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Biomedical subjects

G W Barendsen

Publications and source records attributed to G W Barendsen.

At least 19 recordsLinked to original sources
PubMed2001

Radiosensitization by bromodeoxyuridine and hyperthermia: analysis of linear and quadratic parameters of radiation survival curves of two human tumor cell lines.

Sensitization by bromodeoxyuridine (BrdUrd) and hyperthermia (HT) on cell reproductive death induced by ionizing radiation was analyzed using the linear-quadratic [S(D)/S(0)=exp(-(alphaD + betaD2)]] model. Plateau-phase human lung tumor cells (SW-1573) and human colorectal carcinonoma cells (RKO) were treated with BrdUrd, radiation and HT. LQ-analysis was performed at iso-incubation dose and at iso-incorporation level of BrdUrd. and at iso-HT doses and iso-survival levels after HT. Clonogenic assays were performed 24 h after treatment to allow repair of potentially lethal damage (PLD). In SW cells BrdUrd. HT or the combination significantly increased the alpha-parameter (factor 2.0-5.7), without altering the beta-parameter. In RKO cells sensitization with BrdUrd increased both a (factor 1.4) and beta (factor 1.3) while HT only influenced beta (factor 2.1-4.0). The combination did not further increase the a and beta. The results indicate that BrdUrd has its main effect on the parameter alpha, dominant at clinically relevant radiation doses but that HT can affect both a and beta. The addition of BrdUrd and HT provides a method to enhance the efficacy of radiotherapy.

Bromodeoxyuridine↗
PubMed2001

Importance of cell proliferative state and potentially lethal damage repair on radiation effectiveness: implications for combined tumor treatments (review).

The dependence of parameters of the linear-quadratic (LQ) model on cell proliferation kinetics of tumors in relation to potentially lethal damage (PLD) and its repair is evaluated. The influence of sensitizing agents on these parameters during fractionated radiotherapy is assessed. Suggestions for scheduling of radiation combined of with sensitizing agents are derived. The parameters alpha and beta of the linear-quadratic model for dose dependence of cell reproductive inactivation, derived from experimental and clinical data, are evaluated to assess their dependence on cell proliferative state, on PLD repair and on the action of various sensitizing agents. PLD contributes to the linear as well as to the quadratic component of the LQ model. PLD is less effectively repaired in proliferating (P) cells than in clonogenic (G0) cells of the quiescent (Q) cell compartment. PLD is influenced by various agents applied during, as well as after irradiation. The parameters alpha and beta are affected differently by the proliferative state of cells, by some of the sensitizing agents, and by radiation quality. The relative fractions of P cells and Q cells can change during fractionated treatments. If recruitment is effective, the fraction of G0 cells decreases in the latter part of a treatment schedule. PLD from subsequent radiation doses is then repaired less and the effectiveness of radiation combined with sensitizing agents may be enhanced. The analyses using the LQ model show differences in PLD and its repair between P cells and G0 cells in tumors. If due to recruitment the compartment of clonogenic G0 cells diminishes during treatment, the combination of radiation with sensitizing agents and the application of high-LET radiation should be scheduled to take this factor into account. For poorly differentiated tumors with high labeling indices (LI), benefit from combined treatments is expected from early in the course of fractionated radiotherapy. Well differentiated tumors with low LI are suggested to benefit most from irradiation combined with sensitizing agents in the latter part of a treatment schedule. New methods are required to assess the clonogenic G0 cells in the Q cell compartment and to monitor recruitment of these cells into the P cell compartment.

Animals↗
PubMed1999

Correlation between cell reproductive death and chromosome aberrations assessed by FISH for low and high doses of radiation and sensitization by iodo-deoxyuridine in human SW-1573 cells.

PURPOSE: To study the relationship between cell reproductive death and exchange frequency in SW-1573 human lung tumour cells with and without incorporated iodo-deoxyuridine (IdUrd) following irradiation of plateau-phase cultures with y-rays. METHOD: Linear-quadratic (LQ) analysis was performed for the data on clonogenic survival and on the frequency of chromosomal exchanges studied with fluorescence in situ hybridization in chromosomes X and 2. RESULTS: Differences in the LQ parameters alpha and beta of both non-sensitized and sensitized chromosomes were found. In both chromosomes an increase in the number of chromosomal exchanges in IdUrd-radiosensitized cells compared with non-sensitized cells was observed. The alpha-enhancement factors of 1.7 and 1.9 for the X-chromosome and for chromosome 2, respectively, are similar. For the X-chromosome, the beta coefficient increased by a factor of 3.9 and for chromosome 2 by a factor of 1.4. After correction to a full genome equivalence, no significant difference in alpha was found between chromosomes X and 2 for both control and sensitized cells. In contrast, an almost 2.8 times higher beta was found for the sensitized X-chromosome compared to this value for chromosome 2. CONCLUSIONS: It can be concluded that the linear-quadratic analysis of dose-response relationships offers insights into the correlation between cell survival and induction of exchanges in non-sensitized and radiosensitized cells.

