Results 1 - 10
of
16
DESIGNING PROLIFERATING CELL POPULATION MODELS WITH FUNCTIONAL TARGETS FOR CONTROL BY ANTI-CANCER DRUGS
, 2012
"... We review the main types of mathematical models that have been designed to represent and predict the evolution of a cell population under the action of anti-cancer drugs that are in use in the clinic, with effects on healthy and cancer tissue growth, which from a cell functional point of view are ..."
Abstract
-
Cited by 13 (5 self)
- Add to MetaCart
We review the main types of mathematical models that have been designed to represent and predict the evolution of a cell population under the action of anti-cancer drugs that are in use in the clinic, with effects on healthy and cancer tissue growth, which from a cell functional point of view are classically divided between “proliferation, death and differentiation”. We focus here on the choices of the drug targets in these models, aiming at showing that they must be linked in each case to a given therapeutic application. We recall some analytical results that have been obtained in using models of proliferation in cell populations with control in recent years. We present some simulations performed when no theoretical result is available and we state some open problems. In view of clinical applications, we propose possible ways to design optimal therapeutic strategies by using combinations of drugs, cytotoxic, cytostatic, or redifferentiating agents, depending on the type of cancer considered, acting on different targets at the level of cell populations.
Dynamics of p53 in single cells: physiologically based ODE and reaction–diffusion PDE models
, 2013
"... Abstract. The intracellular signalling network of the p53 protein plays important roles in the genome protection and the control of cell cycle phase transitions. Recently observed oscillatory behaviour in single cells under stress conditions inspires several research groups in simulating and studyin ..."
Abstract
-
Cited by 3 (0 self)
- Add to MetaCart
Abstract. The intracellular signalling network of the p53 protein plays important roles in the genome protection and the control of cell cycle phase transitions. Recently observed oscillatory behaviour in single cells under stress conditions inspires several research groups in simulating and studying the dynamics of the protein with the perspective of a proper understanding of physiological meanings of the oscillations. We propose compartmental ODE and PDE models of p53 activation and regulation in single cells following DNA damage and we show that the p53 oscillations can be retrieved by plainly involving p53–Mdm2 and ATM–p53–Wip1 negative feedbacks, which are sufficient for oscillations experimentally, with no further need to introduce any delays into the protein responses and without considering additional positive feedback.
Strain- and sex-dependent circadian changes in abcc2 transporter expression: implications for irinotecan chronotolerance in mouse ileum. PLoS One 6
, 2011
"... Background: ATP-binding cassette transporter abcc2 is involved in the cellular efflux of irinotecan. The drug is toxic for mouse ileum, where abcc2 is highly expressed. Here, we investigate whether circadian changes in local abcc2 expression participate in the circadian rhythm of irinotecan toxicity ..."
Abstract
-
Cited by 1 (0 self)
- Add to MetaCart
Background: ATP-binding cassette transporter abcc2 is involved in the cellular efflux of irinotecan. The drug is toxic for mouse ileum, where abcc2 is highly expressed. Here, we investigate whether circadian changes in local abcc2 expression participate in the circadian rhythm of irinotecan toxicity for ileum mucosa, and further assess whether genetic background or sex modify this relation. Methodology/Principal Findings: Ileum mucosa was obtained every 3–4 h for 24 h in male and female B6D2F1 and B6CBAF1 mice synchronized with light from Zeitgeber Time (ZT)0 to ZT12 alternating with 12 h of darkness. Irinotecan (50 mg/kg i.v. daily for 4 days) was administered at the sex- and strain-specific times corresponding to least (ZT11-15) or largest drug-induced body weight loss (ZT23-03-07). Abcc2 expression was determined with qRT-PCR for mRNA and with immunohistochemistry and confocal microscopy for protein. Histopathologic lesions were graded in ileum tissues obtained 2, 4 or 6 days after treatment. Two- to six-fold circadian changes were demonstrated for mRNA and protein mean expressions of abcc2 in mouse ileum (p,0.05). ZT12 corresponded to high mRNA and protein expressions, with circadian waveforms differing according to genetic background and sex. The proportion of mice spared from ileum lesions varied three-fold according to irinotecan timing, with best tolerability at ZT11-15 (p = 0.00003). Irinotecan was also best tolerated in
Physiologically Based Mathematical Models to Optimize Therapies Against Metastatic Colorectal Cancer: a Mini-Review, in "Current Pharmaceutical Design
"... Abstract: Understanding and improving the effects of combined drug treatments in metastatic colorectal Cancer (mCRC) is a multidisci-plinary and multiscale problem, that can benet from a systems biology approach. Although a quite limited number of active drugs have been approved for clinical applica ..."
Abstract
-
Cited by 1 (0 self)
- Add to MetaCart
(Show Context)
Abstract: Understanding and improving the effects of combined drug treatments in metastatic colorectal Cancer (mCRC) is a multidisci-plinary and multiscale problem, that can benet from a systems biology approach. Although a quite limited number of active drugs have been approved for clinical applications, a variety of combined delivery regimen options are actually used in the clinic, so that choosing between them, or designing new ones, is not an obvious task, which calls for some rationalization based on physiological principles. We propose some physiologically based molecular pharmacokinetics-pharmacodynamics models for the main cytotoxic drugs used in the clinic and call for others describing more recently used agents, such as associated with monoclonal antibodies. We also advocate simulta-neously designing models of the proliferating cell populations under therapeutic control, as cancer is primarily a disruption of physiologi-cal control on tissue proliferation. These two types of models are based on differential equations to continuously describe both the fate of drugs in the organism, from infusion until pharmacological effects, and their impact on the proliferation of cell populations, healthy and tumor. The multiscale nature of colorectal cancer, from the disruption of intracellular pathways to tumor growth observed at the macro-scopic level, together with its frequent multilocal extension by simultaneous metastases in various healthy tissues of the organism at the time of diagnosis, and later, call for multiscale mathematical models. We thus propose a multi-level vision of cytotoxic drug use in the clinic, in which the weapon in the hands of clinicians, a drug combination regimen, the targets-wanted and unwanted –on which it exerts its effects, molecular pathways in proliferating cell populations, and the environment of the latter in a whole organism, are all considered
unknown title
, 2012
"... Author manuscript, published in "Mathematical modelling of cancer growth and treatment Springer (Ed.) (2012)" Physiologically structured cell population dynamic models with applications to combined drug delivery optimisation in oncology ..."
