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PubMed2005

Radiosensitization of tumours by porphyrins.

Our previous data indicate, that hematoporphyrin dimethyl ether (HPde) can totally inhibit the growth of aggressive Ehrlich ascite tumour, when combined with low doses (2Gy) of ionizing radiation. Taking into account these findings, it appears of particular interest to evaluate the dependence of radiosensitizing efficiency of porphyrins on tumour aggressiveness. For this purpose two experimental tumour models (aggressive murine Ehrlich ascite carcinoma, (EAT), and not-aggressive hepatoma MH-22A) were used. Moreover, radiosensitizing properties of three porphyrin-type compounds of different chemical heterogeneity were evaluated (hematoporphyrin dimethyl ether (HPde), photofrin II (PII) and hematoporphyrin derivative (HPD)). Data obtained indicate, that HPde is the most effective one in this context (HPde>PII>HPD). It is important to note, that only the aggressive EAT tumours were radiosensitized by these dyes. No signs of radiosensitization (inhibition of tumour growth, injury of tumour tissue, evaluated by histological analysis) were observed in not-aggressive MH-22A hepatoma. Moreover, it was shown, that ligands of peripheral benzodiazepine receptors (PBR) might diminish the cell growth in aggressive EAT, but not in not-aggressive MH-22A hepatoma. The mechanism of radiosensitization by porphyrins, proposed in our previous studies, was strongly confirmed by these data. Actually, dicarboxylic porphyrins, being ligands of PBR, which are highly expressed in just aggressive tumours, can inhibit tumour cell proliferation and act in concert with ionizing radiation. Thus, combination of porphyrin and ionising radiation reflects the action of two antiproliferative factors, what eventually increases the response of aggressive tumours to the low doses of ionising radiation.

Animals↗

PubMed2005

[Assessment of tumor radiosensitivity using functional and metabolic nuclear imaging in research and clinical practice. A review].

During the last half of century considerable research on radiosensitivity biomarkers has been published. However, to date there is no non-invasive marker of cellular radiosensitivity identified for clinical routinely use. In this review, the main functional and metabolic imaging isotopic techniques for tumor radiosensitivity that have been explored over the last years are being described. This indirect evaluation fall into 3 topics associated with tumor proliferation rate or apoptosis, tumor hypoxic fraction, neoangiogenesis and the intrinsic radiosensitivity of clonogenic tumor cells. The final objective of the radiosensitivity monitoring during radiotherapy would be to adapt treatment strategy for overcoming the identified radioresistance mechanism such as hypoxia by the addition of radiosensitisers for example. This would allow better tumor control rather than continue inefficient and costly treatment delivery, which in addition could compromise outcome.

Cell Hypoxia↗

PubMed2006

Survivin gene RNA interference inhibits proliferation, induces apoptosis, and enhances radiosensitivity in HeLa cells.

OBJECTIVE: Survivin is a new member of the inhibitors of apoptosis (IAPs) family. It is upregulated in various malignancies including human cervical carcinomas. Reduction of this molecule has resulted in chemosensitization, but it is uncertain whether it can lead to radiosensitization. We observed the effect of survivin gene RNA interference (RNAi) on the proliferation, apoptosis, and radiosensitivity of the human cervical carcinoma cells HeLa. STUDY DESIGN: Human cervical carcinoma cells (HeLa) were transfected with the specific siRNA expression vector (pSilencer2.1-s2) designed to target survivin mRNA. A corresponding site-mutated vector was constructed as a negative control (pSilencer2.1-NC). The expression of survivin mRNA and its protein among the stable transfected cells and the untransfected ones was detected by semi-quantitative RT-PCR and Western blotting respectively. The cell growth was examined by methyl thiazolyl tetrazolium (MTT) assay. The cell cycle distribution and cell apoptosis were measured by flow cytometry. The changes in cell radiosensitivity were observed by clonogenic survival assay. RESULTS: Three stable transfected cell lines: HeLa-s2 (with pSilencer2.1-s2), HeLa-NC (with pSilencer2.1-NC), and HeLa-U6 neo (with empty vector pSilencer2.1-U6 neo) were established. The expression levels of survivin gene mRNA and protein in HeLa-s2 were significantly lower than in HeLa-NC, HeLa-U6 neo, and those untransfected HeLa cells. The expression inhibitory rates were 62.8% and 60.1%. The cell proliferation of HeLa-s2 was inhibited, and the highest inhibitory rate was 57.8+/-2.1%. The changes in cell cycle distribution in HeLa-s2 compared with the other three cell lines were obvious, many cells were blocked in the G(0)/G(1) phase 72.7+/-3.1% (P<0.05), reduced sharply in the G(2)/M phase (5.1+/-2.9)% (P<0.05), and also the apoptotic rate was 29.2+/-1.4%, obviously increasing (P<0.05). At the same dose of radiation, the cloning efficiency of HeLa-s2 declined notably (P<0.05); the cell survival curve showed a significant decrease in D(0) and D(q), which were 3.15 and 1.21, respectively (P<0.05), and the radiation enhancement ratios were 2.01 (a ratio of D(0)) and 1.77 (a ratio of D(q)). CONCLUSIONS: Survivin gene RNAi not only could inhibit the proliferation of human cervical carcinoma cells (HeLa), but also could significantly enhance the radiosensitivity of those cells through the reduction of its mRNA and protein. Therefore, an RNAi-targeted survivin gene strategy would be a potential approach to radiosensitization therapy in human cervical carcinomas.

