The point of transition on the dose-effect curve as a reference point in the evaluation of in vitro toxicity data

2012 ◽  
Vol 32 (10) ◽  
pp. 843-849 ◽  
Author(s):  
Salomon Sand ◽  
Joakim Ringblom ◽  
Helen Håkansson ◽  
Mattias Öberg
Keyword(s):  
Reference Point ◽  
Dose Effect ◽  
In Vitro Toxicity ◽  
Toxicity Data ◽  
Effect Curve

Comparative in-Vitro Evaluation of the Myeloid Toxicity of Pentostatin and the Novel PNP-Inhibitor Forodesine.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3766-3766
Author(s):  
Mario Schubert ◽  
Christian Wallenwein ◽  
Larissa Pietsch ◽  
Dan Ran ◽  
Isabel Taubert ◽  
...  
Keyword(s):  
Primary Cultures ◽  
Flow Cytometric Analysis ◽  
Chemotherapeutic Agents ◽  
Dose Effect ◽  
In Vitro Assays ◽  
In Vitro Toxicity ◽  
The Novel ◽  
Xtt Assay ◽  
Cd34 Cells

Abstract Abstract 3766 Poster Board III-702 Inhibitors of the purine metabolism show promising results in the treatment of lymphatic malignancies due to their suppressive effects on lymphogenesis. Their first representative, Pentostatin (Pento), an inhibitor of the deoxyadenosine deaminase, has been in clinical use for several decades. However, early clinical trials with higher dose ranges of the drug reported unforseen severe myelotoxic effects. Recently, Forodesine (Foro), a novel inhibitor of the nucleoside phosphorylase (PNP) has been introduced and is currently deployed in clinical phase I/II trials for the treatment of acute lymphatic leukemia (ALL). In order to systematically evaluate the myelotoxic effects of Pento and Foro, we have now examined their influence on the proliferation and differentiation of primitive and lineage committed hematopoietic progenitor cells (HPCs). In vitro dose/effect-curves for Foro, Pento, and Cytarabine (AraC) were generated for the leukemic cell line jurkat by 48 hours of co-incubation with the compounds. Adequate cytotoxic effects, measured in the XTT assay and by flow cytometric analysis, were observed in clinically relevant dose ranges. For the following studies, an equivalent IC60 dose of each chemotherapeutic agent was selected and CD34+ HPCs from either bone marrow, mobilized peripheral blood, or umbilical cord blood were incubated with the compounds for 48 hours. Subsequently, the rate of vital cells was determined by flow cytometry after stainig with Annexin-V and Propidium Iodide. Compared to the untreated control, the lowest amount of vital CD34+ cells was found in AraC-treated samples (30%); Foro and Pento yielded more vital cells (66% vs 61%). The combination of Foro and Pento unexpectedly had the least toxic effect on CD34+ cells (72%; n=5; p<0.05). Cells from those primary cultures were harvested and short- and long term in vitro assays for colony forming units were performed to evaluate the compounds' toxicity on primitive and lineage committed HPCs. The frequency of primitive myeloic progenitors (LTC-IC) was 2.3% in the untreated samples and diminished after treatment with AraC (1.2%) and Pento (1.9%) but surprisingly significantly increased after Foro-treatment (2.7%); the combination of Foro and Pento resulted in a LTC-IC frequency of 2.3% (p<0.01; n=5) suggesting that Foro may have attenuated the myelotoxicity of Pento. Similar effects of Foro were also observed in the short term colony forming assays where Foro seemed to have a protective effect on multipotent GEMM-progenitors: colony count increased 1.3-fold in comparison to the control; AraC yielded only 0.1-fold, Pento 0.8-fold and the combination of Pento and Foro reached 0.9-fold of the control (p<0.05; n=15). In summary, the novel PNP-inhibitor Forodesine has not only proven to have a low in vitro toxicity on lineage committed HPCs but, surprisingly, the frequency of primitive myeloic progenitors (LTC-IC) increased; clinical studies should therefore be performed to evaluate whether Forodesine, while adding to the therapeutic efficiency, may attenuate adverse effects in combination with other chemotherapeutic agents, such as Pentostatin. Disclosures: Schubert: Mundipharma Int. LTD: Research Funding.

