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- Karlsson, Henning, et al.
(author)
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A novel tumor spheroid model identifies selective enhancement of radiation by an inhibitor of oxidative phosphorylation
- 2019
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In: Oncotarget. - Orchard Park, NY United States : Impact Journals. - 1949-2553. ; 10:51, s. 5372-5382
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Journal article (peer-reviewed)abstract
- There is a need for preclinical models that can enable identification of novel radiosensitizing drugs in clinically relevant high-throughput experiments. We used a new high-throughput compatible total cell kill spheroid assay to study the interaction between drugs and radiation in order to identify compounds with radiosensitizing activity. Experimental drugs were compared to known radiosensitizers and cytotoxic drugs clinically used in combination with radiotherapy. VLX600, a novel iron-chelating inhibitor of oxidative phosphorylation, potentiated the effect of radiation in tumor spheroids in a synergistic manner. This effect was specific to spheroids and not observed in monolayer cell cultures. In conclusion, the total cell kill spheroid assay is a feasible high-throughput method in the search for novel radiosensitizers. VLX600 shows encouraging characteristics for development as a novel radiosensitizer.
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| 2. |
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| 3. |
- Kashif, Muhammad, et al.
(author)
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Bliss and Loewe interaction analyses of clinically relevant drug combinations in human colon cancer cell lines reveal complex patterns of synergy and antagonism
- 2017
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In: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:61, s. 103952-103967
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Journal article (peer-reviewed)abstract
- We analyzed survival effects for 15 different pairs of clinically relevant anticancer drugs in three iso-genic pairs of human colorectal cancer carcinoma cell lines, by applying for the first time our novel software (R package) called COMBIA. In our experiments iso-genic pairs of cell lines were used, differing only with respect to a single clinically important KRAS or BRAF mutation. Frequently, concentration dependent but mutation independent joint Bliss and Loewe synergy/antagonism was found statistically significant. Four combinations were found synergistic/antagonistic specifically to the parental (harboring KRAS or BRAF mutation) cell line of the corresponding iso-genic cell lines pair. COMBIA offers considerable improvements over established software for synergy analysis such as MacSynergy (TM) II as it includes both Bliss (independence) and Loewe (additivity) analyses, together with a tailored non-parametric statistical analysis employing heteroscedasticity, controlled resampling, and global (omnibus) testing. In many cases Loewe analyses found significant synergistic as well as antagonistic effects in a cell line at different concentrations of a tested drug combination. By contrast, Bliss analysis found only one type of significant effect per cell line. In conclusion, the integrated Bliss and Loewe interaction analysis based on non-parametric statistics may provide more robust interaction analyses and reveal complex patterns of synergy and antagonism.
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| 4. |
- Mansoori, Sharmineh, et al.
(author)
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A phase 2a clinical study on the safety and efficacy of individualized dosed mebendazole in patients with advanced gastrointestinal cancer
- 2021
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In: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11:1
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Journal article (peer-reviewed)abstract
- Mebendazole is used extensively for treatment of local gut helminthic and invasive echinococcus infections. Anticancer effects of mebendazole have been shown in experimental cancer models and in case studies in patients with advanced cancer. Given these observations, the aims of this study were to investigate safety and efficacy of individualized dosed mebendazole in the cancer indication. Patients with treatment refractory gastrointestinal cancer were treated with individualized dose adjusted mebendazole up to 4 g/day to target a serum concentration of 300 ng/ml. Efficacy and safety were assessed by CT-scans, clinical surveillance and blood sampling. Eleven patients were included in the study and 10 started the treatment phase. Two patients stopped treatment prior to and the remaining eight after tumour evaluation by CT-scan at 8 weeks, all due to progressive disease. Four patients also fulfilled criteria suggested for hyperprogression. Only five patients reached the target serum-mebendazole concentration. No severe adverse effects were observed. Individualized dose adjusted mebendazole is safe and well tolerated in patients with advanced cancer but all patients experienced rapid progressive disease. New approaches such as prodrug development and combination with other anticancer drugs seem needed for further exploration of mebendazole as an anticancer drug.
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