.01 at 10 and 1% survival levels, respectively. beta-Lapachone enhanced the radiosensitization of deoxycytidine analogues to a greater extent than the structurally related deoxyuridine analogues. Greater DERs and lower Do and Dq values were found for deoxycytidine than for deoxyuridine analogue radiosensitizers following beta-lapachone treatment. This agent may improve presently used radiation therapies and enhance proposed strategies which utilize deoxycytidine analogue radiosensitization together with protection of normal tissues by tetrahydrouridine to achieve tumor-selective radiotherapy.

Bromodeoxycytidine↗

PubMed1986

Hyperthermic radiosensitization of thermotolerant Chinese hamster ovary cells.

Synchronous G1 cells were given a priming dose of heat (45.5 degrees C for 15 min) and then heated and irradiated 6-120 h later. Compared to heat radiosensitization for cells irradiated 10 min after the priming heat dose (thermal enhancement ratio, TER of 2.6 for a 10-fold reduction in survival), heat radiosensitization 18-24 h after the priming heat dose was less (i.e., TER of 1.6 for radiation at 24 h compared with heat-radiation at 24 h). A thermotolerance ratio (TTR) at 24 h was calculated to be 2.6/1.6 = 1.6. TERs at 100-fold or 1000-fold reduction in survival and ratios of slopes of radiation survival curves also showed that the cells developed a similar amount of thermotolerance for heat radiosensitization at 18-24 h. Furthermore, since the TER for heat radiosensitization increased with heat killing either from the priming heat dose or the second heat dose in a similar manner for single or fractionated doses, the TER for nonthermotolerant and thermotolerant cells was the same when related to the heat damage (i.e., amount of killing from heat alone). When the radiation response of cells heated and irradiated 6-120 h after the priming heat dose was compared with the response of cells receiving radiation only, changes in TER as a function of time after the initial priming heat dose were shown to involve: recovery of heat damage interacting with the subsequent radiation dose, thermotolerance for heat radiosensitization, and redistribution of cells surviving the first heat dose into radioresistant phases of the cell cycle. In fact, redistribution resulted in a minimal TER at 72 h for heat-radiation compared with radiation alone, instead of at 24 h where maximal thermotolerance for heat killing was observed [P. K. Holahan and W. C. Dewey, Radiat. Res. 106, 111 (1986)]. These observations are discussed relative to clinical considerations and similar results reported from in vivo experiments.

Animals↗