Carcinoma, Squamous Cell↗
PubMed1997

Hyperthermia and incorporation of halogenated pyrimidines: radiosensitization in cultured rodent and human tumor cells.

PURPOSE: To investigate the possible benefit of hyperthermia (HT) in combination with radiosensitization by halogenated pyrimidines (HPs) in rodent as well as in human tumor cells. METHODS AND MATERIALS: Exponentially growing rodent cells, radiosensitive R-1 and MOS cells and radioresistant RUC-II and V79 cells, and human SW1573 cells, were exposed to 0, 1, 2, and 4 microM of chloro- (CldUrd), bromo- (BrdUrd), or iodo-deoxyuridine (IdUrd) in the culture medium. Survival after irradiation with gamma-rays from a 137Cs source and/or hyperthermic treatment (HT, 60 min at 42 degrees C) was determined by clonogenic assay. Linear-quadratic analyses of the radiation survival curves were performed to assess sensitization in the dose range 1 to 3 Gy relevant to radiotherapy. RESULTS: The incorporation of HPs sensitized all cell lines to HT and resulted in radiosensitization dependent on the percentage of thymidine replacement. At equal levels of thymidine replacement, IdUrd was the most potent radiosensitizer. HT further increased radiation-induced lethality of cells that had incorporated HPs. Linear-quadratic analyses showed that HT further increased the linear parameter of the LQ formula while the quadratic parameter was not significantly changed. CONCLUSION: The combination of HT and HPs act additively in increasing the radiosensitivity of rodent tumor cell lines with varying radiosensitivities as well as of a human tumor cell line. In particular, the ratio of the linear parameter to the quadratic parameter, relevant for fractionation effects in radiotherapy, was increased.

Animals↗
PubMed1997

Modification of potentially lethal damage in irradiated Chinese hamster V79 cells after incorporation of halogenated pyrimidines.

Radiosensitization of exponentially growing and plateau phase Chinese hamster V79 cells by incorporation of halogenated pyrimidines (HP) was investigated for different culture conditions that influenced repair. For this purpose cells were grown for 72 h with 0, 1, 2 and 4 microM of chloro-(CldUrd), bromo- (BrdUrd) or iodo-deoxyuridine (IdUrd) and were subsequently irradiated with gamma-rays from a 197Cs source, either in exponential growth or in plateau-phase. Cell survival after irradiation was determined by clonogenic assay. In exponentially growing cultures thymidine-replacement in the DNA of the cells after incubation with 4 microM of CldUrd, BrdUrd and IdUrd was 22.3, 32.7 and 12.7%, respectively. In plateau-phase cultures the percentage thymidine replacement in the DNA of the cells after incubation during growth with 4 microM CldUrd, BrdUrd and IdUrd was 27.5, 33.8 and 10.7%, respectively. Linear-quadratic analyses of the radiation survival curves were performed. In exponentially growing cells a marked increase by a factor 2-3 of the value of alpha was obtained. The beta term significantly increased only in cells which were grown in the presence of BrdUrd and which were trypsinized and replated immediately after irradiation. In plateau-phase cells which were trypsinized and plated immediately after irradiation both alpha and beta increased up to a factor 2-3 with increasing incorporation of halogenated pyrimidines. In plateau phase cells which were allowed to repair potentially lethal damage (PLD) for 6 h and subsequently trypsinized and plated, alpha increased by a factor 3-4. In these latter conditions changes in beta were smaller. In exponentially growing cells in which repair was allowed after irradiation by plating prior to the treatment, the alpha values decreased for all the HP drugs tested as compared to the alpha of cells plated immediately after irradiation. In contrast, delay of plating for plateau phase cells yielded increased alpha values not only when compared with the alpha of plateau phase cells plated immediately after treatment but also when compared with the alpha value of radiosensitized exponentially growing cells. The increase of alpha might be interpreted as an enhancement in the expression of PLD. The larger contribution of fixation of PLD might be due to initial DNA damage and/or to inhibition of PLD repair resulting from incorporation of HP. The increase of beta might be attributed to enhanced interaction or to fixation of sublethal damage (SLD). In view of clinical applications of HP it is of interest that sensitization is not abolished in plateau-phase cells.

Animals↗
PubMed1997

Parameters of linear-quadratic radiation dose-effect relationships: dependence on LET and mechanisms of reproductive cell death.

An analysis of mammalian cell radiation-dose survival curves, based on the linear-quadratic formalism, is shown to yield insights in the various components of damage that contribute to cell reproductive death. RBE-LET relationships of single-track lethal damage, sublethal damage, potentially lethal damage and DNA double-strand breaks are compared. Single-track lethal damage is derived to be composed of two components: (1) damage that remains unrepaired in an interval between irradiation and assay for proliferative capacity, with a very strong dependence on LET, and (2) potentially lethal damage that is only weakly dependent on LET, similar to sublethal damage and DNA double-strand breaks. The results of this analysis lead to new interpretations of published experimental results and to suggestions for applications in radiotherapy.

Cell Death↗
PubMed1996

Absorbed dose distribution of the auger emitters 67GA and 125I and the beta-emitters 67CU, 90Y, 131I, and 186RE as a function of tumor size, uptake, and intracellular distribution.

PURPOSE: The influence of tumor volume, uptake of radioactive compounds in cells of tumors and normal tissues, and characteristics of the emitted ionizing particles on the efficacy of systemic radiation were studied. METHODS AND MATERIALS: The influence of these variables was assessed using a point kernel approach combined with a distance histogram technique. Simulation calculations were performed to assess dose distributions for three tumor sizes (phi = 200 microns, 2 mm, or 2 cm) and six radionuclides: 67Ga, 125I, 67Cu, 90Y, 131I, and 186Re. RESULTS: The energy deposition patterns depended on the relation of the tumor size and range of the emitted particles. Selective uptake was especially important in cases where the range was short compared to the dimension of the tumor. CONCLUSION: To attain a high dose for treatment of micrometastases, the use of Auger and conversion electron emitters (67Ga and 125I) or beta-emitters with emission spectra including low energetic electrons (67Cu and 131I) was recommended. The results demonstrated the complementary nature of selectivity of energy deposition and crossfire. This implied that for tumor cells or areas with reduced uptake, crossfire from radioactivity in surrounding cells or areas with selective uptake would be provided by intermediate (conversion electrons) or long-range (beta-particles) emissions.

Dose-Response Relationship, Radiation↗
PubMed1996

Local hyperthermic treatment does not enhance mitoxantrone effectiveness for responses of a rat solid tumour regrowing after irradiation.

Tumours regrowing after irradiation may respond differently to chemo-hyperthermia as compared to non- irradiated tumours. In this study, the efficacy of combined treatment of previously irradiated tumors with mitoxantrone and local hyperthermia (HT) was investigated. Rat R-1 tumours were irradiated with dose fractions of 5Gy X-rays applied on 4 consecutive days. Animals were retreated with mitoxantrone (5mg/kg i.p.), HT (1 h at 43 degrees C) or mitoxantrone + HT (3-h interval) on day 9 after the start of irradiation when tumour volumes were decreasing, or on day 16 when tumour volumes were increasing again. Pharmacokinetics were studied in relation to tumor cell survival and tumour growth delay. No Ht=induced changes in the pharmacokinetics of mitoxantrone were observed. The data on clonogenic survival correlated well with these findings and combined treatment were not more effective than mitoxantrone alone. In the treatment schedule applied, HT did not induce pharmacokinetic changes in irradiated tumours leading to an enhanced cytotoxicity of mitoxantrone. The HT- enhanced effectiveness of the drug observed in non- irradiated tumours is much less in pre-irradiated tumours. Responses of regrowing tumours to combined chemo- hyperthermia depend in a complex way on the stage of regrowth and on the treatment schedule.

Animals↗
PubMed1996

RBE-LET relationships for lethal, potentially lethal and sublethal damage in mammalian cells: implications for fast neutron radiotherapy.

The dependence of relative biological effectiveness (RBE) on the linear energy transfer (LET) of radiations is described for different types of cellular damage which contribute to reproductive death. The influence of the capacity for repair of sublethal and of potentially lethal damage of mammalian cells is discussed. The analysis leads to interpretations of differences in the RBE of fast neutrons among tumours and among normal tissues and to suggestions for the application of high LET radiation in radiotherapy.

Animals↗
PubMed1994

A dosimetric model for intrathecal treatment with 131I and 67Ga.

PURPOSE: Calculations were performed of absorbed dose distributions of the beta-emitter 131I and the Auger emitter 67Ga for intrathecal administration. METHODS AND MATERIALS: The proposed dosimetric model accounts for the macroscopic distribution of the activity, by means of a Medical Internal Radiation Dose Committee approach, and for the microscopic distribution of activity, by means of a point kernel technique. This point kernel approach was used in combination with a distance histogram technique, to study in more detail the absorbed dose distribution in the cerebro-spinal fluid, in the surface of the central nervous system, and in tumor sites. We simulated decreased uptake, as well as highly selective uptake in free-floating tumor cells and in meningeal lesions (1-16 cells thick). RESULTS: In case of limited access to lesions adherent to the pia mater, the beta-emitter 131I provides crossfire from the CSF, resulting in a higher absorbed dose (Gy/MBq) in these lesions as compared with the Auger emitter 67Ga. In case of increasing radionuclide uptake, the increment of the absorbed dose in the adherent lesions and the free floating cells from 67Ga is considerable because of the local deposition of energy by this radionuclide. CONCLUSIONS: The model might be useful to select the optimal emission characteristics of radionuclides applicable for intrathecal therapy, which is demonstrated in a comparison of the Auger emitter 67Ga and the beta-emitter 131I.

Gallium Radioisotopes↗
PubMed1994

RBE-LET relationships for different types of lethal radiation damage in mammalian cells: comparison with DNA dsb and an interpretation of differences in radiosensitivity.

Relative biological effectiveness (RBE), as a function of linear energy transfer (LET), is evaluated for different types of damage contributing to mammalian cell reproductive death. Survival curves are analysed assuming a linear-quadratic dose dependence of lethal lesions. The linear term represents lethal damage due to single particle tracks, the quadratic term represents lethality due to interaction of lesions from independent tracks. RBE-LET relationships of single-track lethal damage, sublethal damage, potentially lethal damage and DNA double-strand breaks (dsb) are compared. Single-track lethal damage is shown to be composed of two components: damage that remains unrepaired in an interval between irradiation and assay, characterized by a very strong dependence on LET, with RBEs up to 20, and potentially lethal damage, which is weakly dependent on LET with RBEs < 3. Potentially lethal damage and sublethal damage depend similarly on LET as DNA dsb. The identification of these different components of damage leads to an interpretation of differences in radiosensitivity and in RBEs among various types of cells.

Animals↗
PubMed1994

The relationships between RBE and LET for different types of lethal damage in mammalian cells: biophysical and molecular mechanisms.

The relative biological effectiveness (RBE) of radiations as a function of linear energy transfer (LET) is analyzed for different types of damage causing reproductive death of mammalian cells. Survival curves are evaluated assuming a linear-quadratic dose dependence of the induction of reproductive death of cells. The linear term represents damage from single particle tracks and the quadratic term represents damage due to interaction of lesions from independent tracks. Differences and similarities are discussed of the LET dependence of single-track lethal damage, sublethal damage, potentially lethal damage and DNA double-strand breaks. The RBE-LET relationships are correlated with local energy deposition in small regions of the cells. The analysis shows that single-track lethal damage is composed in part of a type of damage that is not repaired by delayed plating and is very strongly dependent on LET with maximum RBE values up to 20, while another component consists of potentially lethal damage that is weakly dependent on LET with maximum RBE values less than 3. Potentially lethal damage and sublethal damage depend similarly on LET as DNA double-strand breaks. The sector of single-track damage which is not repaired by delayed plating is hypothesized to be caused through a repair-exchange mechanism involving two double-strand breaks induced close together. The identification of these different components of damage leads to an interpretation of differences in radiosensitivity and in RBE-LET relationships among various types of cells.

Alpha Particles↗
PubMed1993

Application of a DNA double labelling method for the flow cytometric analysis of recruitment of non-cycling cells in a mixed population of P and Q cells.

In this paper we describe the application of a non-radioactive DNA double labelling and staining method to an analysis of cell proliferation kinetics by flow cytometry, aimed at the direct measurement of recruitment rates in cell cultures. The method is based on the application of two halogenated deoxyuridines: iododeoxyuridine (IdUrd) and chlorodeoxyuridine (CldUrd) which are incorporated into DNA synthesizing cells. By applying two commercially available monoclonal antibodies both deoxyuridines can be detected separately. To measure recruitment all proliferating cells in a plateau phase culture were labelled first with IdUrd applied during a time interval approximately equal to the cell cycle time. Subsequently, recruitment induced by a medium change was analysed by flow cytometric assessment of incorporation of CldUrd in cells which had not taken up IdUrd. Experiments designed to determine the toxicity of continuous labelling with IdUrd in different concentrations and of pulse labelling with CldUrd showed that there was no effect on the progression of cells through the cell cycle. The aim of this study is to test the sensitivity of the procedure to detect changes in proliferation kinetics, in particular the entrance of resting cells into the S phase. Although the cell culture model used is very simple, the results demonstrate clearly that a low rate of recruitment can be detected. It is suggested that the procedure described here is specific and sensitive enough to quantify changes in cell proliferation in tumours induced by various treatments and has advantages over other methods, which measure recruitment indirectly, or directly by using two radioactive thymidines.

Animals↗