| 1. |
- Andersson, Claes, et al.
(författare)
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Assessment in vitro of interactions between anti-cancer drugs and noncancer drugs commonly used by cancer patients
- 2023
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Ingår i: Anti-Cancer Drugs. - : Lippincott Williams & Wilkins. - 0959-4973 .- 1473-5741. ; 34:1, s. 92-102
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Tidskriftsartikel (refereegranskat)abstract
- Cancer patients often suffer from cancer symptoms, treatment complications and concomitant diseases and are, therefore, often treated with several drugs in addition to anticancer drugs. Whether such drugs, here denoted as 'concomitant drugs', have anticancer effects or interact at the tumor cell level with the anticancer drugs is not very well known. The cytotoxic effects of nine concomitant drugs and their interactions with five anti-cancer drugs commonly used for the treatment of colorectal cancer were screened over broad ranges of drug concentrations in vitro in the human colon cancer cell line HCT116wt. Seven additional tyrosine kinase inhibitors were included to further evaluate key findings as were primary cultures of tumor cells from patients with colorectal cancer. Cytotoxic effects were evaluated using the fluorometric microculture cytotoxicity assay (FMCA) and interaction analysis was based on Bliss independent interaction analysis. Simvastatin and loperamide, included here as an opioid agonists, were found to have cytotoxic effects on their own at reasonably low concentrations whereas betamethasone, enalapril, ibuprofen, metformin, metoclopramide, metoprolol and paracetamol were inactive also at very high concentrations. Drug interactions ranged from antagonistic to synergistic over the concentrations tested with a more homogenous pattern of synergy between simvastatin and protein kinase inhibitors in HCT116wt cells. Commonly used concomitant drugs are mostly neither expected to have anticancer effects nor to interact significantly with anticancer drugs frequently used for the treatment of colorectal cancer.
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| 2. |
- Frost, Britt-Marie, et al.
(författare)
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In vitro activity of the novel cytotoxic agent CHS 828 in childhood acute leukemia
- 2002
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Ingår i: Anti-Cancer Drugs. - 0959-4973 .- 1473-5741. ; 13:7, s. 735-742
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Tidskriftsartikel (refereegranskat)abstract
- CHS 828, a pyridyl cyanoguanidine, is a new drug candidate now in phase I/II trials, that has shown promising anticancer activity in experimental tumor models and primary cultures of cancer cells from patients. In this study the fluorometric microculture cytotoxicity assay was used for evaluation of CHS 828 in primary cell cultures from children with acute leukemia. The activity of and interaction with the standard drugs, doxorubicin, melphalan, etoposide and cytosine arabinoside (Ara-C), were also assessed. Samples from 65 patients, 42 with acute lymphocytic leukemia (ALL) and 23 with acute myelocytic leukemia (AML) were tested with 72-h continuous drug exposure. There was 50% cell kill at very low CHS 828 concentrations; median IC50 was 0.01 microM in ALL and 0.03 in AML samples (NS) with large interindividual variability in both groups. ALL samples were significantly more sensitive than AML samples to melphalan, doxorubicin and etoposide, but not to Ara-C. In AML samples, combinations between CHS 828 and each of the four standard drugs resulted in significantly lower cell survival than either drug alone. This was also observed in ALL samples, except for Ara-C. Using the additive interaction model, CHS 828 showed a synergistic effect with melphalan in 67%, doxorubicin in 47%, etoposide in 38% and Ara-C in 14% of AML samples. In most ALL samples subadditive effects were found. Further exploration of CHS 828 in childhood leukemia is warranted, especially in AML.
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| 3. |
- Hallböök, Helene, et al.