scholarly journals Model-based contextualization of in vitro toxicity data quantitatively predicts in vivo drug response in patients

2016 ◽  
Vol 91 (2) ◽  
pp. 865-883 ◽  
Author(s):  
Christoph Thiel ◽  
Henrik Cordes ◽  
Isabel Conde ◽  
José Vicente Castell ◽  
Lars Mathias Blank ◽  
...  
Keyword(s):  
Drug Response ◽  
In Vitro Toxicity ◽  
Toxicity Data ◽  
Model Based

Toward More Useful In Vitro Toxicity Data with Measured Free Concentrations

2004 ◽  
Vol 38 (23) ◽  
pp. 6263-6270 ◽  
Author(s):  
Minne B. Heringa ◽  
Richard H. M. M. Schreurs ◽  
Frans Busser ◽  
Paul T. Van Der Saag ◽  
Bart Van Der Burg ◽  
...  
Keyword(s):  
In Vitro Toxicity ◽  
Toxicity Data

The Necessity of Biokinetic Information in the Interpretation of In Vitro Toxicity Data

2002 ◽  
Vol 30 (2_suppl) ◽  
pp. 85-91 ◽  
Author(s):  
Bas J. Blaauboer
Keyword(s):  
Critical Concentration ◽  
In Vitro Toxicity ◽  
Toxicity Data ◽  
Animal Data ◽  
Hazard And Risk ◽  
Hazard And Risk Assessment ◽  
Critical Site ◽  
Dose Metric

Data derived from in vitro toxicity studies are not directly applicable in an assessment of the toxicity of compounds in intact organisms. The major limitation is the lack of knowledge of biokinetic behaviour in vivo. Since the toxicity of a compound will be determined by the critical concentration (or other dose metric) of the critical compound (or a metabolite thereof) at the critical site of toxic action, biokinetic behaviour must be taken into account. Possibilities of biokinetic modelling on the basis of in vitro and other non-animal data are discussed, and the application of the results in hazard and risk-assessment schedules is considered.

MEIC Evaluation of Acute Systemic Toxicity

1998 ◽  
Vol 26 (1_suppl) ◽  
pp. 93-129 ◽  
Author(s):  
Cecilia Clemedson ◽  
Frank A. Barile ◽  
Barbro Ekwall ◽  
Maria José Gómez-Lechón ◽  
Tony Hall ◽  
...  
Keyword(s):  
Cell Lines ◽  
Primary Cultures ◽  
Toxicity Testing ◽  
Preceding Paper ◽  
In Vitro Toxicity ◽  
Toxicity Data ◽  
Animal Cells ◽  
Basal Cytotoxicity

Results from tests on the first 30 MEIC reference chemicals in 16 different systems are presented as a prerequisite to the subsequent in vitro/in vivo comparisons of acute toxicity data, i.e. the final MEIC evaluation of all test results of the study. The study is a supplement to the previously published results from 68 methods (including methods 45B and 46B [old numbers]) used to test the same set of chemicals. The strategies and methods of the preceding paper were employed to enable a comparative cytotoxicity analysis of the results from these 68 methods and from the 16 new methods to be made. Principal components analysis (PCA) of 82 assays demonstrated a dominating first component which described as much as 83% of the variance in the toxicity data. This remarkable similarity of all toxicity data was the main finding of the present study, and confirmed the results of the previous study with a less-extensive database. Also, the influence on the general variability of results of several key methodological factors was evaluated by analysis of selected sets of data, including linear regression of the results of pairs of methods, which were similar in all respects except for the factor under analysis. This analysis of the same 82 assays as before also confirmed previous results from the 68 assay database: a) the toxicities of a third of the chemicals increased considerably with exposure time; b) in general, cytotoxicity for human cells was well predicted by cytotoxicity tests with animal cells; c) this prediction was poor for two chemicals, i.e. digoxin and malathion; d) prediction of human cytotoxicity by ecotoxicological tests was only fairly good; e) 25 comparisons of similar assays employing different cell lines showed strikingly similar toxicities (mean R2 = 0.86); f) 22 comparisons of similar pairs of assays employing different primary cultures and cell lines also revealed similar toxicities (mean R2 = 0.79); and g) 15 comparisons of similar assays with different growth/viability endpoint measurements demonstrated strikingly similar toxicities (mean R2 = 0.89). Results b, e, f and g must be the main causes of the general similarity of results, while results a, c and d, together with other factors, could explain the 20% dissimilarity. These findings support the basal cytotoxicity concept and may assist in guiding and refining in vitro toxicity testing in the future.

