Cure, regression and cell survival: a comparison of common radiobiological endpoints using an in vitro tumour model

Re, Durand

doi:10.1259/0007-1285-48-571-556

Cited by 42 publications

(8 citation statements)

References 17 publications

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“…Thus, the data of animal tumors described above may be possibly due to large variations.5) The study of spheroids is advantageous in such analysis. 2,8,9,13,15,16,19,20,25,27) In our study, with small spheroids the values of D0 and N0 ,E , n derived from both the cell survival and spheroid control rate curves were almost the same, confirming the reliabili ty of this experimental system. Similar results have been obtained in studies of small spheroids of human melanoma cells and V-79 cells.…”

Section: IIIsupporting

confidence: 69%

<I>Effects of X-irradiation Alone and in Combination with ACNU on Human Glioblastoma Cells in Vitro</I>

Mashiyama

Katakura

Takahashi

et al. 1990

Neurol. Med. Chir.(Tokyo)

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The combined effects of x-irradiation and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloro ethyl)-3-nitrosourea (ACNU) on multicellular glioblastoma A-7 spheroids were analyzed by means of cell survival and dose-response curves. The actual dose-response curve for small spheroids was almost identical to that estimated from the cell survival curve. It was strongly suggested that a small number of radiation-resistant cells, which were not detected in the cell survival curve, were present in large spheroids with central necrosis. The enhancing effect of ACNU was greater with large sphe roids than with monolayer cells or small spheroids. A possible explanation for this is that ACNU is higher effective against the few radiation-resistant cells that may be present in larger spheroids.

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Section: IIIsupporting

confidence: 69%

<I>Effects of X-irradiation Alone and in Combination with ACNU on Human Glioblastoma Cells in Vitro</I>

Mashiyama

Katakura

Takahashi

et al. 1990

Neurol. Med. Chir.(Tokyo)

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“…We calculated the effect of a dosedependent mitotic delay and found relatively little influence on derived Do (Figure la). However, Durand (1975) observed an apparently dose-dependent delay of up to 3 days in the regrowth of clonogenic cells of V79-171 spheroids. This would tend to lower the derived surviving fraction of SRU at high doses.…”

Section: Discussionmentioning

confidence: 89%

“…Durand, 1975;. They should therefore be better models than macroscopic tumours to test rigorously how close is the correlation between overall response and clonogenic cell survival.…”

Section: Discussionmentioning

confidence: 99%

Deriving cell survival curves from the overall responses of irradiated tumours: Analysis of published data for tumour spheroids

Moore

West²,

Hendry³

1987

Br J Cancer

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Summary Curves of growth delay (GD) or 'cure' after graded doses of radiation have been analysed for 16 lines of human and animal tumours grown as multicellular spheroids in vitro. Dose-survival curves were derived for those cellular units from which spheroids regrow after unsuccessful irradiation (spheroidregenerating cellular units, SRU). For 10 sets of data from 6 spheroid lines, the Do's and extrapolation numbers of the SRU derived by GD could be compared with the response of the clonogenic cells of the spheroids. For Do, a good correlation (r=0.910) was found between the two; this was true also for Do derived from curves of spheroid 'cure' (7 sets of data from 6 spheroid lines) and clonogenic cells (r=0.986). Using GD, the correlation of extrapolation numbers was less good (r=0.682), the values for SRU commonly being higher than those for clonogenic cells. This may reflect features of the growth curves of spheroids after the lower range of doses of radiation. For human and animal tumour spheroids of 250 tm or less, derived Do ranged from 0.5 to 2.5Gy. For spheroids of 350pm or more, derived Do for animal tumour lines ranged from 3.4 to 4.2Gy, for human lines from 1.5 to 2.1 Gy.Several attempts have been made to infer the radiobiological characteristics of the cells (tumour-regenerating cellular units; TRU) that determine whether in situ tumours regrow or not after irradiation. Deductions have been made from the overall responses of populations of tumours, i.e. from the shapes of dose-response curves for delay in tumour regrowth (e.g. Thomlinson and Craddock, 1967;Denekamp and Harris, 1975) or for tumour local control (e.g. Suit, 1966;Moore et al., 1983). There exist a few experimental studies on macroscopic tumours in which good agreement has been found between the Do's for clonogenic cells and values for TRU derived from local control, e.g. for the RI rhabdomyosarcoma made artificially hypoxic by clamping (Rheinhold & de Bree, 1968). However, in most cases the derived Do for TRU has been 2 to 3 times higher than that for clonogenic cells of tumours treated either 'in air' (Moore et al., 1983) or clamped (from an analysis of data quoted by Moulder & Rockwell, 1984). Although, in principle, an equation between the overall response of a macroscopic tumour and the response of its clonogenic cells may be realisable, heterogeneity in number of TRU, degree of oxygenation, repair capabilities, and possibly in some cases radiation dose received, will usually result in derived values of Do that are systematically higher than those for clonogenic cells. Additionally, as noted most recently by Wheldon et al. (1985), the outcome of these calculations for tumours in situ may be complicated by factors such as the tumour bed effect, possible immunological responses, and the maximum size that tumours can be allowed to attain in experimental animals. It was suggested that tumour spheroids growing in vitro might be particularly suitable experimental models in this context, for studying the primary features of cell and tumour...

