| 1. |
- Delwar, Zahid M., et al.
(author)
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Cytotoxic effect of menadione and sodium orthovanadate in combination on human glioma cells
- 2012
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In: Investigational New Drugs. - : Springer Science and Business Media LLC. - 0167-6997 .- 1573-0646. ; 30:4, s. 1302-1310
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Journal article (peer-reviewed)abstract
- Gliomas are the most common primary brain tumor, and their treatment is still a challenge. Here, we evaluated the antiproliferative effect of a novel combination of two potent oxidative stress enhancers: menadione (M) and sodium orthovanadate (SO). We observed both short-term and prolonged growth inhibitory effects of M or SO alone as well as in combination (M:SO) on DBTRG.05MG human glioma cells. A stronger antiproliferative effect was observed in the short-term proliferation assay with the M:SO combination compared to either investigated agent alone. In the long-term proliferation assay, a 10-day exposure to M:SO at concentrations of 10 mu M:17.5 mu M or 17.5 mu M:10 mu M was enough to kill 100% of the cells; no cell regrowth was observed after re-incubation in drug-free media. When used in combination, the single concentration of M and SO could be decreased by 2.5- to 5-fold of those used for each experimental drug alone and still obtain a similar antiproliferative effect. The underlying molecular mechanism was investigated by co-incubating M:SO with dithiothreitol (DTT) and genistein. Both substances partially neutralized the effects of the M:SO combination, showing additive effects. This observation suggests a role of oxidative stress and tyrosine kinase stimulation in the M:SO cytotoxic effect. Our results indicate that M:SO combination is an attractive alternative for glioma treatment that encourages further study. The neutralizing effects of genistein and DTT reveal a possibility for their use in the minimization of potential M:SO systemic toxicity.
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| 2. |
- Felth, Jenny, 1979-, et al.
(author)
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Gambogic acid is cytotoxic to cancer cells through inhibition of the ubiquitin-proteasome system
- 2013
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In: Investigational new drugs. - : Springer Science and Business Media LLC. - 0167-6997 .- 1573-0646. ; 31:3, s. 587-598
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Journal article (other academic/artistic)abstract
- Gambogic acid (GA), displays cytotoxicity towards a wide variety of tumor cells and has been shown to affect many important cell-signaling pathways. In the present work, we investigated the mechanism of action of GA by analysis of drug-induced changes in gene expression profiles and identified GA and the derivative dihydro GA as possible inhibitors of the ubiquitin-proteasome system (UPS). Both GA and dihydro GA inhibited proteasome function in cells resulting in the accumulation of polyubiquitin complexes. In vitro experiments showed that both GA and dihydro GA inhibited 20S chymotrypsin activity and the inhibitory effects of GA and dihydro GA on proteasome function corresponded with apoptosis induction and cell death. In conclusion, our results show that GA and dihydro GA exert their cytotoxic activity through inhibition of the UPS, specifically by acting as inhibitors of the chymotrypsin activity of the 20S proteasome.
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| 3. |
- Friberg, Lena E, et al.
(author)
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Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model
- 2010
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In: Investigational new drugs. - : Springer Science and Business Media LLC. - 0167-6997 .- 1573-0646. ; 28:6, s. 744-753
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Journal article (peer-reviewed)abstract
- AIM: To investigate the potential of a model for chemotherapy-induced myelosuppression to predict the full time-course of myelosuppression in patients based on rat data. METHODS: White blood cell counts were determined in rats after administration of 5-fluorouracil, epirubicin, cyclophosphamide, docetaxel, paclitaxel or etoposide. Pharmacokinetic models were used to predict the concentration-time profile in each rat. A semi-physiological model of myelosuppression was applied to the rat data. The drug-related parameter Slope was allowed to differ between drugs. The analysis was performed in NONMEM VI. Time-courses of myelosuppression in patients were predicted for each drug based on patient pharmacokinetic models, typical system-related parameters previously determined in patients and the rat Slope estimates in the present study. RESULTS: The semi-physiological model of myelosuppression fit the rat data well and the estimated maturation time in rats (53 h) was approximately half of the previous estimate in patients. The relative difference in Slope estimates for rats and patients based on total drug concentrations ranged between 28% to 8-fold for the six drugs. The differences reduced to 8-37% for all drugs when correcting the rat Slope estimates for species difference in protein binding and in CFU-GM assay sensitivity. CONCLUSIONS: This method for interspecies scaling was successful in predicting the time-course of myelosuppression in patients based on rat data. Predictions improved when species differences in protein binding and CFU-GM assay sensitivity were accounted for. The approach appears promising for predicting myelosuppression in patients early in development.