Apoptosis↗

PubMed2004

Radiosensitization of vinorelbine and gemcitabine in NCI-H460 non-small-cell lung cancer cells.

PURPOSE: Results from recent clinical studies of gemcitabine and vinorelbine have encouraged the use of this combination concurrently with radiotherapy in the treatment of non-small-cell lung cancer, although preclinical data are limited. The present study aimed to quantify the in vitro interaction and radiosensitizing effect of gemcitabine and vinorelbine individually and in combination. METHODS AND MATERIALS: Cytotoxicity was measured by exposing NCI-H460 cells to gemcitabine and/or vinorelbine simultaneously or sequentially, followed by irradiation at 0-10 Gy. Clonogenic cell survival assays were performed. Flow cytometry was used to measure the effects of both drug and radiation on cell cycle distribution. Apoptosis was assessed by morphologic criteria, by sub-G1 changes using flow cytometry assay, and by Annexin-V binding assay. RESULTS: Both drugs showed single-agent activity against NCI-H460 cells and targeted different phases of the cell cycle. When both drugs were used in combination, they showed schedule-dependent interaction. An antagonistic effect was observed with simultaneous exposure to the two drugs. The optimum combination schedule was sequential exposure to vinorelbine followed by gemcitabine 24 h later. Both drugs showed radiosensitization effects. The radiosensitization effect of gemcitabine was evident when radiation was given immediately after 4-h incubation. However, the radiosensitization effect of vinorelbine was time dependent and observed with radiation given at 24 h postincubation. Apoptosis induced by gemcitabine increased gradually, reaching 20% at 72 h posttreatment. In contrast, apoptotic cell death was an early feature in vinorelbine-treated cells, reaching approximately 40% at 24 h. CONCLUSIONS: The individual cytotoxic effects of gemcitabine and vinorelbine on NCI-H460 cells are phase specific, and the combined effect of gemcitabine and vinorelbine is sequence dependent. The radiosensitizing effects of both drugs seem to be related to enhanced apoptosis.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Regional differences in radiosensitivity across the rat cervical spinal cord.

PURPOSE: To study regional differences in radiosensitivity within the rat cervical spinal cord. METHODS AND MATERIALS: Three types of inhomogeneous dose distributions were applied to compare the radiosensitivity of the lateral and central parts of the rat cervical spinal cord. The left lateral half of the spinal cord was irradiated with two grazing proton beams, each with a different penumbra (20-80% isodoses): lateral wide (penumbra = 1.1 mm) and lateral tight (penumbra = 0.8 mm). In the third experiment, the midline of the cord was irradiated with a narrow proton beam with a penumbra of 0.8 mm. The irradiated spinal cord length (C1-T2) was 20 mm in all experiments. The animals were irradiated with variable single doses of unmodulated protons (150 MeV) with the shoot-through method, whereby the plateau of the depth-dose profile is used rather than the Bragg peak. The endpoint for estimating isoeffective dose (ED(50)) values was paralysis of fore and/or hind limbs within 210 days after irradiation. Histology of the spinal cords was performed to assess the radiation-induced tissue damage. RESULTS: High-precision proton irradiation of the lateral or the central part of the spinal cord resulted in a shift of dose-response curves to higher dose values compared with the homogeneously irradiated cervical cord to the same 20-mm length. The ED(50) values were 28.9 Gy and 33.4 Gy for the lateral wide and lateral tight irradiations, respectively, and as high as 71.9 Gy for the central beam experiment, compared with 20.4 Gy for the homogeneously irradiated 20-mm length of cervical cord. Histologic analysis of the spinal cords showed that the paralysis was due to white matter necrosis. The radiosensitivity was inhomogeneously distributed across the spinal cord, with a much more radioresistant central white matter (ED(50) = 71.9 Gy) compared with lateral white matter (ED(50) values = 28.9 Gy and 33.4 Gy). The gray matter did not show any noticeable lesions, such as necrosis or hemorrhage, up to 80 Gy. All lesions induced were restricted to white matter structures. CONCLUSIONS: The observed large regional differences in radiosensitivity within the rat cervical spinal cord indicate that the lateral white matter is more radiosensitive than the central part of the white matter. The gray matter is highly resistant to radiation: no lesions observable by light microscopy were induced, even after a single dose as high as 80 Gy.

