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PubMed1995

[Can an extremely elevated radiosensitivity in patients be recognized by the in-vitro testing of lymphocytes?].

BACKGROUND: We have examined the in-vitro radiosensitivity of lymphocytes in patients with extreme acute and chronic reactions after curative radiotherapy under the assumption of increased genetic radiosensitivity. PATIENTS AND METHODS: 16 patients (14 females, 2 males, age 40 to 69 years) were retrospectively examined 1 to 108 months after radiotherapy. All had undergone definitive or postoperative curative radiotherapy for cancer (12 breast cancer, 2 lung, 1 bladder, and 1 head and neck cancer). None of them had known genetic disorders with increased radiosensitivity. Four patients were considered as having probably increased radiosensitivity; they had shown poor tolerance to radiotherapy (1 severe acute reaction with cessation of radiotherapy in bladder cancer and subsequent bladder shrinkage after 45 Gy, 1 acute skin reaction well above average with subsequent fibrosis after irradiation for regional recurrence of breast cancer, 1 radiation myelitis after palliative irradiation with 5 x 5 Gy for lung cancer, 1 severe acute reaction after mediastinal irradiation for lung cancer). Twelve patients were considered as having normal tolerance to radiotherapy. They had tolerated radiotherapy well with normal acute reactions and no or minimal signs of late radiation sequelae. Lymphocyte cultures were prepared from all patients and irradiated with 0.7 and 2 Gy, respectively; 1 culture served as control (0 Gy). Chromosomes 1, 2, and 4 were stained using fluorescence in-situ hybridization (FISH) with a 3-colour-chromosome-in-situ suppression technique. Chromosomal breaks were counted in 200 to 1000 mitoses. Radiation sensitivity was expressed as radiation-induced breaks per mitoses corrected for breaks at 0 Gy. The probes were coded and the examiner did not know the clinical course. RESULTS: Significant differences in interindividual radiation sensitivity were detectable. The frequency of radiation-induced breaks/1000 mitoses ranged from 70 to 556 after 0.7 Gy and from 420 to 1210 after 2 Gy. The 4 patients with increased clinical radiation sensitivity showed also increased chromosomal radiation-induced damage as compared to the 12 patients with normal radiation tolerance (469 +/- 103 vs. 126 +/- 79 breaks/1000 mitoses induced by 0.7 Gy, p = 0.0011, and 864 +/- 258 vs. 574 +/- 119 breaks/1000 mitoses induced by 2 Gy, p = 0.019). CONCLUSIONS: Patients with increased clinical radiosensitivity exhibited increased chromosomal damage in lymphocytes in vitro measured with chromosome painting with a FISH-technique. This technique may be useful to detect patients with severely enhanced radiosensitivity. The results suggest that if radiosensitivity is abnormally elevated this may be present and detectable in different organs.

Aged↗

PubMed1997

The intrinsic radiosensitivity of some human tumor cells throughout their cell cycles.

The intrinsic radiosensitivity of tumor cells is most frequently reported for asynchronous populations, although cell cycle variation in radiosensitivity is known to be significant. Linear-quadratic analyses of survival data for asynchronous human tumor cells show wide variations in the alpha coefficient with smaller variations in the beta coefficient. HT-29 (colon), OVCAR10 (ovary) and A2780 (ovary) tumor cells with alpha coefficients of 0.03, 0.16 and 0.47 Gy(-1), respectively, and square-root of beta coefficients of 0.23-0.27 Gy(-1) for asynchronous populations were amenable to synchronization by mitotic selection. Selection procedures were optimized for each cell line and produced mitotic populations of >90%, approximately 80% and approximately 65% purity for HT-29, OVCAR10 and A2780 cells, respectively. Mitotic cells from each line exhibited similar and maximum radiosensitivities with alpha coefficients of approximately 1.3 Gy(-1) after irradiation with 137Cs gamma rays and after correction for genome multiplicity. Their relative radiosensitivities observed with asynchronous cells were maintained as they progressed through interphase of the cell cycle. All cells in early G1 phase exhibited a marked radioresistance relative to their sensitivity in mitosis, and maximum interphase radiosensitivity was observed near the G1/S-phase boundary. All cells became increasingly radioresistant as they moved through S phase, the effect being most pronounced for OVCAR10 cells and least pronounced for A2780 cells. HT-29 cells remained relatively radioresistant in G2 phase. The different interphase radiosensitivities observed for these cell lines were determined mainly by the single-hit inactivation mechanism. These studies clearly demonstrate the dominant role of single-hit inactivation in determining the intrinsic radiosensitivity of human tumor cells to 137Cs gamma rays, especially at doses of 2 Gy and less.

