The dynamics of drug resistance: A mathematical perspective

Lavi, Orit; Gottesman, Michael M.; Levy, Doron

doi:10.1016/j.drup.2012.01.003

Cited by 92 publications

(95 citation statements)

References 69 publications

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“…Although many resistance mechanisms have been described, those that involve proteins belonging to the ABC (ATP binding cassette) transporter superfamily are of particular interest. Drug transport proteins such as P-glycoprotein (P-gp) and multidrug resistance protein (MRP), unwanted plasma membrane occupants in tumor cells, continue to be a major focus of laboratory and clinical studies in drug resistance [72,73]. By and large, research in this area has been directed towards overcoming the chemotherapy efflux capacity of the transporters with the goal of attaining lethal drug concentrations within tumor cells [74-78].…”

Section: Tamoxifen As Modulator Of Multidrug Resistance In Cancermentioning

confidence: 99%

Tamoxifen regulation of sphingolipid metabolism—Therapeutic implications

Morad

Cabot

2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Tamoxifen, a triphenylethylene antiestrogen and one of the first-line endocrine therapies used to treat estrogen receptor-positive breast cancer, has a number of interesting, off-target effects, and among these is the inhibition of sphingolipid metabolism. More specifically, tamoxifen inhibits ceramide glycosylation, and enzymatic step that can adventitiously support the influential tumor-suppressor properties of ceramide, the aliphatic backbone of sphingolipids. Additionally, tamoxifen and metabolites N-desmethyltamoxifen and 4-hydroxytamoxifen, have been shown to inhibit ceramide hydrolysis by the enzyme acid ceramidase. This particular intervention slows ceramide destruction and thereby depresses formation of sphingosine 1-phosphate, a mitogenic sphingolipid with cancer growth-promoting properties. As ceramide-centric therapies are becoming appealing clinical interventions in the treatment of cancer, agents like tamoxifen that can retard the generation of mitogenic sphingolipids and buffer ceramide clearance via inhibition of glycosylation, take on new importance. In this review, we present an abridged, lay introduction to sphingolipid metabolism, briefly chronicle tamoxifen’s history in the clinic, examine studies that demonstrate the impact of triphenylethylenes on sphingolipid metabolism in cancer cells, and canvass works relevant to the use of tamoxifen as adjuvant to drive ceramide-centric therapies in cancer treatment. The objective is to inform the readership of what could be a novel, off-label indication of tamoxifen and structurally-related triphenylethylenes, an indication divorced from estrogen receptor status and one with application in drug resistance.

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Section: Tamoxifen As Modulator Of Multidrug Resistance In Cancermentioning

confidence: 99%

Tamoxifen regulation of sphingolipid metabolism—Therapeutic implications

Morad

Cabot

2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…Mathematical modeling studies in particular have been used to explore both broad and detailed aspects of cancer drug resistance, as reviewed in [43,7,25]. The fundamental question of how the presence of drug resistant cells influences tumor dynamics and treatment outcomes has been thoroughly explored in mathematical models under a wide variety of assumptions [14,37,39,47,58,40,23,24,70,16,45,60,63,4,22,33,44,52,65,3,32,80,13,26,29,46,49,51,57,59,77,18,68,1,9,10,20].…”

mentioning

confidence: 99%

A mathematical approach to differentiate spontaneous and induced evolution to drug resistance during cancer treatment

Greene

Gevertz

Sontag

2017

Preprint

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Resistance to chemotherapy is a major impediment to the successful treatment of cancer. Classically, resistance has been thought to arise primarily through random genetic mutations, after which mutated cells expand via Darwinian selection. However, recent experimental evidence suggests that the progression to drug resistance need not occur randomly, but instead may be induced by the therapeutic agent itself. This process of resistance induction can be a result of genetic changes, or can occur through epigenetic alterations that cause otherwise drug-sensitive cancer cells to undergo phenotype switching. This relatively novel notion of resistance further complicates the already challenging task of designing treatment protocols that minimize the risk of developing drug resistance. In an effort to better understand resistance to treatment, we have developed a mathematical modeling framework that incorporates both random and drug-induced resistance. Our model demonstrates that the ability (or lack thereof) of a drug to induce resistance can result in qualitatively different responses to the same drug dose and delivery schedule. The importance of induced resistance in treatment response led us to ask if, in our model, one can determine the resistance induction rate of a drug for a given treatment protocol. Not only could we prove that the induction parameter in our model is theoretically identifiable, we have also proposed a possible in vitro protocol which could potentially be used to determine a treatment's propensity to induce resistance. (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/235150 doi: bioRxiv preprint first posted online Dec. 15, 2017; Tumor resistance to chemotherapy and targeted drugs is a major cause of treatment failure. Both molecular and microenvironmental factors have been implicated in the development of drug resistance [34]. As an example of molecular resistance, the upregulation of drug efflux transporters can prevent sufficiently high intracellular drug accumulation, limiting treatment efficacy [31]. Other molecular causes of drug resistance include modification of drug targets, enhanced DNA damage repair mechanisms, dysregulation of apoptotic pathways, and the presence of cancer stem cells [31,17,34,78,81]. The irregular tumor vasculature which results in inconsistent drug distribution and hypoxia is an example of a microenvironmental factor that impacts drug resistance [76]. Other characteristics of the tumor microenvironment that influence drug resistance include regions of acidity, immune cell infiltration and activation, and the tumor stroma [27,76,56,15,34,55].Research continues to shed light on the multitude of factors that contribute to cancer drug resistance. Mathematical modeling studies in particular have been used to explore both broad and detailed aspects of cancer drug resistance, as reviewed in [43,7,25]. The fundamental ques...

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“…It is well known that both the division and apoptosis rates depend on the cell-density (see [3, 20, 21, 30]). The specific functional form of these terms plays a key role in the overall dynamics as demonstrated in Section 3.…”

Section: A Mathematical Model For Cancer Dynamicsmentioning

confidence: 99%

The Impact of Cell Density and Mutations in a Model of Multidrug Resistance in Solid Tumors

et al. 2014

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In this paper we develop a mathematical framework for describing multidrug resistance in cancer. To reflect the complexity of the underlying interplay between cancer cells and the therapeutic agent, we assume that the resistance level is a continuous parameter. Our model is written as a system of integro-differential equations that are parametrized by the resistance level. This model incorporates the cell-density and mutation dependence. Analysis and simulations of the model demonstrate how the dynamics evolves to a selection of one or more traits corresponding to different levels of resistance. The emerging limit distribution with nonzero variance is the desirable modeling outcome as it represents tumor heterogeneity.

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The dynamics of drug resistance: A mathematical perspective

Cited by 92 publications

References 69 publications

Tamoxifen regulation of sphingolipid metabolism—Therapeutic implications

Tamoxifen regulation of sphingolipid metabolism—Therapeutic implications

A mathematical approach to differentiate spontaneous and induced evolution to drug resistance during cancer treatment

The Impact of Cell Density and Mutations in a Model of Multidrug Resistance in Solid Tumors

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