Animals↗

PubMed2005

Wound healing morbidity in STS patients treated with preoperative radiotherapy in relation to in vitro skin fibroblast radiosensitivity, proliferative capacity and TGF-beta activity.

BACKGROUND AND PURPOSE: In a recent study, we demonstrated that the ability of dermal fibroblasts, obtained from soft tissue sarcoma (STS) patients, to undergo initial division in vitro following radiation exposure correlated with the development of wound healing morbidity in the patients following their treatment with preoperative radiotherapy. Transforming growth factor beta (TGF-beta) is thought to play an important role in fibroblast proliferation and radiosensitivity both of which may impact on wound healing. Thus, in this study we examined the interrelationship between TGF-beta activity, radiosensitivity and proliferation of cultured fibroblasts and the wound healing response of STS patients after preoperative radiotherapy to provide a validation cohort for our previous study and to investigate mechanisms. PATIENTS AND METHODS: Skin fibroblasts were established from skin biopsies of 46 STS patients. The treatment group consisted of 28 patients who received preoperative radiotherapy. Eighteen patients constituted a control group who were either irradiated postoperatively or did not receive radiation treatment. Fibroblast cultures were subjected to the colony forming and cytokinesis-blocked binucleation assays (low dose rate: approximately 0.02 Gy/min) and TGF-beta assays (high dose-rate: approximately 1.06 Gy/min) following gamma-irradiation. Fibroblast radiosensitivity and initial proliferative ability were represented by the surviving fraction at 2.4 Gy (SF(2.4)) and binucleation index (BNI), respectively. Active and total TGF-beta levels in fibroblast cultures were determined using a biological assay. Wound healing complication (WHC), defined as the requirement for further surgery or prolonged deep wound packing, was the clinical endpoint examined. RESULTS: Of the 28 patients treated with preoperative radiotherapy, 8 (29%) had wound healing difficulties. Fibroblasts from patients who developed WHC showed a trend to retain a significantly higher initial proliferative ability after irradiation compared with those from individuals in the treatment group with normal wound healing, consistent with the results of our previous study. No link was observed between fibroblast radiosensitivity and WHC. Neither active nor total TGF-beta levels in cultures were significantly affected by irradiation. Fibroblast proliferation in unirradiated and irradiated cultures, as well as radiosensitivity, was not influenced by TGF-beta content. TGF-beta expression in fibroblast cultures did not reflect wound healing morbidity. CONCLUSIONS: These data are consistent with our previous study and combined the results suggest that in vitro fibroblast proliferation after irradiation may be a useful predictor of wound healing morbidity in STS patients treated with preoperative radiotherapy. TGF-beta levels in culture do not predict WHC, suggesting that the role of TGF-beta in wound healing is likely controlled by other in vivo factors.

Adolescent↗

PubMed2004

Chromosomal aberrations and in vitro radiosensitivity: intra-individual versus inter-individual variability.

In order to assess the applicability of the micronucleus (MN) and G2 assays as biomarkers of in vitro radiosensitivity and cancer susceptibility, we investigated the inter- and intra-individual variation of these endpoints. For the MN assay unstimulated blood cultures from 57 healthy donors were exposed in vitro to 3.5 Gy Co gamma-rays and for the G2 assay PHA stimulated cultures were irradiated with a dose of 0.4 Gy Co gamma-rays in the G2 phase of the cell cycle. For 14 donors, 2-15 repeat samples were tested over a period of 3 years. The repeat experiments revealed that the intra-individual variability was not significantly different from the inter-individual variability for both G2 and MN assays. As the intra-individual variability determines the reproducibility of the assay, our results highlight the limitations of these endpoints in detecting reproducible differences in radiation sensitivity between individuals within a normal population. Due to the high intra-individual variability and no significant difference with the inter-individual variability found in our study we conclude that care has to be taken when results obtained with chromosomal aberration assays based on one blood sample are used to assess the individual radiosensitivity. Multiple blood sampling may be necessary to draw reliable conclusions. Although more validation studies on the reliability of the G2 and MN assay will be required before they can be used in a confident way as biomarkers of individual radiosensitivity or cancer susceptibility the assays are very valuable to examine population radiosensitivity and the relationship between radiosensitivity, cancer predisposition and genotype.