Cell Cycle↗

PubMed1998

Cancer predisposition, radiosensitivity and the risk of radiation-induced cancers. IV. Prediction of risks in relatives of cancer-predisposed individuals.

Individuals carrying cancer-predisposing germline mutations are known to be at a higher risk for cancers than those who do not carry them. This is also true of their biological relatives because they have a higher probability of being carriers of such mutant genes than unrelated individuals in the population. Further, there are now sufficient grounds for assuming that cancer-predisposed individuals may also be at a higher risk for cancers induced by ionizing radiation. In our earlier work, we examined the impact of this heterogeneity (with respect to cancer predisposition and radiosensitivity differentials) on risks of radiation-induced cancer at the population level. This paper is focused on the question of risks of radiation-induced cancer in relatives of cancer-predisposed individuals. Using an autosomal dominant model of cancer predisposition and radiosensitivity developed earlier and applying it to breast cancer risks associated with mutations in the BRCA1 gene, we show that: (1) The risk ratio (i.e. the ratio of risk of radiation-induced cancer in relatives to that in unrelated individuals) in the population increases with the degree of biological relatedness of the relative, being higher for close than for distant relatives; incomplete penetrance of the mutant gene "dilutes" this risk ratio. (2) The proportion of excess radiation-induced cancers in relatives (i.e. the attributable fraction) is higher than in unrelated individuals. (3) In relatives, the proportion of excess cancers due to radiosensitivity differentials alone depends on the strength of predisposition, the radiosensitivity differentials assumed, the radiation dose, the proportion of cancers due to predisposition, the mutant gene frequency and the penetrance of the mutant gene. This is in contrast to the situation for unrelated individuals, for whom the above-mentioned proportion is dependent on the first three but not on the last three of these factors. Further, even when the proportion of excess cancers is small, most of it is due to radiosensitivity differential alone both in unrelated individuals and in relatives. (4) For values of predisposition strength and radiosensitivity differential <10, even when the estimated frequency of a mutant BRCA1 gene is 0.0047 and the proportion of breast cancers due to these mutations is 38% (as is the case for Ashkenazi Jewish women under age 30), the increase in breast cancer risks is only marginal even for first-degree relatives. (5) These findings support the conclusion that increases in radiation risks to relatives (compared to those in unrelated individuals), to be detectable epidemiologically, will occur only when the mutant alleles are common and the strength of predisposition and radiosensitivity differentials are conjointly dramatic.

Breast Neoplasms↗

PubMed1999

The mechanism of retinoic acid radiosensitization is independent of AP-1 repression in a cervical carcinoma cell line.

INTRODUCTION: Retinoic acid (RA) has been shown to radiosensitize some tumor cell lines. RA regulates gene expression through nuclear receptors that bind to retinoic acid response elements in gene promoters and that inhibit activator protein-1 (AP-1) transcription factor activity. OBJECTIVE: The aim of this study was to determine if the mechanism of radiosensitization of the CC-1 human cervical carcinoma cell line by 9-cis-RA (9cRA) involves repression of AP-1 activity. METHODS: The CCA reporter cell line was established from CC-1 by permanent transfection with the ColCAT reporter plasmid which consists of the chloramphenicol acetyltransferase (CAT) gene under the control of the AP-1-responsive collagenase gene promoter. CCA cultures were treated with various combinations of 9cRA, 60Co radiation, and an AP-1 inducer called O-tetradecanoylphorbol 13-acetate (TPA). Cultures were then evaluated in parallel for CAT expression as a measure of AP-1 activity and for clonogenic survival as a measure of radiosensitization. RESULTS: The CCA reporter line exhibited a radiation dose-responsive induction of AP-1 activity that was decreased by 5 microM 9cRA and increased by 50 ng/ml TPA. Simultaneous treatment with TPA and 9cRA prevented 9cRA repression of AP-1 and resulted in AP-1 activity above basal level. The 9cRA radiosensitized CC-1 cultures with a dose modification factor of 1.5. The survival of cultures treated simultaneously with TPA and 9cRA was statistically identical to that of cultures treated with 9cRA alone. CONCLUSION: Although TPA prevented AP-1 repression by 9cRA, it did not prevent radiosensitization in CCA cultures, therefore the mechanism of radiosensitization of CCA by 9cRA is independent of AP-1 repression.

