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- 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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- Hassan, Saadia Bashir, et al.
(författare)
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Model for time dependency of the cytotoxic effect of CHS 828 in vitro suggests two different mechanisms of action
- 2001
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Ingår i: Journal of Pharmacology and Experimental Therapeutics. - 0022-3565 .- 1521-0103. ; 299:3, s. 1140-1147
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Tidskriftsartikel (refereegranskat)abstract
- CHS 828 is a novel drug belonging to the cyanoguanidines. It has shown promising anticancer activity in many preclinical systems and is currently in early clinical trials. Our aim in this study was to assess the growth inhibitory effect of CHS 828 in comparison with paclitaxel, etoposide, and topotecan as a function of concentration and time. U937 GTB, RPMI 8226/S, MDA 231, primary cells from chronic lymphocytic leukemia, and normal mononuclear cells were exposed to CHS 828 and U937 GTB cells were exposed to paclitaxel, etoposide, and topotecan in 18 concentrations for times ranging from 1 to 72 h. Cell survival was measured after 72-h incubation by using the fluorometric microculture cytotoxicity assay. Nonlinear mixed effect modeling was used to model the concentration-effect curves with a modified Hill equation. Patterns of change of drug potency (IC(50)), slope of the concentration-effect curves, and plateau with time were studied. The log IC(50) for CHS 828 decreased with log time in a sigmoid manner for all cell types tested. Although very steep at short and long incubation, the concentration-effect curves became shallow at intermediate times. The log IC(50) for etoposide and topotecan was decreased with log time in a sigmoid manner. The log IC(50) for paclitaxel decreased linearly with log time. The information obtained from modeling the cytotoxic effect of CHS 828 and changes of IC(50) and slope parameters with exposure time suggests a heterogeneous cell response to CHS 828. This could indicate two distinct mechanisms of induction of cell death.
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- Hovstadius, Peter, et al.
(författare)
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A Phase I Study of CHS 828 in Patients with Solid Tumor Malignancy
- 2002
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 8:9, s. 2843-2850
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Tidskriftsartikel (refereegranskat)abstract
- CHS 828 is a cyanoguanidine, which has demonstrated potent antitumor activity in preclinical tumor models. The activity of CHS 828 in vitro showed only low to moderate correlation to other antineoplastic agents suggesting a unique mechanism of action. Ten females and 6 males (median age 58 years) with solid tumors refractory to standard therapy were included in this Phase I study. The study drug was administered to fasting patients as a single oral dose on days 1–5 of each treatment cycle. Patients received one to six cycles of treatment. The doses ranged from 30 mg to 200 mg (total dose within a cycle). Hematological toxicity was generally mild and dominated by transient thrombocytopenia and lymphocytopenia. Nonhematological toxicity most frequently consisted of nausea, vomiting, diarrhea, fatigue, and localized genital mucositis. The dose-limiting toxicities were thrombocytopenia, thrombosis, esophagitis, diarrhea, and constipation. The recommended Phase II dose of CHS 828 was 20 mg once daily for 5 days in cycles of 28 days duration. The extent of systemic exposure of CHS 828 across patients was approximately dose proportional. The time at which the highest drug concentration occurs was 2.2 ± 1.3 h and half-life was 2.1 ± 0.52 h (mean ± SD). Large intra- and interindividual variation in dose level-adjusted maximum plasma concentration and the area under the curve from time 0 h to infinity were observed. There was an apparent inverse relationship between systemic exposure of CHS 828, and thrombocyte and lymphocyte nadir levels. No objective tumor responses were observed, and 7 patients showed stable disease after two courses of therapy.
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| 8. |
- Jonsson, Elin
(författare)
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Application of new methodology for preclinical development of anticancer drugs : With special focus on camptothecin derivatives and the cyanoguanidine CHS 828
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This work describes the development and evaluation of new methods for preclinical anticancer drug development. The methods were specifically applied to study camptothecin analogues and the new compound CHS 828 (N-(4-chlorophenoxyhexyl)-N'-cyano-N"-4-pyridylguanidine) currently in early clinical trials.The tumour type-specific patterns of cytotoxicity of several anticancer drugs were evaluated ex vivo in fresh human tumour cells from patients using a non-clonogenic cytotoxicity assay (FMCA). The activity pattern ex vivo correlated well with known clinical activity.The camptothecin analogues topotecan, irinotecan and its active metabolite SN-38 were studied and differential activity patterns were observed in fresh human tumour cells but not in a panel of ten human tumour cell lines. Topotecan showed synergistic interactions with cisplatin in a high fraction of fresh human tumour samples, while CHS 828 seemed to interact positively with melphalan.CHS 828 showed a high activity in vivo on MCF-7 breast cancer and NYH small-cell lung cancer xenografts in nude mice, at doses with low host animal toxicity.A recently described in vivo hollow-fiber model, where tumour cells were cultured in semipermeable fibers, was developed further. The model allowed simultaneous monitoring of antitumour effect, host animal toxicity and pharmacokinetics in immunocompetent rats. In one study, the hollow fibers were filled with cells from breast-cancer cell lines, and the effectand pharmacokinetics of some standard cytotoxic agents and CHS 828 was measured. CHS 828 showed the highest activity of the drugs studied, and the effect was more pronounced when the drug was administered five days instead of one. Tumour cells from patients with chronic lymphocytic leukaemia and ovarian cancer were also cultured in the hollow fibers, and promising antitumour effect of CHS 828 was demonstrated in vivo.The results indicate a feasibility of using primary human tumour cells from patients in anticancer drug development and they also describe a new in vivo hollow-fiber model that can be used to study drug pharmacokinetics, toxicity and antitumour effect. The preclinical data on the cyanoguanidine CHS 828 appears promising.
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- Jonsson, Elin, et al.
(författare)
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Determination of drug effect on tumour cells, host animal toxicity and drug pharmacokinetics in a hollow-fibre model in rats
- 2000
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 46:6, s. 493-500
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE Based on the previously published hollow-fibre assay mainly used for early in vivo anticancer drug screening, we wanted to develop an extended hollow-fibre model in which antitumour activity, haematological toxicity and pharmacokinetics could be studied in the same animal. METHOD The breast cancer cell lines MDA-MB-231 and MCF-7 were cultured in semipermeable hollow fibres. The fibres were implanted subcutaneously into immunocompetent male Sprague Dawley rats, and the rats were treated with 5-fluorouracil (5-FU, 125 mg/kg), epirubicin (EPI, 10 mg/kg) or cyclophosphamide (CP, 120 mg/kg) intraperitoneally, the new cyanoguanidine CHS 828 (375 mg/kg or 75 mg/kg x 5) orally, or vehicle only. After 6 days the fibres were retrieved and the cell density was evaluated. Haematological parameters were monitored and two to four samples per animal were drawn to determine the pharmacokinetic parameters in NONMEM. RESULTS Drug treatment had generally low effects on the tumour cells. Of the standard drugs (5-FU, EPI and CP), only CP exerted a statistically significant antiproliferative effect. CHS 828 had only a minor effect as a single dose, but divided into five daily doses had a pronounced effect on both cell lines. 5-FU, EPI and CP all caused a marked decrease in leucocytes, platelets and haemoglobin, while CHS 828 did not seem to affect these parameters. The pharmacokinetics of 5-FU and EPI were in accordance with previously established pharmacokinetic models. The pharmacokinetics of CP and CHS 828 were both described by one-compartment models. CONCLUSIONS This study illustrates the possibility of measuring antitumour effect, haematological toxicity and pharmacokinetics in the same animal using the hollow-fibre model.
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