Adult↗

PubMed2005

Potential application of the ATP cell viability assay in the measurement of intrinsic radiosensitivity in cervical cancer.

BACKGROUND: Intrinsic radiosensitivity using the clonogenic assay and the cell surviving fraction at 2 Gy (SF2) has been shown to be an independent prognostic factor for patient response to radiotherapy in carcinoma of the cervix. The clonogenic assay has significant shortcomings, making it unsuitable for routine clinical use. The ATP cell viability assay (ATP-CVA) has been shown to have a high tumor evaluability rate, technical simplicity, and reproducibility in chemosensitivity testing. AIMS: This study compares the ATP-CVA with the clonogenic assay in the in vitro radiosensitivity testing of cervical cancer cell lines. Correlation of in vitro radiosensitivity and in vivo patient response was also determined. METHODS: Five cervical carcinoma cell lines (SiHa, HeLa, Caski, C-33A, and C4-1) were tested using the ATP-CVA and the clonogenic assay. Survival curves were plotted and the mean SF2 values obtained by the two different assay methods were compared using ANOVA to see if there were significant differences. Mean SF2 values obtained from 27 cervical cancers were compared with clinical outcomes. RESULTS: The SF2 values for the cell lines ranged from 0.28 to 0.67 when tested using the ATP-CVA. Using the clonogenic assay, the SF2 values ranged from 0.27 to 0.70. ANOVA with Bonferroni pairwise multiple comparison showed no significant difference between the mean SF2 values for the individual cell lines between the two assay methods. Twenty-three cervical cancer samples (85%) were evaluable for SF2 using ATP-CVA. The mean SF2 values of patients who had locoregional failure were significantly higher than those who achieved local control (P <0.01). CONCLUSIONS: Testing intrinsic radiosensitivity using the surviving fraction at 2 Gy (SF2) is comparable using the two assay methods of ATP-CVA and clonogenic assay. The ATP-CVA should be further investigated in the testing of intrinsic radiosensitivity in patients with cervical cancer.

Adenosine Triphosphate↗

PubMed1999

Relationship between tumour cell in vitro radiosensitivity and clinical outcome after curative radiotherapy for squamous cell carcinoma of the head and neck.

BACKGROUND AND PURPOSE: Clinically, it is recognized that individual tumours respond differently to radiation treatment. Variation in tumour cell radiosensitivity is believed to be an important underlying factor. In the current study, cellular in vitro radiosensitivity was estimated as the fraction of surviving cells after a radiation dose of 2 Gy (SF2) and related to clinical outcome after curative radiotherapy. PATIENTS AND METHODS: Thirty-eight patients with squamous cell carcinoma of the head and neck were treated with curative radiotherapy alone. Pre-treatment biopsies were disaggregated to form a single-cell suspension and cells were cultured in the modified Courtenay-Mills soft agar clonogenic assay. Directly from this assay and with no respect to cell type, overall SF2 was assessed. By collecting the obtained colonies on a preparation slide using a colony-filter technique, and with immunocytochemical staining, it was possible to measure the surviving fraction of tumour cells selectively as tumour cell SF2. RESULTS: Experimentally, a broad inter-tumour variation was found for both tumour cell SF2 and overall SF2. Using weighted linear regression, it was demonstrated that tumour cell SF2 and overall SF2 were two independent measures of tumour radiosensitivity. In general, the measures of tumour radiosensitivity were independent of patient sex and age, T- and N-category, disease stage, tumour size and plating efficiency. Among the 38 patients grouped in loco-regional failures and patients with loco-regional control, respectively, sex, age, total radiation dose, overall treatment time and tumour grade were equally distributed. Advanced stage, lymph node involvement and tumour size correlated statistically significantly with poor loco-regional control. Neither tumour cell SF2, overall SF2, nor plating efficiency predicted loco-regional tumour control probability. In a multivariate analysis with respect to the risk of loco-regional tumour failure, only disease stage yielded independent prognostic significance. This significance suggests that this patient sample was representative for the patient population with head and neck cancer. CONCLUSION: In 38 patients with squamous cell carcinoma of the head and neck, the estimated tumour radiosensitivities were not statistically related to clinical outcome after curative radiotherapy alone.

Adult↗

PubMed1999

Potentially lethal damage repair and its inhibitory effect of caffeine in two yolk sac tumor cell lines with different radiosensitivities.

PURPOSE: In order to investigate the role of potentially lethal damage repair (PLDR) in cellular radiosensitivity, PLDR and its inhibitory effect by caffeine was examined. In addition, cell cycle distribution was also examined. MATERIALS AND METHODS: Two rat yolk sac tumor cell lines, NMT-1 and NMT-1R, with different radiosensitivities in vitro were used. The capacity for PLDR was examined using confluent-phase cells, and evaluated by calculating the recovery ratio. Inhibitory effect of caffeine on PLDR was examined with doses of 1, 5 and 10 mM. RESULTS: The capacity of PLDR in two cell lines reflected radiosensitivity. The recovery ratio after irradiation of 5 Gy was 2.8 in the radiosensitive NMT-1 and 5.2 in the radioresistant NMT-1R, and recovery reached its peak level at 6 h in both cell lines. The degree of inhibition of PLDR was weaker in NMT-1R than that in NMT-1 at the same dose level, and was correlated with reduction of G2-arrested cells by caffeine. CONCLUSIONS: The results of this study suggest that the capacity of PLDR may be one of the determinant factors for radiosensitivity in the two cell lines used, and the inhibitory effect of caffeine on PLDR was in part attributable to the modification of the cell cycle progression.

Animals↗

PubMed2000

Radiosensitization produced in vivo by once- vs. twice-weekly 2'2'-difluoro-2'-deoxycytidine (gemcitabine).

PURPOSE: Gemcitabine (2'2'-difluoro-2'-deoxycytidine, dFdCyd) is a potent radiosensitizer of rodent and human tumor cells. Our Phase I clinical trial using once-weekly dFdCyd as a radiosensitizer in the treatment of patients with Stage IV squamous cell head and neck cancer has produced a high rate of tumor response and significant normal mucosal toxicity. These findings raised the question of whether we are using dFdCyd in the optimal dose and schedule. In vitro studies suggest that twice-weekly dFdCyd has the potential to be more effective than once-weekly dFdCyd when administered in combination with radiation (RT) given 5 days per week. Therefore, we have used a mouse model to assess whether the therapeutic ratio of combined modality therapy may be improved by using a twice-weekly drug regimen. We asked two questions: 1) Does a once-weekly or twice-weekly dFdCyd regimen cause more normal tissue radiosensitization? 2) Does a once-weekly or twice-weekly dFdCyd + RT regimen produce a better therapeutic index? METHODS AND MATERIALS: To assess normal tissue toxicity, C3H mice underwent mouth (60)Co RT (27.5 Gy in 5 daily fractions) +/- dFdCyd delivered intraperitoneally (IP) either once or twice weekly 6 hours prior to irradiation. Acute lip reactions were quantified according to a standard scoring system, and weight loss was measured. We measured tumor control using squamous cell carcinoma (SCC) VII murine squamous cell flank tumors (50-125 mm(3)) treated with the same regimens used in the mouth irradiation model. RESULTS: We found that dFdCyd delivered 800 mg/kg once weekly or 150 mg/kg twice weekly caused similar (and maximal tolerable) weight loss; therefore these regimens were chosen to test which schedule produced more acute lip radiosensitization. Twice-weekly dFdCyd + RT was somewhat more toxic by weight loss (800 mg/kg once weekly: 11.9%; 150 mg/kg twice weekly: 17.7%; p = 0.09). To assess therapeutic index, we treated SCC VII flank tumors with RT combined with isotoxic drug/RT regimens (dFdCyd 800 mg/kg once weekly or 100 mg/kg twice weekly). Tumors treated with twice-weekly dFdCyd + RT were significantly smaller than tumors treated with once-weekly drug + RT at 28 days from the start of treatment (p < 0.03). CONCLUSIONS: These findings demonstrate that equitoxic once- versus twice-weekly dFdCyd regimens cause differing levels of oral mucosal radiosensitization. This would suggest that each radiation-dFdCyd schedule will require its own dFdCyd dose escalation trial (which cannot be determined by the maximum tolerated dose (MTD) for dFdCyd alone using that schedule). In addition, our findings suggest that for head and neck cancers twice-weekly dFdCyd may have a higher therapeutic index compared with once-weekly dFdCyd when combined with daily RT.

Animals↗

PubMed2001

Adenovirus-mediated overexpression of dominant negative epidermal growth factor receptor-CD533 as a gene therapeutic approach radiosensitizes human carcinoma and malignant glioma cells.