Alitretinoin↗

PubMed1995

Comparison of cellular radiosensitivity between different localizations of head and neck squamous-cell carcinoma.

The prognosis of carcinomas arising from various sites in the head and neck varies even when the stage of the disease is taken into consideration, e.g. laryngeal carcinoma has a more favourable prognosis compared to oral-cavity malignancies. The purpose of this study was to evaluate intrinsic cellular radiosensitivity as one possible explanation for the observed differences in the survival rates of different anatomical groups. The radiation survival curves were determined for well characterized cell lines derived from laryngeal carcinoma (n = 14), pharyngeal carcinoma (n = 6), carcinoma of the oral cavity (n = 14) and the skin of the face (n = 3). The intrinsic radiosensitivity was expressed as area under the survival curve (AUC) values, and this cellular parameter was compared with clinical data and survival of the patients. The intrinsic radiosensitivity in the whole group varied between 1.0 Gy and 2.8 Gy with an average of 1.9 Gy. The mean AUC values for the laryngeal cell lines were 2.0 Gy +/- 0.2, for the oral cavity 1.8 +/- 0.3 Gy, for the pharynx 1.8 +/- 0.2 Gy and for cutaneous carcinoma 2.1 +/- 0.1 Gy. There was a slight difference between the groups of glottic and supraglottic cell lines (mean 1.8 +/- 0.2 Gy and 2.1 +/- 0.3 Gy, respectively), which is consistent with the differences in clinical curability of these cancers. Otherwise, the differences in cellular radiosensitivity of the carcinoma groups studied did not reach statistical significance. These results indicate that the intrinsic radiosensitivity of squamous-cell carcinoma (SCC) of the larynx does not significantly differ from that of SCC of other sites of the head and neck. Variations in the intrinsic radiosensitivity do not as such seem to explain the observed differences in radiocurability of SCC variously localized in the head and neck.

Carcinoma, Squamous Cell↗

PubMed1991

Heterogeneity in antigenic expression and radiosensitivity in human colon carcinoma cell lines.

A panel of human colon carcinoma cell lines were characterized regarding both antigenic heterogeneity and variations in radiosensitivity. Monoclonal antibodies were used to study the expression of carcinoembryonic antigen (CEA), gastrointestinal cancer antigen (GICA or CA 19-9) and carcinoma-associated antigen (CA-50). Radiosensitivity was studied with the clonogenic survival technique. Three cell lines, LS 174T, HCTC, and SW 1116 stained positive for all three antigens. HT-29 was positive for CA 19-9 and CA-50 whereas Caco-2 was positive for CEA and CA 19-9. The cell lines SW 620 and LIM 1215 only stained positive for one of the antigens, CA-50 and CEA, respectively. In nearly all positive cases the stainings were very heterogeneous with mixtures of positive and negative cells. One exception was the HCTC cells which stained homogeneously for the CA 19-9 and CA-50 antigens. The neuroendocrinelike COLO 320 cells were negative in all cases. The radiosensitivity varied strongly between the cell lines with Dq-values between 0.8 and 1.9, extrapolation numbers between 2.0 and 4.7, Do-values between 1.1 and 2.8. The surviving fraction at 2 Gy varied between 0.3 and 0.7 with HCTC as the most radiosensitive and HT-29 as the most radioresistant cell line. Thus, there were differences in antigenic expression and intrinsic radiosensitivity between the cell-lines and antigenic heterogeneities within each cell line. The analyzed panel of cell lines will be valuable in studies of dose-effect relations for monoclonal antibodies labeled with toxic radionuclides simulating both antigenic heterogeneity and variations in radiosensitivity.

Adenocarcinoma↗

PubMed2004

Pentoxifylline enhances tumor oxygenation and radiosensitivity in rat rhabdomyosarcomas during continuous hyperfractionated irradiation.

