Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience

Şimşek, Halis; Esin, Ece; Yalçın, Şuayib

doi:10.1155/2019/5483791

Cited by 102 publications

(125 citation statements)

References 250 publications

(231 reference statements)

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“…In order to limit the side effects of the standard chemotherapy protocols and considering the impact of dose and administration scheduling on therapeutic efficacy [7], innovative schedules for cancer treatment have been proposed [8]. Among them, metronomic chemotherapy has been developed as an alternative regimen based on the frequent or continuous administration of low-dose anticancer drugs, without prolonged drug-free periods, whereas the maximum tolerated dose at 2-or 3-week intervals is administered under conventional protocols [9]. This approach enables practitioners to use low drug concentrations while minimizing severe toxicities.…”

Section: Introductionmentioning

confidence: 99%

Potentiation of Low-Dose Doxorubicin Cytotoxicity by Affecting P-Glycoprotein through Caryophyllane Sesquiterpenes in HepG2 Cells: an in Vitro and in Silico Study

Sotto

Irannejad

Eufemi

et al. 2020

IJMS

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Doxorubicin represents a valuable choice for different cancers, although the severe side effects occurring at the high effective dose limits its clinical use. In the present study, potential strategies to potentiate low-dose doxorubicin efficacy, including a metronomic schedule, characterized by a short and repeated exposure to the anticancer drug, and the combination with the natural chemosensitizing sesquiterpenes β-caryophyllene and β-caryophyllene oxide, were assessed in human hepatoma HepG2 cells. The involvement of P-glycoprotein (P-gp) in the HepG2-chemosensitization to doxorubicin was evaluated. Also, the direct interaction of caryophyllene sesquiterpenes with P-gp was characterized by molecular docking and dynamic simulation studies. A metronomic schedule allowed us to enhance the low-dose doxorubicin cytotoxicity and the combination with caryophyllane sesquiterpenes further potentiated this effect. Also, an increased intracellular accumulation of doxorubicin and rhodamine 123 induced by caryophyllane sesquiterpenes was found, thus suggesting their interference with P-gp function. A lowered expression of P-gp induced by the combinations, with respect to doxorubicin alone, was observed too. Docking studies found that the binding site of caryophyllane sesquiterpene was next to the ATP binding domain of P-gp and that β-caryophyllene possessed the stronger binding affinity and higher inhibition potential calculated by MM-PBSA. Present findings strengthen our hypothesis about the potential chemosensitizing power of caryophyllane sesquiterpenes and suggest that combining a chemosensitizer and a metronomic schedule can represent a suitable strategy to overcome drawbacks of doxorubicin chemotherapy while exploiting its powerful activity.Int. J. Mol. Sci. 2020, 21, 633 2 of 28 Int. J. Mol. Sci. 2020, 21, 633 5 of 28 oxide were selected for the combination experiments. Under our experimental conditions, both the sesquiterpenes were able to potentiate the effect of doxorubicin in different experimental conditions, although with different profiles. Particularly, after 24 h exposure, the lower chemosensitizing concentration (50 µM) of β-caryophyllene significantly enhanced the doxorubicin-cytotoxicity starting from the concentration of 10 µM, achieving almost the maximum potentiation of about 32% at concentration of 20 µM (Figure 2a).

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Section: Introductionmentioning

confidence: 99%

Potentiation of Low-Dose Doxorubicin Cytotoxicity by Affecting P-Glycoprotein through Caryophyllane Sesquiterpenes in HepG2 Cells: an in Vitro and in Silico Study

Sotto

Irannejad

Eufemi

et al. 2020

IJMS

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“…two to three administrations a week [155]. This concept has recently been reintroduced in clinical research, partly due to understanding of the involvement of the immune system and possible combinations with immunotherapy [155][156][157].…”

Section: Position Of Inhaled Cytotoxic Chemotherapy In the Standard Omentioning

confidence: 99%

Inhaled cytotoxic chemotherapy: clinical challenges, recent developments, and future prospects