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“…Clonogenic assay. Tumor cell survival was determined using a standard clonogenic assay (23). 4TCD y cells were plated at 150 per T-25 flask 18 hours before treatments.…”

Section: Methodsmentioning

confidence: 99%

Novel Cytosine Deaminase Fusion Gene Enhances the Effect of Radiation on Breast Cancer in Bone by Reducing Tumor Burden, Osteolysis, and Skeletal Fracture

Goblirsch

Zwolak

Ramnaraine

et al. 2006

Clinical Cancer Research

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Background: Painful breast carcinoma metastases in bone are a common manifestation of malignant disease. Eradication of these tumors can be evasive, and as a result, skeletal morbidity increases with disease progression. Experimental Design: The treatment potential of cytosine deaminase (CD) gene therapy combined with radiation treatment was evaluated in vitro and in vivo using a 4T1 murine breast carcinoma model. 4T1 carcinoma cells were transduced with a fusion gene encoding the extracellular and transmembrane domains of the human nerve growth factor receptor and the cytoplasmic portion of the yeast CD gene (NGFR-CD y ). Results and Conclusions: CD-expressing tumor cells (4TCD y ) were highly sensitive to treatment by 5-fluorocytosine prodrug (P < 0.0001). 5-Fluorocytosine treatment of 4TCD y , but not 4T1 cells, enhanced the effects of radiation in vitro (P < 0.0001). 5-Fluorocytosine prodrug treatment also increased the therapeutic potential of radiation in vivo. Mice with 4TCD y intrafemoral tumors showed increased effectiveness of radiation based on improved reductions in tumor size, reductions in tumorigenic osteolysis, and a decrease in skeletal fractures (P < 0.01).Enzyme/prodrug gene therapy involves expression of a nonmammalian enzyme that converts a nontoxic prodrug to a cytotoxic agent at sites of tumor. The cytosine deaminase (CD)/5-fluorocytosine (5-FC) enzyme/prodrug system converts 5-FC to the highly cytotoxic compound 5-fluorouracil (5-FU) and is a promising therapeutic approach for the treatment of tumors because of its potential for sensitizing tumor cells to radiation treatment. Deamination of 5-FC by CD-expressing tumor cells produces 5-FU. Intracellular 5-FU is then converted to the active metabolites 5-fluoro-2-dUMP (FdUMP) or 5-fluoro-2-dUTP. 5-FU can passively diffuse across the cell membrane and enter adjacent cells where intracellular conversion of 5-FU to FdUMP is done by thymidine kinase. FdUMP inhibits cellular DNA synthesis by binding to and inhibiting thymidylate synthase (1, 2). Although 5-FU has both DNA-directed and RNA-directed effects, its radiationenhancing effects result from DNA-directed mechanisms (3). These include lethal influences on radioresistant S-phase cells and reduction in DNA repair after radiation-induced DNA injury (1).Because 5-FU has been shown to enhance the effect of radiation on tumor cells, the CD/5-FC enzyme/prodrug system is attractive as an adjuvant for treating tumors that will receive radiation treatment (4). The CD/5-FC enzyme/prodrug system has been used in conjunction with radiation treatment in experimental animal models and clinical trials for treating softtissue cancers. Soft-tissue cancers studied with this concomitant therapy include colon, nasopharyngeal, prostate, esophageal, and breast cancers, malignant gliomas and sarcomas, and epidermoid carcinoma (4 -10). Treatment of soft-tissue cancers in experimental models has involved delivery of the CD gene via tumor cell transduction or delivery of adenovirus containing the CD gene fo...

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Cure, regression and cell survival: a comparison of common radiobiological endpoints using an in vitro tumour model

Cited by 42 publications

References 17 publications

<I>Effects of X-irradiation Alone and in Combination with ACNU on Human Glioblastoma Cells in Vitro</I>

<I>Effects of X-irradiation Alone and in Combination with ACNU on Human Glioblastoma Cells in Vitro</I>

Deriving cell survival curves from the overall responses of irradiated tumours: Analysis of published data for tumour spheroids

Novel Cytosine Deaminase Fusion Gene Enhances the Effect of Radiation on Breast Cancer in Bone by Reducing Tumor Burden, Osteolysis, and Skeletal Fracture

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