(författare)
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In vitro activity of imatinib in cells from patients with adult acute lymphoblastic leukemia
- 2005
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Ingår i: Anti-Cancer Drugs. - 0959-4973 .- 1473-5741. ; 16:6, s. 631-634
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the in vitro activity of imatinib on BCR-ABL-positive and -negative tumor cells from patients with adult acute lymphoblastic leukemia (ALL), and investigated in vitro interactions between imatinib and conventional agents. A non-clonogenic cytotoxicity assay was used to analyze p190 BCR-ABL-positive (n = 4), p210 BCR-ABL-positive (n = 2) and BCR-ABL-negative (n = 9) tumor cells from adult ALL patients. The in vitro cytotoxic effect of imatinib was studied alone, and in combination with the cytotoxic agents cytarabine, prednisolone, vincristine, daunorubicin, asparaginase and mercaptopurine. The BCR-ABL-positive samples were significantly (p < 0.05) more sensitive to imatinib than the BCR-ABL-negative at the concentrations 0.1, 1 and 10 muM. Interestingly, the two p210 samples were somewhat less sensitive to imatinib than the p190 samples. Daunorubicin, prednisolone and cytarabine showed the largest benefit from combination with imatinib compared to the most active single agent. The study confirms that drug sensitivity to imatinib is specific for BCR-ABL-positive samples. The results also suggest that combinations between imatinib and daunorubicin, predisolone or cytarabine may be advantageous for the treatment of Philadelphia-positive ALL.
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| 4. |
- Hassan, Saadia Bashir, et al.
(författare)
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A hollow fiber model for in vitro studies of cytotoxic compounds : Activity of the cyanoguanidine CHS 828
- 2001
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Ingår i: Anti-Cancer Drugs. - 0959-4973 .- 1473-5741. ; 12:1, s. 33-42
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Tidskriftsartikel (refereegranskat)abstract
- The hollow fiber assay is currently used as an in vivo model for anticancer drug screening in nude mice, but it can also be used as an in vitro model. In the current study, an in vitro hollow fiber model was used to study the effect and mode of induced cell death of a new cyanoguanidine, CHS 828. Human leukemia, adenocarcinoma and lymphoma cell lines as well as primary cultures of human tumor cells from patients with chronic lymphocytic leukemia (CLL) and ovarian cancer (OC) and normal human lymphocytes were cultured in semipermeable hollow fibers. The fibers were incubated for 3 or 14 days prior to CHS 828 exposure for 72 h, followed by determination of living cell density by MTT staining. For cell morphology, using harvested cultures on cytospin slides had technical advantages compared to using paraffin sections of the formalin-fixed fibers. CHS 828 showed higher antitumor activity on CLL and normal human lymphocyte cultures compared to OC cultures, and cell lines cultured 3 days were more sensitive than those cultured 14 days. Morphological examination of CHS 828-treated cultures revealed a mixture of apoptosis and necrosis.
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| 5. |
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| 6. |
- Johansson, Senia, et al.
(författare)
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Cytotoxicity of digitoxin and related cardiac glycosides in human tumor cells
- 2001
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Ingår i: Anti-Cancer Drugs. - 0959-4973 .- 1473-5741. ; 12:5, s. 475-83
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Tidskriftsartikel (refereegranskat)abstract
- The saponin digitonin, the aglycone digitoxigenin and five cardiac glycosides were evaluated for cytotoxicity using primary cultures of tumor cells from patients and a human cell line panel (representing different cytotoxic drug-resistance patterns). Of these seven compounds, proscillaridin A was the most potent (IC(50): 6.4--76 nM), followed by digitoxin, and then ouabain, digoxin, lanatoside C, digitoxigenin and digitonin. Correlation analysis of the log IC(50) values for the cell lines in the panel showed that compound cytotoxicity was only slightly influenced by resistance mechanisms that involved P-glycoprotein, topoisomerase II, multidrug resistance-associated protein and glutathione-mediated drug resistance. Digitoxin and digoxin expressed selective toxicity against solid tumor cells from patients, while proscillaridin A expressed no selective toxicity against either solid or hematological tumor cells. The results revealed marked differences in cytotoxicity between the cardiac glycosides, both in potency and selectivity, and modes of action for cytotoxicity that differ from that of commonly used anticancer drugs.