PURPOSE: Epidermal growth factor receptor (EGFR) and other members of the ErbB family of receptor tyrosine kinases (RTK) mediate autocrine growth regulation in a wide spectrum of human tumor cells. We have previously demonstrated that in stably transfected mammary carcinoma cells a dominant negative (DN) mutant of EGFR, EGFR-CD533 is a potent inhibitor of EGFR and its cytoprotective signaling after exposure to ionizing radiation. In the present study, we further investigate the capacity of a genetic approach, using replication-incompetent adenovirus (Ad)-mediated transfer of EGFR-CD533 (Ad-EGFR-CD533), to enhance the radiosensitivity in vitro of four cell lines representative of three major cancer phenotypes. METHODS AND MATERIALS: The cell lines MDA-MB-231 and T-47D mammary carcinoma, A-431 squamous carcinoma, and U-373 MG malignant glioma cells were used. The ErbB expression profiles and the EGFR tyrosine phosphorylation (Tyr-P) levels following irradiation were quantified by Western blotting. The relative radiosensitivities of tumor cells were assessed by standard colony formation assays after infection with control vector (Ad-LacZ) or Ad-EGFR-CD533. RESULTS: The expression profiles demonstrated varying levels of EGFR, ErbB2, ErbB3, and ErbB4 expression. The overexpression of EGFR-CD533 after infection with Ad-EGFR-CD533 completely inhibited the radiation-induced stimulation of EGFR Tyr-P relative to the immediate 2.4- to 3.1-fold increases in EGFR Tyr-P in control infected cells (Ad-LacZ). Ad-EGFR-CD533-infected cells demonstrated significant (p < 0.001) radiosensitization over a range of radiation doses (1-8 Gy), yielding dose-enhancement ratios (DER) between 1.4 and 1.7. This radiosensitization was maintained under conditions of repeated radiation exposures, using 3 x 2 Gy, yielding DERs of 1.6 and 1.7 for MDA-MB-231 and U-373 cells, respectively. CONCLUSIONS: Overexpression of EGFR-CD533 significantly sensitizes human carcinoma and glioma cells to single and repeated radiation exposures irrespective of their ErbB expression levels. Therefore, transduction of human tumor cells with EGFR-CD533 holds promise as a gene therapeutic approach for the radiosensitization of neoplastic cells that are growth-regulated by EGFR or other ErbB receptors.

Adenoviridae↗

PubMed2002

Pronounced radiosensitization of cultured human cancer cells by COX inhibitor under acidic microenvironment.

PURPOSE: To demonstrate the influence of pH on the cytotoxicity and radiosensitization by COX (cyclooxygenase) -1 and -2 inhibitors using established human cancer cells in culture. METHODS AND MATERIALS: Nonselective COX inhibitor, ibuprofen (IB), and selective COX-2 inhibitor, SC-236, were used to determine the cytotoxicity and radiosensitization at varying pH of culture media. Human colon carcinoma cell line (HT-29) was exposed to the drug alone and in combination with radiation at different pH of the cell culture media. The end point was clonogenic ability of the single-plated cells after the treatment. RESULTS: Cytotoxicity and radiosensitization of IB increased with higher drug concentration and longer exposure time. The most significant radiosensitization was seen with IB (1.5 mM) for 2-h treatment at pH 6.7 before irradiation. The dose-modifying factor as defined by the ratio of radiation doses required to achieve the same effect on cell survival was 1.8 at 10% survival level. In contrast, SC-236 (50 microM for 2-8 h) showed no pH-dependent cytotoxicity. There was modest increase in the cell killing at lower doses of radiation. CONCLUSION: An acidic pH was an important factor affecting the increased cytotoxicity and radiosensitization by ibuprofen. Radiation response was enhanced at shoulder portion of the cell survival curve by selective COX-2 inhibitor.

Cell Survival↗

PubMed2003

Why recent studies relating normal tissue response to individual radiosensitivity might have failed and how new studies should be performed.

PURPOSE: New insights into the kinetics of late complications occurring after radiation therapy indicated that all patients have a constant risk of developing late tissue complications. These observations might have a great impact on studies relating normal tissue complications to individual radiosensitivity. METHODS AND MATERIALS: Data previously published by Peacock et al. were used for analysis. In this study, 39 breast cancer patients with severe reactions (responders) were compared with 65 matched patients showing no reactions (nonresponders). Cellular radiosensitivity as measured in vitro in terms of D(0.01) did not show significant differences between the two groups, both for high-dose-rate (5.84 +/- 0.06 vs. 5.85 +/- 0.07 Gy) and low-dose-rate (7.44 +/- 0.10 vs. 7.56 +/- 0.09 Gy) irradiation. RESULTS: A theoretical distribution was calculated for the individual radiosensitivity of patients with Grade or=(MV + SD), a normal group with a sensitivity between MV - SD and MV + SD, and a sensitive group <or=(MV - SD), the relative fractions being 16%, 68%, and 16%, respectively. It was assumed that these groups differed in the risk of developing late complication; for Grade 3 the annual incidence rate was set at 1%, 2%, and 4% and for Grade 2 at 5%, 10%, and 20% per year, respectively. It was shown that the mean cellular sensitivity calculated for Grade 3 (7.39 +/- 0.10 Gy) or Grade 2 patients (7.46 +/- 0.06 Gy) was slightly but not significantly lower than that of Grade <or= 1 patients (7.65 +/- 0.04 Gy). This result demonstrated that even if the risk was assumed to depend clearly on the individual radiosensitivity, significant differences in the mean cellular sensitivity between responders and nonresponders were not expected, just as found by Peacock et al. It was shown that a significant correlation between these two parameters could be detected only when the risk was analyzed separately for each group of patients. CONCLUSION: Most data published so far aiming at establishing a relationship between cellular radiosensitivity and the risk of late complications might need to be reevaluated, because the questions asked up to now were inadequate to arrive at a meaningful answer.