P02.02 Modeling of response to irradiation in recurrence glioblastoma’s cells culture

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii17-ii17
Author(s):  
N Antipina ◽  
A Belyashova ◽  
G Pavlova ◽  
A Nikolaeva ◽  
E Savchenko ◽  
...  
Keyword(s):  
Experimental Data ◽  
Proliferative Activity ◽  
Dose Range ◽  
Combined Treatment ◽  
Mathematical Expression ◽  
Dose Effect ◽  
Proliferating Cells ◽  
Culture Cells ◽  
Effect Curve

Abstract BACKGROUND Radiosensitivity of glioblastoma (GB) cells of local relapses may be markedly different from the primary tumor. Optimal doses and regimes of re-irradiation GB recurrence is not determined yet. MATERIAL AND METHODS GO1 primary GB cell culture was obtained during removal of a recurrent tumor after combined treatment, including irradiation of the surgical bed. Сell’s culture was irradiated by photon beams with energy 6 MeV and dose rate 600 MU/min. Irradiation performed in 1, 3 and 5 fractions, by 10 different doses for each regime. The dose range was determined experimentally for one fraction (5–250 Gy); for other regimes it was calculated according to the biological equivalent dose conception (3 fractions: 5–450 Gy, 5 fractions: 5–550 Gy). The proliferative activity of cells was investigate by MTT test. The results were normalized to the control. Dose-effect curves were plotted for each irradiation regime.The experimental data were approximated by calculated curves obtained by selecting the optimal parameters of the LQ-model and it’s modification. RESULTS Irradiation of GO1 by 1 fraction with the dose 5–250 Gy, causes a slow decrease in proliferative activity, which reaches a minimum value of 23% at 150 Gy and then remains constant. After irradiation by 3 fractions, proliferative activity of the GO1 gradually decrease only at a total dose over 120 Gy and reaches 37% after 450 Gy. When GO1 was irradiated in 5 fractions, a similar dose-effect curve was obtained, gradual decrease was observed to a value of 52% in the range of 250–500 Gy. Thus, the experimental dose-effect curves for irradiation of recurrence GB cells for 3 and 5 fractions have the appreciable “shoulder”, which could be explained by increased radioresistance. When approximating the experimental data by fitting the parameters of the LQ-model, the use of α/β = 8 provided the slope of the curve, close to the experimental data. For reflecting the “shoulder” an additional summand was introduced into the mathematical expression for the number of proliferating cells - a 105 Gy for 3 fractions and 255 Gy for 5 fractions. CONCLUSION Modified LQ-model could be used for an adequate mathematical description of the effectiveness of fractionated irradiation in relapsed GB culture cells in vitro. It’s necessary to introduce a summand into the formula that determines the formation of a “shoulder” on the dose-effect curve for this. The research was supported financially by RFBR (Project No. 18-29-01061).

scholarly journals The Use of In Vitro Toxicity Data and Physiologically Based Kinetic Modeling to Predict Dose-Response Curves for In Vivo Developmental Toxicity of Glycol Ethers in Rat and Man

2010 ◽  
Vol 118 (2) ◽  
pp. 470-484 ◽  
Author(s):  
Jochem Louisse ◽  
Esther de Jong ◽  
Johannes J. M. van de Sandt ◽  
Bas J. Blaauboer ◽  
Ruud A. Woutersen ◽  
...  
Keyword(s):  
Kinetic Modeling ◽  
Dose Response ◽  
Developmental Toxicity ◽  
In Vitro Toxicity ◽  
Toxicity Data ◽  
Glycol Ethers ◽  
Response Curves ◽  
Physiologically Based
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