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Methods for Preclinical Evaluation of Cytotoxic Drugs: With Special Reference to the Cyanoguanidine CHS 828 and Hollow Fiber Method
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The novel cyanoguanidine CHS 828 has shown promising antitumor activity in many in vitro and in vivo studies.

The long-term 14 days in vitro hollow fiber cultures, where tumor cells from different tumor cell lines were cultured inside semipermeable fibers, were more resistant to CHS 828 and other cytotoxic drugs than the shorter-term 3 days cultures. CHS 828 was generally more effective against haematological than solid tumor cells from both cell lines and patients samples.

In vivo, the hollow fibers were implanted into immunocompetent rats and the pharmacokinetics, tumor response and/or toxicity (pharmacodynamics) of CHS 828 were successfully assayed. CHS 828 showed higher activity in this model when a more protracted schedule was used. The quantitative relationships between dose, plasma concentration and response (PK/PD model) developed for CHS 828 explained this phenomenon partly by dose-dependent fraction absorbed and partly by a schedule-dependent pharmacodynamic effect.

Modelling of the in vitro CHS 828 and standard cytotoxic drugs concentration-time effect data in different tumor cell types and characterization of pattern of change of the potency and the slope of the concentration-time effect curves were performed. The results suggest two different mechanisms of action for CHS 828 and that CHS 828 cytotoxicity may depend on the schedule used.

The NF-kB pathway that regulates the transcription of anti-apoptotic genes proved to be inhibited by CHS 828 in different tumor cell lines and the inhibition was correlated to the cell death induced by this agent. CHS 828 did not seem to induce the NF-kB inhibition by affecting the proteasome activity.

The in vitro and in vivo hollow fiber methods were also used successfully to evaluate the new paclitaxel formulation, Pacliex. Pacliex had a similar activity to that of the clinically used formulation Taxol®.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2004. , p. 48
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1395
Keywords [en]
Pharmacology, CHS 828, in vitro, in vivo, hollow fiber, models, NF-kB
Keywords [sv]
Farmakologi
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-4696ISBN: 91-554-6113-1 (print)OAI: oai:DiVA.org:uu-4696DiVA, id: diva2:165533
Public defence
2004-12-16, Rudbecsalen, Rudbeck laboratory, SE-751 85, Uppsala, 09:15
Opponent
Supervisors
Available from: 2004-11-24 Created: 2004-11-24 Last updated: 2018-01-13Bibliographically approved
List of papers
1. A hollow fiber model for in vitro studies of cytotoxic compounds: Activity of the cyanoguanidine CHS 828
Open this publication in new window or tab >>A hollow fiber model for in vitro studies of cytotoxic compounds: Activity of the cyanoguanidine CHS 828
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2001 (English)In: Anti-Cancer Drugs, ISSN 0959-4973, E-ISSN 1473-5741, Vol. 12, no 1, p. 33-42Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-92448 (URN)11272284 (PubMedID)
Available from: 2004-11-24 Created: 2004-11-24 Last updated: 2017-12-14Bibliographically approved
2. Model for time dependency of the cytotoxic effect of CHS 828 in vitro suggests two different mechanisms of action
Open this publication in new window or tab >>Model for time dependency of the cytotoxic effect of CHS 828 in vitro suggests two different mechanisms of action
2001 (English)In: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 299, no 3, p. 1140-1147Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-92449 (URN)11714905 (PubMedID)
Available from: 2004-11-24 Created: 2004-11-24 Last updated: 2017-12-14Bibliographically approved
3. Pharmacokinetic-Pharmacodynamic modelling of the schedule-dependent effect of the anti-cancer agent CHS 828 in a rat hollow fibre model
Open this publication in new window or tab >>Pharmacokinetic-Pharmacodynamic modelling of the schedule-dependent effect of the anti-cancer agent CHS 828 in a rat hollow fibre model
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2005 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 25, no 1, p. 163-173Article in journal (Refereed) Published
Abstract [en]

N-(6-Chlorophenoxyhexyl)-N'-cyano-N''-4-pyridylguanidine (CHS 828) is a novel anticancer agent that shows schedule-dependent effects in vitro and in vivo, as well as in Phase I clinical trials. A rat hollow fibre model was used to investigate whether this dependency is due to pharmacokinetic and/or pharmacodynamic factors. The effect on two cell lines, MDA-MB-231 (breast cancer) and CCRF-CEM (leukaemia) were studied after CHS 828 was administered orally as a single dose or in a 5-day schedule, at different total dose levels. The 5-day schedules were associated with greater effects on both cell lines compared with single doses. A one-compartment pharmacokinetic model, with a half-life of 2.3h and a consecutive zero- and first-order process to describe dissolution and absorption, fit the concentration data. Pharmacokinetics were dose-dependent, as the fraction absorbed decreased with increasing dose. Clearance increased with accumulative exposure. Twenty hours after administration, concentrations started to increase again, probably due to coprophagy. Pharmacokinetic-pharmacodynamic models characterized the cell growth and cell kill over time and showed that schedule-dependent antitumour effects were present also when the dose-dependent pharmacokinetics were accounted for. The prolonged schedules of CHS 828 were therefore associated with greater antitumour effects than single doses of the same total exposure.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-92450 (URN)10.1016/j.ejps.2005.02.006 (DOI)15854812 (PubMedID)
Available from: 2004-11-24 Created: 2004-11-24 Last updated: 2017-12-14Bibliographically approved
4. Does the novel anticancer agent CHS 828 induces tumor cell death by inhibiting the transcription factor NF-kB translocation through down regulation of the proteasome?
Open this publication in new window or tab >>Does the novel anticancer agent CHS 828 induces tumor cell death by inhibiting the transcription factor NF-kB translocation through down regulation of the proteasome?
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Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-92451 (URN)
Available from: 2004-11-24 Created: 2004-11-24 Last updated: 2011-03-01
5. Cytotoxic activity of a new paclitaxel formulation, Pacliex, in vitro and in vivo
Open this publication in new window or tab >>Cytotoxic activity of a new paclitaxel formulation, Pacliex, in vitro and in vivo
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2005 (English)In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 55, no 1, p. 47-54Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

The paclitaxel formulation, Taxol (Bristol-Myers Squibb), is one of the most effective anticancer agents used today. However; it is associated with serious side effects believed to be caused by the Cremophor EL used for its formulation.

AIM:

To evaluate the cytotoxic activity of a new paclitaxel formulation, Pacliex (developed by Oasmia Pharmaceutical, Uppsala, Sweden), a mixed micelles preparation in which an amphiphilic synthetic derivative of retinoic acid replaced Cremophor EL/ethanol vehicle.

METHOD:

In this study, three model systems were used to evaluate the cytotoxic activity of Pacliex and other paclitaxel preparations. The cytotoxic activities of Pacliex, Taxol and paclitaxel in ethanol were investigated against a panel of ten human tumor cell lines using the fluorometric microculture cytotoxicity assay (FMCA). Low- and high- proliferating in vitro hollow fiber model of two cell lines, the leukemia CCRF-CEM and the myeloma RPMI 8226/S cell lines, were used to assess the cytotoxic activity of the three formulations. The in vivo hollow fiber model of the two cell lines was used for assessment of Pacliex and Taxol activity. The [3-4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay was utilized to analyze the in vitro and in vivo hollow fiber data.

RESULT:

Pacliex was somewhat more effective than Taxol in the more sensitive cell lines. The activity of Taxol was more pronounced in the resistant cell lines due to an additive effect of the vehicle used. The three formulations showed similar activity in both the low- and high-proliferating in vitro hollow fiber cultures. The in vivo hollow fiber cytotoxic activity of Pacliex was similar to that of Taxol. Putting all the results together, it was found that all the three formulations had similar in vitro and in vivo activity.

CONCLUSION:

The three in vitro and in vivo models confirmed the similarity of the cytotoxic activities of Pacliex and Taxol. Considering the above, Pacliex could be an interesting alternative Cremophor EL-free formulation of paclitaxel.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-92452 (URN)10.1007/s00280-004-0855-5 (DOI)15565443 (PubMedID)
Available from: 2004-11-24 Created: 2004-11-24 Last updated: 2017-12-14Bibliographically approved

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