Abstract
- Add to MetaCart
(Show Context)
Author manuscript, published in "Mathematical modelling of cancer growth and treatment Springer (Ed.) (2012)" Physiologically structured cell population dynamic models with applications to combined drug delivery optimisation in oncology
Author manuscript, published in "BBA- Biochimica et Biophysica Acta- Proteins and Proteomics (2013)" The p53 protein and its molecular network: modelling a missing link between DNA damage and cell fate
, 2013
"... Various molecular pharmacokinetic–pharmacodynamic (PK–PD) models have been proposed in the last decades to represent and predict drug effects in anticancer chemotherapies. Most of these models are cell population based since clearly measurable effects of drugs can be seen, much more easily than in i ..."
Abstract
- Add to MetaCart
Various molecular pharmacokinetic–pharmacodynamic (PK–PD) models have been proposed in the last decades to represent and predict drug effects in anticancer chemotherapies. Most of these models are cell population based since clearly measurable effects of drugs can be seen, much more easily than in individual cells, on populations of cells, healthy and tumour. The actual targets of drugs are, however, cells themselves. The drugs in use either disrupt genome integrity by causing DNA strand breaks, and consequently initiate programmed cell death, or block cell proliferation mainly by inhibiting factors that enable cells to proceed from one cell cycle phase to the next through checkpoints in the cell division cycle. DNA damage caused by cytotoxic drugs (and also cytostatic drugs at high concentrations) activates, among others, the p53 protein-modulated signalling pathways that directly or indirectly force the cell to make a decision between survival and death. This paper aims at becoming a brick in a larger scale scale enterprise that
Author manuscript, published in "Journal of Mathematical Biology (2012)" DOI: 10.1007/s00285-012-0518-9 J. Clairambault Theorems to treat cancer? Can theorems help treat cancer?
, 2013
"... Can mathematicians who prove theorems be useful to physicians who treat patients with cancer? Can mathematics have an impact on cancer biology? Is mathematics more than just a tool in the hands of [a few open-minded] physicians willing to understand and treat cancer from an innovative point of view? ..."
Abstract
- Add to MetaCart
(Show Context)
Can mathematicians who prove theorems be useful to physicians who treat patients with cancer? Can mathematics have an impact on cancer biology? Is mathematics more than just a tool in the hands of [a few open-minded] physicians willing to understand and treat cancer from an innovative point of view?...and is mathematical biology more than just a toy in the hands of mathematicians? I imagine that most readers of this journal would join me in answering “yes ” to these questions. But let me be more explicit in my questioning: Is there a place for a very abstract theoretical activity, as is proving theorems, in a team of physicians daily committed to treating human diseases (in particular cancer)? Can these physicians see the contribution of mathematicians to their difficult task as more than helping them to “think differently ” (as some of them state it), but further as actually taking part in a therapeutic decision? As regards mathematical biology, when it is applied to medical questions, do we mathematicians feel enough committed to go beyond a few publications in the numerous journals dedicated to applications of maths to biology, and to collaborate with medical teams in a long term effort to improve in common medical treatments? Building on recent articles [3, 4] in which I have outlined technical ways by which one can achieve a working collaboration between mathematicians and physicians toward such mutual usefulness, I
J. Clairambault Theorems to treat cancer? Can theorems help treat cancer?
"... Can mathematicians who prove theorems be useful to physicians who treat patients with can-cer? Can mathematics have an impact on cancer biology? Is mathematics more than just a tool in the hands of [a few open-minded] physicians willing to understand and treat cancer from an innovative point of view ..."
Abstract
- Add to MetaCart
(Show Context)
Can mathematicians who prove theorems be useful to physicians who treat patients with can-cer? Can mathematics have an impact on cancer biology? Is mathematics more than just a tool in the hands of [a few open-minded] physicians willing to understand and treat cancer from an innovative point of view?...and is mathematical biology more than just a toy in the hands of math-ematicians? I imagine that most readers of this journal would join me in answering “yes ” to these questions. But let me be more explicit in my questioning: Is there a place for a very abstract theo-retical activity, as is proving theorems, in a team of physicians daily committed to treating human diseases (in particular cancer)? Can these physicians see the contribution of mathematicians to their difficult task as more than helping them to “think differently ” (as some of them state it), but further as actually taking part in a therapeutic decision? As regards mathematical biology, when it is applied to medical questions, do we mathematicians feel enough committed to go beyond a few publications in the numerous journals dedicated to applications of maths to biology, and to collaborate with medical teams in a long term effort to improve in common medical treatments? Building on recent articles [3, 4] in which I have outlined technical ways by which one can achieve a working collaboration between mathematicians and physicians toward such mutual usefulness, I
