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PubMed2002

Regional specification of rodent and human neurospheres.

Neural precursor cells were isolated from various regions of the developing rat and human brain and grown in culture as aggregates termed neurospheres. We asked whether cells within human and rodent neurospheres are identical, or whether they have species specific characteristics or differences based on their region of origin. Under our culture conditions, rodent neurospheres isolated from the cortex (ctxNS) and striatum (strNS) grew faster than those from the mesencephalon (mesNS), but stopped growing after only eight to ten population doublings. In contrast, human neurospheres under identical culture conditions, continued to grow for over 40 population doublings. Following migration and differentiation of both rodent and human cultures, ctxNS and strNS generated high numbers of small neurons whereas mesNS generated small numbers of large neurons with many long fibres. Only very rare neurons from mesNS expressed dopaminergic markers, and thus may require further signals to fully mature. While the rat neurospheres generated high numbers of oligodendrocytes, very few were found to develop from human neurospheres from any region after a few weeks of passaging. FACS analysis revealed a unique population of smaller cells within human strNS and ctxNS, which appeared to be neuronal progenitors. However, large cells within neurospheres were capable of generating these small neuronal progenitors following further proliferation. Together, our data show that rat and human neurospheres have unique characteristics with regard to growth and differentiation, and that the majority of precursor cells within neurospheres are regionally specified to generate set numbers of neurons. These findings have important implications for understanding the nature of proliferating neural precursors isolated from the developing CNS, and their potential for brain repair.

Animals↗
PubMed2002

Behavior of human neural progenitor cells transplanted to rat brain.

Human neural stem/progenitor cells provide a useful tool for studies of neural development and differentiation, as well as a potential means for neuroreplacement therapeutic needs in the human CNS. Stem cells isolated from developing human central nervous system of 8-12-week fetuses were transplanted to the forebrain and cerebellum of young and adult rats after 14 days of in vitro expansion. Cells were labeled by bisbenzimide prior to transplantation without immunosuppression. Recipient brains were examined 10 and 20 days after transplantation. Labeled stem cells were found in the neocortex, lateral ventricle and caudate nucleus in the forebrain, and in the molecular layer, Purkinje cell layer, and granular layer of the cerebellum. Mitotically dividing stem cells were observed in graft core, confirming their proliferative potential in new microenvironment. Engrafted cells migrate through the parenchyme of striatum, along the ventricular ependymal layer and callosal fibers, some of them reaching the opposite hemisphere. Some cells migrating along the capillaries express glial acid fibrillary protein, demonstrating their differentiation into astrocytes. Grafted cells expressing calbindin were found in the Purkinje cell layer, suggesting their differentiation into the Purkinje cells. At the same time, some grafted cells were undifferentiated and expressed vimentin. Our results demonstrate that cultured human neural stem/progenitor cells migrate and differentiate into both neurons and astrocytes after transplantation to the rat forebrain or cerebellum of young and adult rats.

Animals↗
PubMed2002

Evaluation of progenitor cell cultures from human embryos for neurotransplantation.

Human neural stem cells (HNSCs) are used in studies of neural development and differentiation, and are regarded as an alternative source of tissue for neural transplantation in degenerative diseases. Selection and standardization of HNSC samples is an important task in research and clinical approaches. We evaluated embryonal brain matter obtained from human 8-12-week-old fetuses by means of flow cytometry on a panel including: nestin; vimentin; NeuN; GFAP; beta-tubulin III; CD56; N-Cad; OB-Cad; HLA-ABC; HLA-DR; CD34, and annexin. Samples from embryos of even the same gestation differ dramatically regarding neural cell development, their phenotype and viability. The samples containing the highest proportion of stem cells and multipotent progenitors of neural types, and the least of definitive cells and antigens of histocompatibility, were selected for further expansion in serum-free medium. Secondary phenotyping 14 days later revealed again a marked heterogeneity of the cultures. For the final culturing for 24 h in a serum-containing medium we selected only samples having following phenotype: nestin+, and vimentin+ no less than 25%; HLA-DR+ and CD34+ no more than 5%; GFAP+ no more than 10%; beta-tubulin+ no more than 20%; CD56+, N-Cad+, OB-Cad+, HLA-A,B,C+, and annexin+ no more than 15%; cell viability no less than 60%. Immunocytochemical study of selected samples proved that numerous neural stem cells, and neuro- and glioblasts necessary for transplantation were present. Our results demonstrate that the flow cytometry phenotyping allows the screening and standardization of HNSC samples for further expansion and transplantation.

Brain↗
PubMed2003

Turning teratocarcinoma cells into neurons: rapid differentiation of NT-2 cells in floating spheres.

Cells from the human teratocarcinoma line NTera-2 can be induced to terminally differentiate into postmitotic neurons when treated with retinoic acid. However, this differentiation process is rather time consuming as it takes between 42 and 54 days. Here, we propose a modified differentiation protocol which reduces the time needed for differentiation considerably without compromising the quantity of the neurons obtained. The introduction of a proliferation step as free floating cell spheres cuts the total time needed to obtain high yields of purified NT-2 neurons to about 24-28 days. The cells obtained show neuronal morphology and migrate to form ganglion-like cell conglomerates. Differentiated cells express neuronal polarity markers such as the cytoskeleton associated proteins MAP2 and Tau. Moreover, the generation of neurons in sphere cultures induced immunoreactivity to the ELAV-like neuronal RNA-binding proteins HuC/D, which have been implicated in mechanisms of nerve cell differentiation.

Biomarkers↗
PubMed1998

Cell kinetics and repopulation mechanisms during multifraction irradiation of spheroids.

BACKGROUND AND PURPOSE: The objective of the present study was to evaluate the predictive potential of cell kinetic parameters and repopulation rates determined by flow cytometry during multifraction irradiation of spheroids, a system in which the fate of all cells can be determined with high precision. Ultimately, similar analytical techniques should provide a reproducible and prognostically significant clinical predictive assay. MATERIALS AND METHODS: Multicellular spheroids of Chinese hamster V79 lung cells were irradiated with 2.5 Gy of 250 kVp X-rays twice daily to a total dose of 25 Gy. Repopulation parameters and cell kinetic parameters were followed throughout the irradiation period and for 5 days after completion of exposure. RESULTS: (1) Regrowth (RG) took place early during multifraction irradiation. (2) Potential doubling time (Tpot) decreased steadily from the early part of treatment, remaining of short duration until the spheroids almost attained the pre-treatment number of clonogenic cells. (3) Accelerated repopulation was mainly due to a decreased cell loss factor (phi) and increased growth fraction (GF), although a modest decrease in cell cycle time (tc) was suggested. (4) Phi decreased during exponential RG. (5) Other parameters such as observed doubling time (td) and labelling index (LI) paralleled these findings. CONCLUSIONS: Clonogen repopulation that began early in the irradiation scheme and accelerated rapidly is not consistent with the prevailing view that accelerated repopulation begins several weeks into clinical protocols. Also, pre-treatment Tpot did not adequately estimate the repopulation speed in the spheroids. Equivalent studies in animal tumour systems, and then in the clinic, are consequently indicated and of some urgency.

Animals↗
PubMed2001

Human hepatocyte cell lines proliferating as cohesive spheroid colonies in alginate markedly upregulate both synthetic and detoxificatory liver function.

BACKGROUND/AIMS: Bio-artificial liver support systems for treatment of hepatic failure require maintained expression of hepatocyte function in vitro. We studied cultures of human hepatocyte cell-lines proliferating within alginate beads, investigating the hypothesis that 3-dimensional cohesive colonies of hepatocyte cell-lines would achieve polarity and cell-to-cell contact resulting in upregulation of function. METHODS: HepG2 and HHY41 human cell lines in alginate beads were cultured for >20 days. RESULTS: Proliferation was maintained for 20 days. Production of albumin, prothrombin, fibrinogen, alpha-1-acid glycoprotein and alpha-1-antitrypsin was maintained throughout, maximal at days 8-10, when upregulation was 300-1100% compared with monolayer cultures at similar cell number per unit volume. Detoxificatory functions: ethoxyresorufin deethylase activity, androstenedione metabolism, and urea synthesis from arginine was also increased several-fold. Function returned to pre-freezing levels within 18 h of thawing after cryopreservation of cells in alginate. Electron microscopy revealed spherical colonies of cells of cuboidal shape, with cell-to-cell contact via desmosomes and junctional complexes, abundant microvilli, and cytoplasmic appearances suggesting transcriptionally active hepatocytes. CONCLUSION: Hepatocyte cell-lines, proliferating in alginate express a range of liver-specific functions at levels approaching those found in vivo, relevant to their use in liver support systems.

Alginates↗
PubMed1997

In vitro confirmation of newly established lung cancer cell lines using flow cytometry and multicellular tumor spheroids.

We report on a simplified method of cytomorphological in vitro confirmation of newly established lung cancer cell lines by using multicellular tumor spheroids (MTS) and flow cytometry (FCM). Eleven cell lines were established from 11 patients with lung cancer. The MTS were produced by culturing cells in agar-coated dish. Cytomorphological studies were made using smears of crushed MTS and frozen sections of MTS. The MTS were fixed doubly with paraformaldehyde and osmic acid for scanning and transmission electron microscopy. Bivariate fluorescence of fluorescein isothyocyanate (FITC, tumor associated antigen, TAA) and propidium iodide (DNA) were measured by FCM. The MTS grew anchorage-independently. Cytopathological and electron microscopic findings of MTS were similar to those of the original clinical specimens. The DNA index and TAA were useful in evaluating the presence or absence of contamination by cells of non-tumor origin. The new cell lines satisfied a minimum of four conditions to confirm their establishment: (a) they originated from humans, (b) they were cytomorphologically identified with specimens from primary lesions, (c) they showed tumorigenicity, and (d) they were free from contamination by cells of different origin. From these findings, the establishment of new cell lines can be confirmed in vitro by using MTS and FCM.

Antigens, Neoplasm↗
PubMed1997

A morphologic study of nodular lung carcinomas and their possible pathogenesis from a cluster of non-obstructive bronchiectasis.

A very simple procedure has enabled us to show that nodular lung carcinomas correspond, to a high degree, to neoplasias arising in a cluster of bronchiectasis of the non-obstructive type. This pathogenesis explains their peculiar features: the round shape with a sharp borderline on the surrounding lung, the frequent cavitation, the prevailing histologic type of epidermoid carcinomas. At present, when thin-section CT allows discovery of bronchiectasis with no need for bronchography, this interpretation suggests the possibility of carrying out a prevention program which should consist of identifying the high-risk group of patients with bronchiectasis, 'sputum producers' and smokers, in which an early diagnosis of nodular lung carcinoma might be realized by periodical diagnostic cytology.

Adult↗
PubMed1998

High-frequency ultrasound properties of multicellular spheroids during heating.

High-frequency ultrasound monitoring is a possible method for real-time imaging of thermal therapy in tissues at microscopic resolution. The objective of this work was to measure changes in the ultrasound properties of V79 spheroids (grown from Chinese Hamster lung fibroblasts) exposed to heating. Spheroids are clonal aggregates of cells that provide a useful model for investigating the ultrasound properties of cells in the absence of connective tissue. Relative echo signal power and attenuation coefficients were measured over the frequency range 30 MHz to 70 MHz, from spheroids heated from 37 degrees C to 50 degrees C or 60 degrees C. Echo signal power from the viable rim decreased during the first 5 min by a factor of 1.08 before the spheroid reached 50 degrees C. For the next 25 min, echo signal power rose to a factor of 1.27 above the initial level, after which it remained relatively constant over the remainder of the 50 degrees C heating period. At 60 degrees C, echo signal from the viable rim remained relatively constant, although it appeared to have possibly decreased slightly over the duration of the heating period. Echo signal power from the necrotic core fell to a factor of 1.4 and 1.54 below the initial level at 50 degrees C and 60 degrees C, respectively. First-order chemical rate analysis applied to the echo signal power results in the viable rim at 50 degrees C revealed a rate constant for the 5-15-min heating interval. Interpretation of the echo signal power results in terms of histological stains indicates that the rise in echo signal power at 50 degrees C was due to a loss of cell cohesion, and the possible drop in echo signal power at 60 degrees C was due to spheroid coagulation. Attenuation coefficients decreased by up to 1.54 dB mm-1 over a 30-min period at 60 degrees C. The appearance of a real-time ultrasound image of lesion formation in cells is discussed.

Animals↗
PubMed1996

In vitro evaluation of Taxol combined with radiations in human squamous cell carcinoma spheroids.

The effect of Taxol on the radiation sensitivity of human squamous carcinoma of the head and neck region was determined in vitro, using clonogenic assays and multicellular tumor spheroids (MTS). Radiosensitivity parameters were determined by alpha and beta for clonogenic assays, and by the residual/control volume ratios at 2 Gy (RSV2) and the dose inducing 50% decrease in MTS number (SCD50) for spheroids. In HTB43 and CAL27 colonies, the combination was antagonist. In spheroids, Taxol induced a decrease of RSV2 and SCD50 in HTB43 and CAL27 MTS and their combinations with radiation were synergistic and additive, respectively. Therefore, the different results obtained by clonogenic assays and MTS may suggest higher drug incorporation through the multiple cell layers of the spheroids than in monolayers.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Photodynamic therapy of ovarian tumours and normal cells using 5,10,15,20-tetra-(3-carboxymethoxyphenyl)-chlorin.

The photosensitizing ability of the second generation photosensitizer 5,10,15,20-tetra-(3-carboxymethoxyphenyl)-chlorin (m-TCMPC), a derivative of m-THPC, was tested on both three-dimensional multicellular spheroids of varying sizes and on monolayer cultures. These experiments were carried out on two spheroid-forming cell lines, A2780 (a human ovarian adenocarcinoma) and CHO (Chinese hamster ovarian cells). For both cell lines, photodynamic therapy (sensitizer plus visible light) treatments were carried out. The chlorin m-TCMPC was shown to have considerable promise as a photosensitizing agent. Cell kill was achieved for all situations tested, i.e. monolayer, 100, 500 and 750 microm spheroids. In addition no significant dark toxicity was observed.

Animals↗
PubMed1998

Multicellular spheroids as an in vitro tumor model.

Multicellular spheroids (MCS) have been used as an in vitro model system of micrometastases and avascular tumor regions for studying cell adhesion-dependent resistance to cytotoxic drugs and possible reversal by chemosensitizers and adhesion-reversing agents. Multicellular drug resistance has been linked to limited accessibility of cell subpopulations, active drug efflux, quiescence of cells in deeper layers due to cell contact inhibition and adverse microenvironmental conditions like acidic extracellular pH, hypoxia and nutritional depletion. The shortcomings of MCS as a tumor model include limited knowledge of the mechanisms leading to necrosis/apoptosis of core cells, the production of an extracellular matrix (ECM) by tumor cells instead of intratumoral normal cell populations and the complex relationship of MCS parameters like size, growth regulation, synthesis of ECM components and others on the origin and pretreatment of the tumor cells and specific culture conditions.

Animals↗
PubMed1998

Reversal of intrinsic and acquired forms of drug resistance by hyaluronidase treatment of solid tumors.

There are two broad categories of drug resistance encountered during cancer chemotherapy, i.e. intrinsic and acquired. They are observed in virtually every type of tumor with every known anticancer chemotherapeutic drug. As such there is an urgent need to develop innovative approaches of preventing or reversing these types of resistance. One strategy to do so is to develop completely new drugs which may be resistance free, such as direct acting angiogenesis inhibitors (T. Boehm, J. Folkman, T. Browder, M.S. O'Reilly, Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance, Nature 390 (1997) 404-407; R.S. Kerbel, Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents, BioEssays 13 (1991) 31-36; R.S. Kerbel, A cancer therapy resistant to resistance, Nature 390 (1997) 335-336). Another is to devise methods which will improve significantly the effectiveness of those conventional drugs already in use, such as adriamycin, cyclophosphamide and taxol. We have directed efforts towards the latter. They depend on the discovery of a new class of chemosensitizers which act as antiadhesive agents rendering solid tumors more susceptible to such conventional cytotoxic therapeutic drugs. Examples of this concept are illustrated with bovine testicular hyaluronidase and a mouse mammary tumor called EMT-6. When this enzyme preparation is used to treat intact multicellular spheroids of the EMT-6 tumor, the spheroids are substantially disaggregated. Dispersed spheroids are more susceptible to the cytotoxic effects of cyclophosphamide than intact spheroids. Moreover, this antiadhesive chemosensitizing effect can actually be reproduced in BALB/c mice when EMT-6 cells are grown intraperitoneally as an ascites tumor (consisting mostly of multicellular aggregates) and the mice are given injections of hyaluronidase and cyclophosphamide. In a similar fashion, the indifference of P-glycoprotein-positive multidrug-resistant EMT-6 spheroids to the P-glycoprotein reversal agent PSC-833 (a cyclosporin A analogue) can be reversed by disaggregation of the intact spheroids by hyaluronidase. This renders the treated cells highly sensitive to a combination of adriamycin and PSC-833 in a manner similar to the striking chemosensitization effects commonly observed in monolayer culture systems. Thus, hyaluronidase has the potential to reverse forms of both intrinsic and acquired drug resistance in solid tumors, such as EMT-6, which are sensitive to its antiadhesive effects.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

NMDA-induced increases in rat brain glutamine synthetase but not glial fibrillary acidic protein are mediated by free radicals.

Both excitotoxicity and oxidative stress are implicated in the pathophysiology of central nervous system (CNS) ischaemia-reperfusion injury whereby astrocytes offer neural protection through the production of endogenous antioxidants and removal of glutamate from the extracellular milieu. This study investigated whether exogenous alpha-tocopherol, an antioxidant, could prevent N-methyl-D-aspartate (NMDA)-produced increases of the glial specific proteins, glutamine synthetase (GS) and glial fibrillary acidic protein (GFAP) in rat brain spheroids in vitro. NMDA (320 microM; 3 days in vitro (DIV)) was unable to induce lipid peroxidation in rat brain spheroids implying that excitotoxicity in this system did not involve substantial free radical formation. However at non-cytotoxic concentrations, increases in astroglial GS were prevented by alpha-tocopherol treatment, suggesting a role for ROS in the excitotoxic process. In contrast, NMDA-induced increases in GFAP remained unchanged by alpha-tocopherol indicating that oxidative stress may not be involved in reactive gliosis at non-cytotoxic NMDA concentrations.

Animals↗
PubMed1995

Volume estimation of multicellular colon carcinoma spheroids using Cavalieri's principle.

Multicellular tumour-spheroids are regarded as suitable models for cancer research, similar to avascular tumour parts. As a size parameter of the spheroids, usually their maximum diameter is used, estimated on a section presumed to be equatorial or near equatorial. Estimation of the volume of spheroids is of interest for the detection of subtle changes in different kinds of investigations. Since spheroids are often not truly spherical, and because model-based methods for volume determination may be biased, Cavalieri's principle, rediscovered recently for stereology, was used to determine the volume of the spheroids. Here we report the results of the volume estimation of colon carcinoma spheroids, together with an outline of the basic stereological principle and formulas used. The spheroids investigated had a volume between 1.4 and 92.3 mm3 (mean 33.9). The volume fraction of necrotic to viable tissue cells was between 0.6:1 and 2.2:1. The coefficient of error (CE) was remarkably low with 3.7% for the volumes. Both inter- and intraobserver-variability were extremely low with correlation coefficients (r2) of 99%. Thus, the high precision of the stereological method, combined with a low workload, make it ideally suitable for routine volume estimation.

Carcinoma↗
PubMed2000

Dynamic optimization of a linear-quadratic model with incomplete repair and volume-dependent sensitivity and repopulation.

PURPOSE: The linear-quadratic model typically assumes that tumor sensitivity and repopulation are constant over the time course of radiotherapy. However, evidence suggests that the growth fraction increases and the cell-loss factor decreases as the tumor shrinks. We investigate whether this evolution in tumor geometry, as well as the irregular time intervals between fractions in conventional hyperfractionation schemes, can be exploited by fractionation schedules that employ time-varying fraction sizes. METHODS: We construct a mathematical model of a spherical tumor with a hypoxic core and a viable rim, which is most appropriate for a prevascular tumor, and is only a caricature of a vascularized tumor. This model is embedded into the traditional linear-quadratic model by assuming instantaneous reoxygenation. Dynamic programming is used to numerically compute the fractionation regimen that maximizes the tumor-control probability (TCP) subject to constraints on the biologically effective dose of the early and late tissues. RESULTS: In several numerical examples that employ five or 10 fractions per week on a 1-cm or 5-cm diameter tumor, optimally varying the fraction sizes increases the TCP significantly. The optimal regimen incorporates large Friday (afternoon, if 10 fractions per week) fractions that are escalated throughout the course of treatment, and larger afternoon fractions than morning fractions. CONCLUSION: Numerical results suggest that a significant increase in tumor cure can be achieved by allowing the fraction sizes to vary throughout the course of treatment. Several strategies deserve further investigation: using larger fractions before overnight and weekend breaks, and escalating the dose (particularly on Friday afternoons) throughout the course of treatment.

Algorithms↗
PubMed2001

Radiation response and cure rate of human colon adenocarcinoma spheroids of different size: the significance of hypoxia on tumor control modelling.

PURPOSE: To evaluate the adequacy of a Poisson tumor control probability (tcp) model and the impact of hypoxia on tumor cure. METHODS AND MATERIALS: A human colon adenocarcinoma cell line, WiDr, was grown as multicellular spheroids of different diameters. Measurements were made of cell survival and spheroid cure following 300-kV X-ray external beam irradiation in air and nitrogen. Cell survival data were fitted using a two-compartment and an oxygen diffusion model. Spheroid cure data were fitted using the tcp model. RESULTS: Hypoxia was seen only for spheroids greater than 500 microm in diameter. For small spheroids tcp estimates of radiosensitivity and clonogenic number showed excellent agreement with experimentally derived values. For large spheroids, although tcp estimates of radiosensitivity were comparable with measurements, estimates of the clonogenic number were considerably lower than the experimental count. Reoxygenation of large spheroids before irradiation resulted in the tcp estimates of the number of clonogenic cells agreeing with measured values. CONCLUSIONS: When hypoxia was absent, the tcp model accurately predicted cure from measured radiosensitivity and clonogen number. When hypoxia was present, the number of cells capable of regrowth in situ was considerably lower than the number of clonogenic cells that initially survived irradiation. As this counteracted the decreased radiosensitivity, hypoxia was less important for cure than predicted from cell survival assays. This finding suggests that chronic hypoxia may not limit directly the success of radiation therapy.

Adenocarcinoma↗
PubMed2002

The effects of pentoxifylline on the survival of human glioma cells with continuous and intermittent stereotactic radiosurgery irradiation.

PURPOSE: In linac-based stereotactic radiosurgery, treatment is delivered intermittently via multiple individual small radiotherapy arcs. The time lapses between the individual arcs permit greater damage repair and increased tumor cell survival in comparison with continuous irradiation. Because pentoxifylline (PTX) has been reported to prevent radiation-induced cell cycle arrest at the G2/M checkpoint, where damage repair is critically linked to cell survival, we hypothesized that PTX would exert a favorable radiosensitization effect by reducing the recovery observed during intermittent stereotactic radiosurgery. METHODS AND MATERIALS: The human glioma cell line T98G was used to study the effects of continuous vs. intermittent irradiation with or without PTX. Cell cycle patterns were studied using flow cytometry. Clonogenic assays of single cells and spheroid outgrowth assays provided a quantitative measure of PTX-mediated radiosensitization. The PTX effect upon cells in low oxygen conditions was also studied in vitro after enzymatic oxygen scavenging. RESULTS: Flow Cytometry: T98G cells exposed to both continuous and intermittent irradiation exhibit similar arrest at the G2/M checkpoint. The addition of 2 mM PTX significantly reduced the radiation-induced G2/M block in both irradiation schemes. Clonogenic Assays: The same PTX concentration applied before a continuous dose of 12 Gy, two intermittent doses of 6 Gy, or three intermittent doses of 4 Gy, all given within a 1-h interval, consistently caused radiosensitization. The drug enhancement ratios for PTX were 1.5, 2.7, and 6.0 for the continuous and two different intermittent dose schedules, respectively. Adding PTX after irradiation yielded lower enhancement ratios than pre-irradiation application. A similar pattern was observed after total doses of 4, 6, 9, or 12 Gy, as well. In low oxygen conditions, PTX was seen to have the same effects as in normoxic conditions. Spheroid Outgrowth Assays: The in vitro PTX effects were replicated in the spheroid outgrowth assays. CONCLUSION: In human glioma cells, PTX abrogates the radiation-induced G2/M block observed after either continuous radiation exposure or intermittent exposures modeling clinical linac-based radiosurgery. The PTX-mediated reduction of the G2/M block translates into radiosensitization, most notably during intermittent exposures, and is presumably a consequence of diminished DNA damage repair at the G2/M checkpoint, though other contributing effects cannot be ruled out. The radiosensitization effect of PTX is sustained under low oxygen conditions. These results support consideration of the clinical evaluation of PTX to enhance the efficacy of linac-based radiosurgery involving intermittent irradiation through multiple arcs.

Cell Survival↗