Breast Neoplasms↗

PubMed1996

Evaluation of the radiosensitizing effects of RK28 intravenous, intraarterial, and intratumoral injections on the rabbit VX2 tumor system.

PURPOSE: To evaluate the differences in the radiosensitizing effects of intravenous (i.v.) injection, intraarterial (i.a.) injection, and intratumoral (i.t.) injections of the hypoxic cell radiosensitizer RK28 ([1-(4'-hydroxy-2'-butenoxy)methyl-2-nitroimidazole], a 2-nitroimidazole with an acyclic sugar analogue substituted at the N-1 position of the imidazole ring) using an animal experimental system. METHODS AND MATERIALS: Rabbit VX2 tumors, which were implanted in the muscle of left hind legs and grown to 3 cm in diameter, were treated with RK28 (80 mg/kg x b.wt.) before 15 Gy of local x-ray irradiation. The auricular vein and the left saphenous artery were used for systemic injection and regional injection, respectively. For i.t. injection, a 21-gauge needle with three lateral holes was positioned in the central area of the tumor. Tumor regression was precisely evaluated by computed tomograpy (CT), and survival time was also studied. Using high-performance liquid chromatography (HPLC), pharmacokinetic studies for RK28 and its seven major metabolites were performed in tumor and serum at 0, 10, 20, 30, and 60 min after drug injection was completed. RESULTS: Radiosensitizing effects of RK28 were considered present after i.a. injection (p < 0.05) and i.t. injection (p < 0.05) after analyzing tumor volumes on day 21 after treatment. Increased survival was not observed in any group with RK28 injection compared with survival in the group treated by x-ray irradiation alone. Pharmacokinetic studies showed the average concentration of RK28 in the tumor during x-ray irradiation was 1.3 times higher after i.a. injection and 3.5 times higher after i.t. injection than that after i.v. injection. The time modifying factor50 (TMF50: ratio of time for tumor to decrease by 50%, radiation alone vs. radiation plus drug) was calculated to be 1.5 after i.v. injection, 1.7 after i.a. injection, and 2.3 after i.t. injection. The values of TMF50 correlated to the average concentrations of RK28 in the tumor. As to metabolites of RK28, beta-glucuronated compound and cysteine conjugate were highly detected. The concentrations of cysteine conjugate were higher in the tumor than in serum via i.v. injection. CONCLUSIONS: Radiosensitizing effects of RK28 were observed on the rabbit VX-2 tumor system after i.a. or i.t. injection. Pharmacokinetic studies proved that radiosensitizing effects depended on the concentration in the tumor, though the administration routes were different. Combined forms with nonprotein thiols were detected. However, survival benefits were not obtained by RK28. For clinical applications of RK28, i.a. or i.t. injection could facilitate better local control of cancer.

Animals↗

PubMed1997

Rapid assay of intrinsic radiosensitivity based on apoptosis in human CD4 and CD8 T-lymphocytes.

