Metronomics: towards personalized chemotherapy?

André, Nicolas; Carré, Manon; Pasquier, Eddy

doi:10.1038/nrclinonc.2014.89

Cited by 277 publications

(271 citation statements)

References 194 publications

Supporting

Mentioning

260

Contrasting

Unclassified

Order By: Relevance

“…thrompospondin-1 | tumor perfusion | oxygenation | immune response | drug delivery M etronomic chemotherapy is based on the frequent administration of chemotherapeutic drugs at lower doses than the maximum tolerated dose (MTD) and with minimal drug-free breaks (1)(2)(3). Although metronomic chemotherapy was initially thought to work as an antiangiogenic therapy (4,5), it also has been shown to affect the immune system and to directly affect cancer cells, including the more chemoresistant stem-like cancer cells.…”

mentioning

confidence: 99%

“…Given these complex interactions, predicting the outcomes of preclinical and clinical studies a priori is difficult (2,3,(23)(24)(25). We hypothesize that a mathematical model that incorporates the known mechanisms of the benefit of metronomic chemotherapy may explain these diverse outcomes reported in the literature, and provide guidelines for its optimal use and future experiments.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Role of vascular normalization in benefit from metronomic chemotherapy

Mpekris

Baish

Stylianopoulos

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

148

119

View full text Add to dashboard Cite

Metronomic dosing of chemotherapy-defined as frequent administration at lower doses-has been shown to be more efficacious than maximum tolerated dose treatment in preclinical studies, and is currently being tested in the clinic. Although multiple mechanisms of benefit from metronomic chemotherapy have been proposed, how these mechanisms are related to one another and which one is dominant for a given tumor-drug combination is not known. To this end, we have developed a mathematical model that incorporates various proposed mechanisms, and report here that improved function of tumor vessels is a key determinant of benefit from metronomic chemotherapy. In our analysis, we used multiple dosage schedules and incorporated interactions among cancer cells, stem-like cancer cells, immune cells, and the tumor vasculature. We found that metronomic chemotherapy induces functional normalization of tumor blood vessels, resulting in improved tumor perfusion. Improved perfusion alleviates hypoxia, which reprograms the immunosuppressive tumor microenvironment toward immunostimulation and improves drug delivery and therapeutic outcomes. Indeed, in our model, improved vessel function enhanced the delivery of oxygen and drugs, increased the number of effector immune cells, and decreased the number of regulatory T cells, which in turn killed a larger number of cancer cells, including cancer stem-like cells. Vessel function was further improved owing to decompression of intratumoral vessels as a result of increased killing of cancer cells, setting up a positive feedback loop. Our model enables evaluation of the relative importance of these mechanisms, and suggests guidelines for the optimal use of metronomic therapy.thrompospondin-1 | tumor perfusion | oxygenation | immune response | drug delivery

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

Role of vascular normalization in benefit from metronomic chemotherapy

Mpekris

Baish

Stylianopoulos

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

148

119

View full text Add to dashboard Cite

show abstract

“…In addition to the localized delivery strategies aiming to enhance the exposure of tumors to chemotherapeutics, metronomic dosing represents a novel approach defined as the frequent and continuous administration of conventional chemotherapy drugs at low doses without drug-free breaks ( Figure 4E) [98]. Goldberg and coworkers developed slow-release drug delivery systems based on dual layer surface coating of PLGA PEGylated NPs loaded with PTX for IP treatment of mice bearing BR5FVB1-Akt drug resistant ovarian cancer tumors.…”

Section: Strategies For Ip Delivery and Sustained Release Of Nanomedimentioning

confidence: 99%

Nanomedicine-based intraperitoneal therapy for the treatment of peritoneal carcinomatosis — Mission possible?

Dakwar

Shariati

Willaert

et al. 2017

Advanced Drug Delivery Reviews

View full text Add to dashboard Cite

Intraperitoneal (IP) drug delivery represents an attractive strategy for the local treatment of peritoneal carcinomatosis (PC). Over the past decade, a lot of effort has been put both in the academia and clinic in developing IP therapeutic approaches that maximize local efficacy while limiting systemic side effects. Also nanomedicines are under investigation for the treatment of tumors confined to the peritoneal cavity, due to their potential to increase the peritoneal retention and to target drugs to the tumor sites as compared to free drugs. Despite the progress reported by multiple clinical studies, there are no FDA approved drugs or formulations for specific use in the IP cavity yet. This review discusses the current clinical management of PC, as well as recent advances in nanomedicines-based IP delivery.We address important challenges to be overcome towards designing optimal nanocarriers for IP therapy in vivo.

show abstract

“…In fact, metronomic administration is currently being tested in clinical trials, as it was shown to be more efficacious than maximum tolerated dose treatment in preclinical studies [27].…”

Section: Strategies To Improve Drug Deliverymentioning

confidence: 99%

“…In fact, metronomic administration is currently being tested in clinical trials, as it was shown to be more efficacious than maximum tolerated dose treatment in preclinical studies [27]. Strikingly, evidence from mathematical modeling shows that the combined use of vascular normalization and stress-alleviation strategies may be more beneficial for certain tumor types [28].…”

Section: Strategies To Improve Drug Deliverymentioning

confidence: 99%

Targeting Inflammation to Improve Tumor Drug Delivery

2017

View full text Add to dashboard Cite

Inefficient delivery of drugs is a main cause of chemotherapy failure in hypo-perfused tumors. To enhance perfusion and drug delivery in these tumors, two strategies have been developed: vascular normalization, aiming at normalizing tumor vasculature and blood vessel leakiness; and stress alleviation, aiming at decompressing tumor vessels. Vascular normalization is based on antiangiogenic drugs, whereas stress alleviation on stroma-depleting agents. Here, an alternatively approach to normalize vessels is presented, considering that malignant tumors tend to develop at chronic inflammation sites. Similarly to tumor vessel leakiness, inflammation is also characterized by vascular hyper-permeability. Therefore, testing the ability of anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs or inflammation resolution mediators, as an alternative way to increase tumor drug delivery, might prove promising.Keywords stress alleviation; vascular normalization; tumor perfusion; anti-inflammatory agents; inflammation resolution The Tumor microenvironment and drug deliveryTumors are complex tissues consisting of cancer cells and their microenvironment [1,2], which includes structural and cellular components. Structural components of the tumor microenvironment comprise tumor blood and lymphatic vessels, and the extracellular matrix (ECM) (see Glossary); while the stromal cell constituents [3] include angiogenic vascular cells (endothelial cells and pericytes), infiltrating immune cells, and cancer-associated fibroblasts (CAFs). Naturally, interactions between cancer cells and the various components of tumor microenvironment affect fundamental cancer cell properties such as proliferation, apoptosis, migration and invasion.It has been postulated that components and features of the tumor microenvironment may also set certain barriers with regard to the effective delivery of therapeutic agents, resulting in compromised therapeutic outcomes and decreased survival [4]. