A coupled drug kinetics-cell cycle model to analyse the response of human cells to intervention by topotecan

Chappell, Michael J.; Evans, Neil D.; Errington, Rachel J.; Khan, Imtiaz; Campbell, Lee Ann; Ali, Reza; Godfrey, K.R.; Smith, Paul J.

doi:10.1016/j.cmpb.2007.11.002

Cited by 10 publications

(5 citation statements)

References 13 publications

(11 reference statements)

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“…2A). The model is based on established pharmacodynamics and known effects of each of the agents [21][22][23][24][25][26][27][28][29] on the cell cycle for 10 tumor types [31][32][33][34][35][36][37][38] and for erythroblasts 39 (erythroblasts have the highest proliferative index of marrow (Fig. 2B).…”

Section: Drug Selectionmentioning

confidence: 99%

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Novel phase I study combining G1 phase, S phase, and G2/M phase cell cycle inhibitors in patients with advanced malignancies

et al. 2015

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PURPOSE:Cancer is a manifestation of aberrant cellular proliferation, and the cell cycle is one of the most successfully drugged targets in oncology. No prior study has been reported that simultaneously targets the 3 principal cell cycle phases populated by proliferating cells -G 1 , S, and G 2 /M.METHODS: Temsirolimus (G 1 inhibitor), topotecan (S inhibitor), and bortezomib (G 2 /M inhibitor) were administered in combination to patients with advanced malignancies using a 3+3 dose escalation schedule to assess the safety and establish the maximum tolerated dose (primary endpoints) of this cell cycle targeting approach. An in silico pharmacodynamic model using established effects of each of these agents on the cell cycle was used to validate the regimen and to guide the dosing regimen.RESULTS: Sixty-two subjects were enrolled. The most common adverse events and dose-limiting toxicities were cytopenias, consistent with the cell cycle targeting approach employed. All cytopenias resolved to baseline values upon holding study drug administration. The maximum tolerated dose was temsirolimus 15 mg/kg IV D1, 8, 15; topotecan 2.8 mg/m 2 IV D1, 8; and bortezomib 0.9 mg/m 2 IV D1, 4, 8, 11 of a 21-day cycle. In silico modeling suggests the regimen induces cell population shifts from G 2 /M and S phases to G 1 phase and the quiescent G 0 phase. Eighteen percent of subjects (11/62) achieved partial response (n D 2, serous ovarian and papillary thyroid) or stable disease for > 6 months (n D 9).

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Section: Drug Selectionmentioning

confidence: 99%

“…f(t) is a probability of effect based on the individual [16][17][18][19][20] or combined [21][22][23][24][25][26][27][28][29] effects of temsirolimus, topotecan, and bortezomib which have been previously described.…”

Section: Monitoring and Treatment Assessmentmentioning

confidence: 99%

Novel phase I study combining G1 phase, S phase, and G2/M phase cell cycle inhibitors in patients with advanced malignancies

et al. 2015

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“…Such models can take into account intracellular modification and delivery to a nuclear DNA target . This can also be extended to model the subsequent perturbation of the cell cycle . Smart DNA‐targeted reporters will enable mathematical constructs of single cells—a systems’ cytometry approach with predictive capacity.…”

Section: One Man's Probe Is Another Man's Poisonmentioning

confidence: 99%

Nuclear cytometry and chromatin organization

2018

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The nuclear-targeting chemical probe, for the detection and quantification of DNA within cells, has been a mainstay of cytometry-from the colorimetric Feulgen stain to smart fluorescent agents with tuned functionality. The level of nuclear structure and function at which the probe aims to readout, or indeed at which a DNA-targeted drug acts, is shadowed by a wide range of detection modalities and analytical methods. These methods are invariably limited in terms of the resolution attainable versus the volume occupied by targeted chromatin structures. The scalar challenge arises from the need to understand the extent and different levels of compaction of genomic DNA and how such structures can be re-modeled, reported, or even perturbed by both probes and drugs. Nuclear cytometry can report on the complex levels of chromatin order, disorder, disassembly, and even active disruption by probes and drugs. Nuclear probes can report defining features of clinical and therapeutic interest as in NETosis and other cell death processes. New cytometric approaches continue to bridge the scalar challenges of analyzing chromatin organization. Advances in super-resolution microscopy address the resolution and depth of analysis issues in cellular systems. Typical of recent insights into chromatin organization enabled by exploiting a DNA interacting probe is ChromEM tomography (ChromEMT). ChromEMT uses the unique properties of the anthraquinone-based cytometric dye DRAQ5™ to reveal that local and global 3D chromatin structures effect differences in compaction. The focus of this review is nuclear and chromatin cytometry, with linked reference to DNA targeting probes and drugs as exemplified by the anthracenediones.

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“…In most cases, the part of the model describing dynamics of intracellular processes is simplified in such way that it accommodates an a priori chosen treatment (Evans et al, 2004; Chappell et al, 2008; Kronik et al, 2008). Some approaches helped to suggest therapy protocols different from those actually in use (Kronik et al, 2008; Shochat and Rom-Kedar, 2008).…”

Section: Models Of Therapy Taking Into Account Dynamics Of Intracementioning

confidence: 99%

Mathematical modeling as a tool for planning anticancer therapy

Świerniak

Kimmel

Śmieja

2009

European Journal of Pharmacology

109

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We review a large volume of literature concerning mathematical models of cancer therapy, oriented towards optimization of treatment protocols. The review, although partly idiosyncratic, covers such major areas of therapy optimization as phase-specific chemotherapy, antiangiogenic therapy and therapy under drug resistance. We start from early cell-cycle progression models, very simple but admitting explicit mathematical solutions, based on methods of control theory. We continue with more complex models involving evolution of drug resistance and pharmacokinetic and pharmacodynamic effects. Then, we consider two more recent areas: angiogenesis of tumors and molecular signaling within and among cells. We discuss biological background and mathematical techniques of this field, which has a large although only partly realized potential for contributing to cancer treatment.

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A coupled drug kinetics-cell cycle model to analyse the response of human cells to intervention by topotecan

Cited by 10 publications

References 13 publications

Novel phase I study combining G1 phase, S phase, and G2/M phase cell cycle inhibitors in patients with advanced malignancies

Novel phase I study combining G1 phase, S phase, and G2/M phase cell cycle inhibitors in patients with advanced malignancies

Nuclear cytometry and chromatin organization

Mathematical modeling as a tool for planning anticancer therapy

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