Wauthoz

Rosière

Amighi

2020

Expert Opinion on Drug Delivery

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Introduction: Since 1968, inhaled chemotherapy has been evaluated and has shown promising results up to phase II but has not yet reached the market. This is due to technological and clinical challenges that require to be overcome with the aim of optimizing the efficacy and the tolerance of drug to reopen new developments in this field. Moreover, recent changes in the therapeutic standard of care for treating the patient with lung cancer also open new opportunities to combine inhaled chemotherapy with standard treatments. Areas covered: Clinical and technological concerns are highlighted from the reported clinical trials made with inhaled cytotoxic chemotherapies. This work then focuses on new pharmaceutical developments using dry powder inhalers as inhalation devices and on formulation strategies based on controlled drug release and with sustained lung retention or based on nanomedicine. Finally, new clinical strategies are described in regard to the impact of the immunotherapy on the patient's standard of care. Expert opinion: The choice of the drug, inhalation device, and formulation strategy as well as the position of inhaled chemotherapy in the patient's clinical care are crucial factors in optimizing local tolerance and efficacy as well as in its scalability and applicability in clinical practice.

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“…drug scheduling schemes, such as metronomic chemotherapy protocol, based on suggestions from mathematical modeling studies to tackle this clinical problem [15]. For example, metronomic therapy, which involves a low-dose frequent-time chemotherapy protocol, was tested in many clinical trials including breast [21], prostate [22], and lung cancer [23].…”

Section: Plos Computational Biologymentioning

confidence: 99%

“…None of the virtual patients treated with MTD schedule receives secondary treatment. We simulate metronomic therapy (MT), which is also called the low-dose frequenttime therapy, similarly to MTD 15 . The difference is that for MT, the frequency is T = 5 days and dosage of cisplatinum is 20 mg/m 2 .…”

Section: Treatment Schedulesmentioning

confidence: 99%

Mathematical model predicts response to chemotherapy in advanced non-resectable non-small cell lung cancer patients treated with platinum-based doublet

et al. 2020

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We developed a computational platform including machine learning and a mechanistic mathematical model to find the optimal protocol for administration of platinum-doublet chemotherapy in a palliative setting. The platform has been applied to advanced metastatic non-small cell lung cancer (NSCLC). The 42 NSCLC patients treated with palliative intent at Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, were collected from a retrospective cohort of patients diagnosed in 2004-2014. Patients were followed-up, for three years. Clinical data collected include complete information about the clinical course of the patients including treatment schedule, response according to RECIST classification, and survival. The core of the platform is the mathematical model, in the form of a system of ordinary differential equations, describing dynamics of platinum-sensitive and platinum-resistant cancer cells and interactions reflecting competition for space and resources. The model is simulated stochastically by sampling the parameter values from a joint probability distribution function. The machine learning model is applied to calibrate the mathematical model and to fit it to the overall survival curve. The model simulations faithfully reproduce the clinical cohort at three levels long-term response (OS), the initial response (according to RECIST criteria), and the relationship between the number of chemotherapy cycles and time between two consecutive chemotherapy cycles. In addition, we investigated the relationship between initial and long-term response. We showed that those two variables do not correlate which means that we cannot predict patient survival solely based on the initial response. We also tested several chemotherapy schedules to find the best one for patients treated with palliative intent. We found that the optimal treatment schedule depends, among others, on the strength of competition among various subclones in a tumor. The computational platform developed allows optimizing chemotherapy protocols, within admissible limits of toxicity, for palliative treatment of metastatic NSCLC. The simplicity of the method allows its application to chemotherapy optimization in different cancers.

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Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience

Cited by 102 publications

References 250 publications

Potentiation of Low-Dose Doxorubicin Cytotoxicity by Affecting P-Glycoprotein through Caryophyllane Sesquiterpenes in HepG2 Cells: an in Vitro and in Silico Study

Potentiation of Low-Dose Doxorubicin Cytotoxicity by Affecting P-Glycoprotein through Caryophyllane Sesquiterpenes in HepG2 Cells: an in Vitro and in Silico Study

Inhaled cytotoxic chemotherapy: clinical challenges, recent developments, and future prospects

Mathematical model predicts response to chemotherapy in advanced non-resectable non-small cell lung cancer patients treated with platinum-based doublet

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