PURPOSE: An assay for radiosensitivity has numerous applications in the clinic. Avoidance of acute responses, prediction of normal tissue toxicity, and individualization of patient radiotherapy are included among these. We have developed a rapid assay (about 24 h) able to predict intrinsic radiosensitivity of CD4 and CD8 T-lymphocytes based on radiation-induced apoptosis. METHODS AND MATERIALS: Fresh blood samples (1-2 ml in heparinized tubes) were irradiated with 0-, 2-, and 8-Gy X rays at a dose rate of approximately 3 Gy/min. Following irradiation, the cells were collected and prepared for flow-cytometric analysis and cell sorting. In conjunction with the CellQuest software available with the FACSVantage cell sorter (Becton-Dickinson), two T-lymphocyte types were analyzed on the basis of their cell-specific antigens (CD4 and CD8), and DNA was stained with DAPI. Following the separation of these cell types, radiation-induced cell death was assessed. Cytotoxicity was characterized by gradual degradation of internucleosomal DNA which results in a sub-G1 peak on the DNA histogram, and by the associated loss of surface antigens causing an intermediate positive peak in the antibody histogram. Using the assay, we investigated the interdonor variation in a cohort of 45 healthy adult blood donors and 5 children [one had immunodeficiency, centromeric instability, and facial anomalies syndrome (ICF), and one had ataxia telangiectasia (AT)]. Intradonor variation was assessed with 10 different experiments from a single donor. RESULTS: CD4 and CD8 T-lymphocyte radiosensitivities were correlated (r = 0.63 and 0.65 for 2 and 8 Gy, respectively) in 45 adult donors. Both for CD4 and CD8 cells, 2 and 8 Gy irradiation responses showed a good correlation (r = 0.77 for both). Interdonor variation was significantly higher than intradonor variation (p < 0.0005) for all CD4 and CD8 data. We observed a decrease in the antigen fluorescence of dying cells, a phenomenon referred to as antigen-ebb. Antigen-ebb was clearly observed in both cell types, and correlated significantly with cytotoxicity. A trend was observed between radiosensitivity and donor age, but there was no correlation for gender. Blood from a 4-year-old girl presenting with ICF demonstrated compromised radiation-induced cytotoxicity in her CD4 T-lymphocytes, and an 11-year-old boy presenting with AT demonstrated compromised radiation-induced cytotoxicity in both his CD4 and CD8 T-lymphocytes. CONCLUSION: We conclude that the assay provides a rapid means of determining radiosensitivity, can discriminate differences in radiation-induced cytotoxicity between individuals, and can be used as a rapid screen for genetically hypersensitive patients. Antigen-ebb offers interesting possibilities for molecular biological investigations, permitting characterization and isolation of abnormal but vital cells in the absence of clastogenic agents.

Adult↗

PubMed1998

Radiosensitizing potential of gemcitabine (2',2'-difluoro-2'-deoxycytidine) within the cell cycle in vitro.

PURPOSE: Gemcitabine (2',2'-difluorodeoxycytidine; dFdCyd) is a new deoxycitidine analog which exhibits substantial activity against solid tumors and radiosensitizing properties in vitro. To examine cell cycle-specific effects of a combined treatment with gemcitabine and radiation, the in vitro clonogenic survival of two different cell lines was measured for cells from log-phase culture, G1 and S-phase cells. METHODS AND MATERIALS: Chinese hamster (V79) and human colon carcinoma (Widr) cells were exposed to different radiation doses and for different points of time relative to gemcitabine treatment (2 h). Experiments were also carried out with different cell-cycle populations obtained after mitotic selection (V79) or after serum stimulation of plateau-phase cells (Widr). The resulting survival curves were analyzed according to the LQ model, and mean inactivation doses (MID) and the cell cycle-specific enhancement ratios (ER) were calculated from the survival curve parameters. RESULTS: Effectiveness of combined treatment of log-phase cells was greatest when cells were irradiated at the end of the gemcitabine exposure [ER: 1.28 (V79), 1.24 (Widr)]. For later times after the removal of the drug, radiosensitization declined, approaching independent toxicity. From the time course of interactive-type damage decay half-life values of 75 min (V79) and 92 min (Widr) were derived. Gemcitabine did not radiosensitize G1 Widr cells or V79 cells from the G1/S border, but substantial radiosensitization was observed for the S-phase cell preparations [ER: 1.45 (V79-lateS), 1.57 (Widr)]. CONCLUSIONS: Treatment of cells with gemcitabine immediately before irradiation eliminates, or at least greatly reduces, the variation in radiosensitivity during the cell cycle that is manifested by radioresistance during S phase. This reversal of S-phase radioresistance could imply that gemcitabine interferes with the potentially lethal damage repair/fixation pathway. Other approaches have been taken to overcome S-phase radioresistance, such as hyperthermia or densely ionizing radiation, and combined treatments with dFdCyd could prove of value to complement such efforts.

Animals↗

PubMedDate not supplied

[Tumor and individual radiosensitivity. An introduction].

This text is intended to introduce the following articles, which correspond to the lectures given at the "Radiosensitivity" session of the 1998 SFRO Meeting. We first underline the somewhat disappointing results obtained so far for evaluating tumoral radiosensitivity. However, a few new tests could bring some hope in a not-too distant future. We then focus on individual radiosensitivity. We first list the syndromes or diseases associated with a known hyperradiosensitivity. We then concentrate on the radiosensitivity tests that are available in 1998, some of them being already used in a few centers in specific situations. However, the "optimal" test is still to be identified. After a brief chapter on the possible modulations of radiosensitivity, we conclude with a few recommendations to the clinician.

Causality↗