PURPOSE: To examine the influence of the hemorrheologic agent pentoxifylline (PTX) on tumor oxygenation and radiosensitivity. MATERIAL AND METHODS: Tumor oxygenation in rat rhabdomyosarcomas R1H after PTX administration (50 mg/kg body weight) was measured using interstitial pO(2) probes (Licox CMP system and Eppendorf pO(2)-Histograph). Tumors were irradiated with (60)Co gamma-irradiation using single doses (15 and 30 Gy), conventional fractionation (60 Gy/30 fractions/6 weeks), and continuous hyperfractionation (54 Gy/36 fractions/18 days) in combination with PTX or an equivalent volume of physiological saline. Radiation effects were determined by tumor growth delay (2V(o)), and by partial and complete tumor remission. RESULTS: PTX increased tumor oxygenation for up to 45 min after administration of the drug. Single doses of 15 and 30 Gy of irradiation, when combined with PTX, produced little radiosensitization of the R1H tumors as indicated by dose-modifying factors (DMFs) of 1.11 and 1.04, respectively. In conventional fractionated irradiation with PTX, a DMF of 1.10 was obtained only. However, in continuous hyperfractionated irradiation with 18 x 50 mg/kg of PTX, the DMF with respect to tumor growth delay was found to be 1.37. Local tumor control was not influenced by PTX. In vitro studies identified R1H cells as p53 wildtype and showed a G1 arrest in response to irradiation. When 2 mM PTX was given prior to irradiation, it did not improve radiosensitivity of R1H cells as measured by clonogenic survival assays. CONCLUSION: PTX effectively enhances tumor oxygenation and radiosensitivity of R1H rhabdomyosarcomas, especially during continuous hyperfractionated irradiation. Given to rats as an adjuvant to fractionated irradiation, PTX does not enhance acute or late skin reactions or tumor metastasis. No radiosensitization was observed in vitro, when oxygen was not limiting. The observed radiosensitization by PTX is caused mainly by improved tumor oxygenation.

Animals↗

PubMedDate not supplied

The clinical rationale for S-phase radiosensitization in human tumors.

Nonhypoxic cell radiosensitizers, principally the halogenated pyrimidines and hydroxyurea, have been studied in the laboratory and clinical setting for more than 30 years. Early clinical experience in the 1960s and 1970s with the thymidine analogs 5-bromodeoxyuridine (BUdR) and 5-iododeoxyuridine (IUdR) was disappointing because normal tissue toxicity eliminated any potential for therapeutic gain. Inadequate delivery systems for intravenous and intraarterial infusions also contributed to the decline of this strategy. More recently, laboratory investigations have revealed further information regarding the mechanism of IUdR/BUdR radiosensitization. This knowledge provided a rationale for the sequence and timing of drug and radiation exposure, which could be both effective and tolerable. Advancing technology also provided safer infusion devices, and a resurgence in clinical trials combining IUdR or BUdR and radiation resulted. Current laboratory studies are now providing data on tumor cell kinetics, which is being applied to ongoing clinical trials. Fluoropyrimidines, principally 5-fluorouracil (5-FU), were also used in early clinical trials and unlike IUdR/BUdR were found to have significant activity as single agents against a variety of tumor types. The clinical integration of 5-FU and radiation occurred more slowly, but recent trials have demonstrated a therapeutic gain. Improved rates of local control and survival with combined 5-FU and radiation versus radiation alone have now been demonstrated in patients with rectal, esophageal, and anal carcinomas. However, the mechanism of interaction between the fluoropyrimidines and radiation remains uncertain and continues to be investigated with the hope of improved clinical outcome. As the cellular pathways influenced by the halogenated pyrimidines have been defined, the potential for biochemical modulation of these agents has been recognized. Leucovorin, the most commonly applied modulator, has been shown to enhance the activity of 5-FU in patients with metastatic colorectal carcinoma. These studies serve as an example for current trials that use biochemical modulators of IUdR, BUdR, and 5-FU as radiosensitizers. Hydroxyurea, currently used in the treatment of chronic leukemia, has also been considered a radiosensitizer. As with IUdR/BUdR, the clinical trials have often been inconclusive and interest in this radiosensitizer has waned. A poor understanding of the mechanism of action and tumor cell/normal tissue kinetics may be responsible for the lack of overall success with this strategy. Current investigations of cell kinetics in humans and potential mechanisms of hydroxyurea action could provide information critical to future trials of hydroxyurea radiosensitization.

Animals↗

PubMed1990

Fluorodeoxyuridine-induced radiosensitization and inhibition of DNA double strand break repair in human colon cancer cells.

The halogenated pyrimidine, fluorodeoxyuridine (FdUrd), has been used in combination with radiation for the treatment of human neoplasms. In an attempt to improve the clinical use of this combination, FdUrd-radiation interactions were studied in vitro using human HT29 colon cancer cells. It was found that FdUrd produced radiosensitization at clinically achievable (1-100 nM) concentrations. Sensitization depended critically on the timing of exposure. When cells were irradiated after a 12-hr exposure to 100 nM FdUrd, marked sensitization was produced (mean inactivation dose (MID) = 2.01 +/- 0.01, compared to control of 4.35 +/- 0.16, p less than .01). No radiosensitization occurred when cells were irradiated 4 hr prior to incubation (MID = 3.95 +/- 0.05, p greater than 0.4). Radiosensitization appeared to result from an inhibition of thymidylate synthase since concentrations of FdUrd which produced radiosensitization depleted intracellular TTP pools and blocked the incorporation of deoxyuridine into DNA. Furthermore, radiosensitization was completely inhibited by co-incubation with thymidine. FdUrd also decreased the repair, but not the formation, of radiation-induced DNA double strand breaks (DSB's). These data are consistent with the hypothesis that FdUrd produces radiosensitization by depleting thymidine pools which leads to a decreased rate of DNA DSB repair. Furthermore, they suggest that in clinical trials FdUrd should be infused at least 8 hr before irradiation.

Cell Survival↗

PubMed1991

A fluorinated 2-nitroimidazole, KU-2285, as a new hypoxic cell radiosensitizer.

To develop new hypoxic cell radiosensitizers, we incorporated fluorine atoms into the side chain of the 2-nitroimidazole. Of the resulting compounds, KU-2285 (a 2-nitroimidazole with an N1-substituent of CH2CF2CONHCH2-CH2OH) was considered the most useful as a hypoxic cell radiosensitizer. In this study, its in vivo radiosensitizing activity and acute toxicity were compared with those of etanidazole. The reduction potentials of KU-2285 and etanidazole were -0.96 V and -1.05 V vs Ag/Ag+ in N,N-dimethylformamide, respectively, and their respective octanol/water partition coefficients were 0.25 and 0.040. The in vivo radiosensitizing activity of KU-2285 was found to be similar to that of etanidazole at the same administration dose when assayed by an in vivo-in vitro assay, a growth delay assay, and a tumor control assay using SCC VII tumor or transplanted mammary tumor in C3H/He mice. Although the radiosensitizing activity of etanidazole was reduced when it was administered orally, there was no significant difference in the radiosensitizing activity of KU-2285 whether it was administered intravenously, intraperitoneally, or orally. The acute toxicity measured as the LD50/7 in 8-week-old female C3H/HeJ mice was found to be 2.4 g/kg (intravenously), 2.1 g/kg (intraperitonealy), and 4.25 g/kg (orally) for KU-2285, whereas it was 4.75 g/kg (intravenously) for etanidazole.

Animals↗

PubMed1992

Modulation of iododeoxyuridine-mediated radiosensitization by 5-fluorouracil in human colon cancer cells.

The incorporation of 5-iodo-2'-deoxyuridine (IdUrd), a thymidine analog radiosensitizer, can be increased by the use of modulators such as 5-fluorouracil (FUra). FUra is a particularly attractive potential modulator to use against colorectal cancer, as it is the most active single agent in the treatment of this disease. To begin to define the conditions for the optimal combination of IdUrd and FUra in the treatment of patients with colorectal cancer, a study was conducted of the effect of FUra on IdUrd-mediated radiosensitization in cultured HT29 human colon cancer cells. It was found that when cells were exposed to concentrations of IdUrd typical of those obtained through intravenous exposure (1-3 microM), FUra (1 microM) increased radiosensitization beyond that which would be predicted for the same extent of incorporation produced by incubation with IdUrd alone. This increase appeared to result from a combination of at least two effects: FUra-mediated cell cycle redistribution and increased IdUrd incorporation. When a higher concentration of IdUrd (10 microM) was used with FUra (1 microM), cell cycle distribution returned to nearly normal, and radiosensitization was equal to that predicted by the extent of incorporation of IdUrd. These data demonstrate that the combination of FUra and IdUrd can produce radiosensitization both through increased IdUrd incorporation and cell cycle redistribution. Furthermore, they suggest that, in the presence of a modulator, it may not be necessary to achieve high levels of IdUrd incorporation to produce significant tumor radiosensitization.