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| 7. |
- Laryea, Daniel, et al.
(författare)
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Characterization of the cytotoxic properties of the benzimidazole fungicides, benomyl and carbendazim, in human tumour cell lines and primary cultures of patient tumour cells
- 2010
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Ingår i: Anti-Cancer Drugs. - 0959-4973 .- 1473-5741. ; 21:1, s. 33-42
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Tidskriftsartikel (refereegranskat)abstract
- The benzimidazoles, benomyl and carbendazim, are fungicides suggested to target microtubules. Benomyl is metabolized to carbendazim, which has already been explored as an anticancer drug in phase 1 clinical trials. We further characterized the cytotoxic properties of benomyl and carbendazim in 12 human cell lines and in primary cultures of patient tumour cells with the overall aims of elucidating mechanisms of action and anticancer activity spectrum. Cytotoxicity was assessed in the short-term fluorometric microculture cytotoxicity assay and was correlated with the activity of other anticancer drugs and gene expression assessed by cDNA microarray analysis. Benomyl was generally more potent than its metabolite, carbendazim. Both showed high drug activity correlations with several established and experimental anticancer drugs, but modest association with established mechanisms of drug resistance. Furthermore, these benzimidazoles showed high correlations with genes considered relevant for the activity of several mechanistically different standard and experimental anticancer drugs, indicating multiple and broad mechanisms of action. In patient tumour samples, benomyl tended to be more active in haematological compared with solid tumour malignancies, whereas the opposite was observed for carbendazim. In conclusion, benomyl and carbendazim show interesting and diverse cytotoxic mechanisms of action and seem suitable as lead compounds for the development of new anticancer drugs.
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| 8. |
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| 9. |
- Olsson-Strömberg, Ulla, et al.
(författare)
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Imatinib activity in vitro in tumor cells from patients with chronic myeloid leukemia in chronic phase and blast crisis
- 2006
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Ingår i: Anti-Cancer Drugs. - : Ovid Technologies (Wolters Kluwer Health). - 0959-4973 .- 1473-5741. ; 17:6, s. 631-639
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Tidskriftsartikel (refereegranskat)abstract
- The aims of this study were to evaluate the feasibility of using the non-clonogenic fluorometric microculture cytotoxicity assay in drug sensitivity testing of tumor cells from patients with chronic myeloid leukemia. In nine samples (six chronic phase, three blast crisis), the drug sensitivities in tumor cells from blood versus from bone marrow and fresh tumor cells versus cryopreserved were compared. In 26 samples obtained in chronic phase (pretreatment), in six samples from patients in blast crisis and in the K 562 cell line, the activity of imatinib alone and in combination with cytarabine, vincristine, daunorubicin, interferon, arsenic trioxide and homoharringtonine was evaluated. All chronic myeloid leukemia chronic phase samples were sensitive to imatinib, with a mean IC50 at 10.3 mumol/l. The chronic myeloid leukemia samples from blast crisis (n=6) were significantly more sensitive to imatinib than the samples from chronic phase (n=26) (P<0.05), with an IC50 mean at 0.4 mumol/l. In blast crisis samples, significant positive interaction effects were observed between imatinib and all other tested drugs except for interferon. In chronic phase samples, interferon, daunorubicin and arsenic trioxide were the drugs with the highest frequency of positive interactions with imatinib (P<0.05). We conclude that the fluorometric microculture cytotoxicity assay may be a useful method for drug sensitivity testing in chronic myeloid leukemia patient samples from both chronic phase and blast crisis, and that testing primary tumor cells may have advantages over cell line studies. Imatinib shows a higher in vitro activity and more positive drug interactions in cells from blast crisis than chronic phase chronic myeloid leukemia patients. Combinations between imatinib and interferon, daunorubicin and arsenic trioxide may be interesting for future clinical trials in patients with chronic myeloid leukemia chronic phase.
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| 10. |
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