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| 4. |
- Israelsson, Stina, et al.
(author)
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Improved replication efficiency of echovirus 5 after transfection of colon cancer cells using an authentic 5' RNA genome end methodology
- 2014
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In: Investigational new drugs. - : Springer Science and Business Media LLC. - 0167-6997 .- 1573-0646. ; 32:6, s. 1063-1070
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Journal article (peer-reviewed)abstract
- Oncolytic virotherapy is a promising novel form of cancer treatment, but the therapeutic efficiency needs improvement. A potential strategy to enhance the therapeutic effect of oncolytic viruses is to use infectious nucleic acid as therapeutic agent to initiate an oncolytic infection, without administrating infectious viral particles. Here we demonstrate improved viral replication activation efficiency when transfecting cells with 5’ end authentic in vitro transcribed enterovirus RNA as compared to genomic RNA with additional non-genomic 5’ nucleotides generated by conventional cloning methods. We used echovirus 5 (E5) as an oncolytoc model virus due to its ability to replicate in and completely destroy five out of six colon cancer cell lines and kill artificial colon cancer tumors (HT29 spheroids), as shown here. An E5 infectious cDNA clone including a hammerhead ribozyme sequence was used to generate in vitro transcripts with native 5’ genome ends. In HT29 cells, activation of virus replication is approximately 20-fold more efficient for virus genome transcripts with native 5’ genome ends compared to E5 transcripts generated from a standard cDNA clone. This replication advantage remains when viral progeny release starts by cellular lysis 22 h post transfection. Hence, a native 5’ genomic end improves infection activation efficacy of infectious nucleic acid, potentially enhancing its therapeutic effect when used for cancer treatment. The clone design with a hammerhead ribozyme is likely to be applicable to a variety of oncolytic positive sense RNA viruses for the purpose of improving the efficacy of oncolytic virotherapy.
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| 5. |
- Keizer, Ron J., et al.
(author)
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Two-stage model-based design of cancer phase I dose escalation trials : evaluation using the phase I program of barasertib (AZD1152)
- 2012
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In: Investigational new drugs. - : Springer Science and Business Media LLC. - 0167-6997 .- 1573-0646. ; 30:4, s. 1519-1530
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Journal article (peer-reviewed)abstract
- Introduction Modeling and simulation of pharmacokinetics and pharmacodynamics has previously been shown to be potentially useful in designing Phase I programs of novel anti-cancer agents that show hematological toxicity. In this analysis, a two-stage model-based trial design was evaluated retrospectively using data from the Phase I program with the aurora kinase inhibitor barasertib. Methods Data from two Phase I trials and four regimens were used (n = 79). Using barasertib-hydroxy QPA plasma concentrations and neutrophil count data from only study 1A, a PKPD model was developed and subsequently used to predict the MTD and a safe starting dose for the other trials. Results The PKPD model based on data from the first study adequately described the time course of neutrophil count fluctuation. The two-stage model-based design provided safe starting doses for subsequent phase I trials for barasertib. Predicted safe starting dose levels were higher than those used in two subsequent trials, but lower than used in the other trial. Discussion The two-stage approach could have been applied safely to define starting doses for alternative dosing strategies with barasertib. The limited improvement in efficiency for the phase I program of barasertib may have been due to the fact that starting doses for the studied phase I trials were already nearly optimal. Conclusion Application of the two-stage model-based trial design in Phase I programs with novel anti-cancer drugs that cause haematological toxicity is feasible, safe, and may lead to a reduction in the number of patient treated at sub-therapeutic dose-levels.
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| 6. |
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| 7. |
- Quartino, Angelica, 1979-, et al.