Cell Cycle↗

PubMed1992

4-Fluorobenzylamine and phenylalanine methyl ester conjugates of 2-nitroimidazole: evaluation as hypoxic cell radiosensitizers.

We have synthesized two 2-nitroimidazole derivatives and evaluated their hypoxic radiosensitization properties. The first, a 4-fluorobenzylamine conjugate of 2-nitroimidazole (PK-110), was designed so that it could also be labeled with the F-18 and used for positron emission tomographic imaging of hypoxia. The second, the L-phenylalanine methyl ester conjugate of 2-nitroimidazole (PK-130), was designed in an attempt to exploit amino acid transport channels to enhance drug transport into the tumor. The effects of these drugs (and SR-2508, for comparison) in vitro on the aerobic and hypoxic radiosensitivity of Chinese hamster V79 cells were evaluated using clonogenic assays. PK-130 and PK-110 at 0.1 and 1.0 mM were more efficient hypoxic cell radiosensitizers than obtained with 1.0 mM SR-2508. Marginal aerobic radiosensitization was observed for 1.0 mM treatment with PK-130 and PK-110, however, no aerobic radiosensitization was observed at 0.1 mM. Glutathione (GSH) depletion (less than 5% of control levels) by L-buthionine sulfoximine (BSO) further enhanced the SER for both PK-130 and PK-110 at 0.1 mM to 3.2 +/- 0.63 and 2.4 +/- 0.16, respectively. The results of this study encourage the in vivo tumor radiosensitization evaluation of PK-130 and PK-110.

Animals↗

PubMed1993

Alterations in growth phenotype and radiosensitivity after fractionated irradiation of breast carcinoma cells from a single patient.

PURPOSE: To investigate growth regulation and radiosensitivity in surviving clonogens after fractionated irradiation. METHODS AND MATERIALS: Four breast carcinoma cell lines isolated from the primary tumor (21NT, 21PT) and metastases (21MT-1, 21MT-2) of a single patient were exposed to cumulative radiation doses of 30 Gy yielding cell lines designated-IR with respect to their parent. The irradiated lines were then compared to their parent for serum-and growth factor-requirements under defined media conditions, ability to proliferate in soft agar, concentration of TGF-alpha in conditioned medium, and radiosensitivity. RESULTS: The irradiated lines showed no change in proliferative doubling times under serum- and growth factor-supplemented media conditions. A single line, 21MT-1-IR, acquired a limited ability to proliferate in serum-and growth factor-deplete medium with a day 2-4 doubling time of 44.5 hr. Three lines, 21MT-1-IR, 21MT-2-IR, and 21NT-IR, formed colonies in soft agar in contrast to none of the unirradiated parent lines. There were significant 6-8 fold increases in conditioned media TGF-alpha concentrations for 21MT-2-IR and 21NT-IR cells. The 21MT-1-IR and 21NT-IR cells were significantly less radiosensitive than their respective parent lines. This decrease in radiosensitivity appeared to be at least partially mediated by a released factor as the radiosensitivity of 21MT-1 cells was significantly decreased by pre-incubation with conditioned medium from 21MT-1-IR cells. CONCLUSION: Radiation-induced changes in growth phenotype vary with respect to clonal origin of the cell line and may influence the radiosensitivity of surviving clonogens after fractionated treatment.

Breast Neoplasms↗

PubMed1993

Radiobiological modeling of combined targeted 131I therapy and total body irradiation for treatment of disseminated tumors of differing radiosensitivity.