(author)
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A simultaneous analysis of the time-course of leukocytes and neutrophils following docetaxel administration using a semi-mechanistic myelosuppression model
- 2012
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In: Investigational new drugs. - : Springer Science and Business Media LLC. - 0167-6997 .- 1573-0646. ; 30:2, s. 833-845
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Journal article (peer-reviewed)abstract
- Purpose: To improve the predictive capacity of a semi-mechanistic myelosuppression model for neutrophils as the model have shown to over-predict the nadir of neutrophils and, secondly, to develop a model describing the time-course of leukocytes and neutrophils simultaneously. Experimental Design: The study included 601 cancer patients treated with a 1 h infusion of docetaxel in monotherapy. A total of 3,549 pairwise observations of leukocytes and neutrophils from one treatment cycle were analyzed simultaneously in NONMEM. Results: A basic model was developed consisting of a neutrophil and a non-neutrophil model, each with the same structure as the semi-mechanistic myelosuppression model. The leukocytes were modeled as the sum of the predicted neutrophils and non-neutrophils. The model described the time-course of the leukocytes well, but was not able to capture the nadir of the neutrophils. Hence the model was further refined and the included modifications (p < 0.001) in the final model are a sigmoid Emax functions for the drug effect, feedback functions on the cell maturation time in bone-marrow and an optimized number of transit compartments for each of the two cell types. Conclusions: A joint semi-mechanistic myelosuppression model describing the time-course of leukocytes and neutrophils following docetaxel administration was developed. The data supported a more complex model compared to the previous model developed by Friberg et al. (2002), and increased the model's capacity to accurately describe the time-course of neutrophils following docetaxel therapy. The combined model also illustrates the differences between the cell types and allows prediction of neutrophil counts from leukocyte measurements.
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| 8. |
- Soto, Elena, et al.
(author)
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Predictive ability of a semi-mechanistic model for neutropenia in the development of novel anti-cancer agents : two case studies
- 2011
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In: Investigational new drugs. - : Springer Science and Business Media LLC. - 0167-6997 .- 1573-0646. ; 29:5, s. 984-995
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Journal article (peer-reviewed)abstract
- In cancer chemotherapy neutropenia is a common dose-limiting toxicity. An ability to predict the neutropenic effects of cytotoxic agents based on proposed trial designs and models conditioned on previous studies would be valuable. The aim of this study was to evaluate the ability of a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for myelosuppression to predict the neutropenia observed in Phase I clinical studies, based on parameter estimates obtained from prior trials. Pharmacokinetic and neutropenia data from 5 clinical trials for diflomotecan and from 4 clinical trials for indisulam were used. Data were analyzed and simulations were performed using the population approach with NONMEM VI. Parameter sets were estimated under the following scenarios: (a) data from each trial independently, (b) pooled data from all clinical trials and (c) pooled data from trials performed before the tested trial. Model performance in each of the scenarios was evaluated by means of predictive (visual and numerical) checks. The semi-mechanistic PK/PD model for neutropenia showed adequate predictive ability for both anti-cancer agents. For diflomotecan, similar predictions were obtained for the three scenarios. For indisulam predictions were better when based on data from the specific study, however when the model parameters were conditioned on data from trials performed prior to a specific study, similar predictions of the drug related-neutropenia profiles and descriptors were obtained as when all data were used. This work provides further indication that modeling and simulation tools can be applied in the early stages of drug development to optimize future trials.
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| 9. |
- Vita, Marina F., et al.
(author)
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Pankiller effect of prolonged exposure to menadione on glioma cells: potentiation by vitamin C
- 2011
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In: Investigational New Drugs. - : Springer Science and Business Media LLC. - 0167-6997 .- 1573-0646. ; 29:6, s. 1314-1320
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Journal article (peer-reviewed)abstract
- Menadione (Vitamin K3) has anti-tumoral effects against a wide range of cancer cells. Its potential toxicity to normal cells and narrow therapeutic range limit its use as single agent but in combination with radiation or other anti-neoplastic agents can be of therapeutic use. In this paper, we first evaluated the early (within 3 h) effect of menadione on ongoing DNA replication. In normal rat cerebral cortex mini-units menadione showed an age dependent anti-proliferative effect. In tissue mini-units prepared from newborn rats, menadione inhibited ongoing DNA replication with an IC (50) of approximately 10 mu M but 50 mu M had no effect on mini-units from prepared adult rat tissue. The effect of short (72 h) and prolonged exposure (1-2 weeks) to menadione alone in the DBTRG.05MG human glioma cells line and in combination with vitamin C was studied. After short period of exposure data show that menadione alone or in combination with vitamin C provided similar concentration-response curves (and IC50 values). Prolonged exposure to these drugs was evaluated by their ability to kill 100% of glioma cells and prevent regrowth when cells are re-incubated in drug-free media. In this long-term assay, menadione:vitamin C at a ratio 1:100 showed higher anti-proliferative activity when compared to each drug alone and allowed to reduce each drug concentration between 2.5 to 5-fold. Similar anti-proliferative effect was demonstrated in 8 patient derived glioblastoma cell cultures. Our data should be able to encourage further advanced studies on animal models to evaluate the potential use of this combination therapy for glioma treatment.
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| 10. |
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