PURPOSE: A model is presented for calculating combinations of targeted 131I and total body irradiation, followed by bone marrow rescue, in the treatment of tumors of different radiosensitivity. The model is used to evaluate the role of the total body irradiation component in the optimal combination regime as a function of the radiosensitivity of the tumor cells. METHODS AND MATERIALS: A microdosimetric model was used to calculate absorbed dose in small tumors and micrometastases when uniformly targeted by the radionuclide 131I. Cell kill was calculated from absorbed dose using an extended version of the linear quadratic model. The addition of varying total doses of total body irradiation, assuming 2 Gy fractions, was also calculated using the linear quadratic model. The net cell kill from combined modality (targeted 131I and total body irradiation) was computed for varying proportions of the two components, for a range of tumor sizes, restricting the total radiation dose to within tolerance for a full-course TBI regime (approximately 14 Gy total) in all cases. The calculations were repeated for a range of presumed tumor uptakes of the targeting agent and for a range of tumor radiosensitivities, typical of those reported for tumor cells of differing type in culture. Optimal regimes were identified as those predicted to yield a high probable tumor cure rate (evaluated using a Poisson statistical model) for all tumor sizes. RESULTS: The analysis supports earlier model studies which predicted that systemic combination treatment with targeted 131I and total body irradiation would be superior to either component used alone. The intrinsic tumor radiosensitivity is found to be a factor which influences the optimal combination of the 131I and external beam total body irradiation components. The total body irradiation component is greater in optimal regimes treating radio-resistant than radiosensitive tumors. However, an obligatory total body irradiation component is also predicted for more radiosensitive tumors; the analysis suggests that the total body irradiation component should in no circumstances be less than 2 x 2 Gy, whilst practical arguments exist in favor of higher doses. CONCLUSION: Total body irradiation is an obligatory component for effective systemic treatment of disseminated malignant tumors to which 131I can be selectively targeted. Clinical studies applying this strategy to the treatment of neuroblastoma by 131I targeted by meta-iodo-benguanidine (mIBG), total body irradiation and bone marrow rescue are now in progress.

Dose-Response Relationship, Radiation↗

PubMed1995

The intrinsic radiosensitivity of cervical carcinoma: correlations with clinical data.

PURPOSE: The aims of the work were to study the intrinsic radiosensitivity of tumor biopsies from patients with cervical carcinoma and to correlate the data with information on patient age, disease stage, differentiation status, tumor volume, and tumor ploidy. METHODS AND MATERIALS: Radiosensitivity was assessed for 145 tumors in vitro as surviving fraction at 2 Gy (SF2) using a clonogenic assay. RESULTS: Although the clonogens in tumors classified as Stage I or II tended to be more radiosensitive than in Stage III or IV disease, the difference was not statistically significant (p > 0.15). There was also no significant difference in the intrinsic radiosensitivity of well, moderately, or poorly differentiated tumors or between squamous cell carcinoma and adenocarcinoma (p > 0.53). There was no correlation between patient age and tumor radiosensitivity (p = 0.49). Large volume (> or = 4 cm) disease was more radioresistant than small volume (< 4 cm) disease, but the difference was not significant (p = 0.08). Finally, diploid tumors tended to be more radioresistant than aneuploid tumors (p = 0.07). CONCLUSION: The intrinsic radiosensitivity of cervix tumors is independent of disease stage, tumor grade, and patient age. Weak trends, however, were observed of increased tumor radioresistance for large volume disease and diploid tumors, suggesting that tumor SF2 may not be a completely independent parameter.

Adenocarcinoma↗

PubMed1994

Prediction of human cell radiosensitivity: comparison of clonogenic assay with chromosome aberrations scored using premature chromosome condensation with fluorescence in situ hybridization.

PURPOSE: The purpose of the present investigation was to determine whether chromosome aberrations scored by premature chromosome condensation (PCC) and fluorescence in situ hybridization (FISH) can predict the radiosensitivity of human cell lines, thereby providing a possible means of assessing the in situ radiosensitivity of normal tissues and the radiocurability of individual human cancers. METHODS AND MATERIALS: We used four cells lines of different radiosensitivity: normal human fibroblasts (AG1522), ataxia-telangiectasia fibroblasts (AT2052), a human fibrosarcoma cell line (HT1080), and a human melanoma cell line (melanoma 903). These were irradiated in plateau phase with a range of doses and assessed both for clonogenic cell survival and for aberrations in a single chromosome (number 4) immediately after, and 24 h after irradiation. RESULTS: The initial number of breaks in chromosome 4 was proportional to irradiation dose and was identical for all the different human cell lines, irrespective of radiosensitivity. On the other hand, the number of chromosome 4 breaks remaining 24 h after irradiation reflected the radiosensitivity of the cells such that the relationship between residual chromosome aberrations and cell survival was the same for the different cell lines. CONCLUSIONS: These results suggest that the scoring of chromosome aberrations in interphase using FISH with PCC holds considerable promise for predicting the radiosensitivity of normal and tumor tissues in situ.

Ataxia Telangiectasia↗

PubMed1994

Dependence of 5-fluorouracil-mediated radiosensitization on DNA-directed effects.

PURPOSE: Although 5-fluorouracil (FUra) has been demonstrated to be a radiation sensitizer both in the laboratory and the clinic, it is not known whether radiosensitization results primarily from FUra's DNA or RNA-directed effects. METHODS AND MATERIALS: We studied the radiosensitizing effects of FUra +/- thymidine (dThd)) on HT29 human colon cancer cells, which are relatively sensitive to the DNA-directed action of FUra, in comparison to SW620 and HuTu80 human colon cancer cells, which are relatively resistant to FUra's DNA-directed effects. We hypothesized that if FUra were acting chiefly through DNA dependent mechanisms, HT29 cells would (a) show greater radiosensitization than SW620 and HuTu80 cells under the same conditions of exposure; and (b) demonstrate selective reversal of radiation sensitivity (compared to cytotoxicity) in the presence of FUra + dThd, compared to FUra alone. RESULTS: We found that the enhancement ratio produced by a 24 h exposure to 10 microM FUra was significantly greater in HT29 cells compared to SW620 and HuTu80 cells (enhancement ratios of 2.1 +/- 0.1; 1.1 +/- 0.1, and 1.3 +/- 0.1, respectively). Furthermore, in HT29 cells, dThd blocked FUra-mediated radiosensitization to a greater extent than FUra-mediated cytotoxicity. Thus, our hypotheses were confirmed. CONCLUSION: These findings support the concept that the manipulation of FUra's DNA-dependent actions, for example, through modulators of thymidylate synthase (TS) activity, may increase radiosensitization in clinical trials in the treatment of gastrointestinal cancers. However, since resistance to the DNA-directed effects of fluoropyrimidines can result from mechanisms unrelated to TS inhibition, additional strategies will be required to potentiate fluoropyrimidine-mediated radiosensitization.

Cell Cycle↗

PubMed2004

Effects of the EGFR/HER2 kinase inhibitor GW572016 on EGFR- and HER2-overexpressing breast cancer cell line proliferation, radiosensitization, and resistance.

PURPOSE: Two members of the epidermal growth factor receptor family, EGFR and HER2, have been implicated in radioresistance in breast cancer and other malignancies. To gauge the potential clinical utility of targeting both EGFR and HER2 to control growth and radiosensitize human breast cancers, we examined the effect of a dual EGFR/HER2 inhibitor, GW572016, on the proliferation and radiation response of either EGFR- or HER2-overexpressing human breast cancer cell lines. METHODS AND MATERIALS: Primary human breast cancer cell lines that endogenously overexpress EGFR or HER2 and luminal mammary epithelial H16N2 cells stably transfected with HER2 were evaluated for the effect of GW572016 on inhibition of ligand-induced or constitutive receptor phosphorylation, proliferation, radiosensitization, and inhibition of downstream signaling. RESULTS: GW572016 inhibited constitutive and/or ligand-induced EGFR or HER2 tyrosine phosphorylation of all five cell lines, which correlated with the antiproliferative response in all but one cell line. GW572016 radiosensitized EGFR-overexpressing cell lines, but HER2-overexpressing cells were unable to form colonies after brief exposure to GW572016 even in the absence of radiation, and thus could not be evaluated for radiosensitization. One cell line was resistant to the antiproliferative and radiosensitizing effects of GW572016, despite receptor inhibition. Exploration of potential mechanisms of resistance in SUM185 cells revealed failure of GW572016 to inhibit downstream ERK and Akt activation, despite inhibition of HER2 phosphorylation. In contrast, sensitive HER2-overexpressing cell lines demonstrated inhibition of both ERK and Akt phosphorylation. CONCLUSION: GW572016 potently inhibits receptor phosphorylation in either EGFR- or HER2-overexpressing cell lines and has both antiproliferative and radiosensitizing effects. Resistance to GW572016 was not due to a lack of receptor inhibition, but rather with a lack of inhibition of ERK and Akt, suggesting that measurement of inhibition of crucial signaling pathways may better predict response than inhibition of receptor phosphorylation. The SUM185 cell line provides a valuable model for studying mechanisms of resistance of EGFR/HER2 inhibitor therapy.

Breast Neoplasms↗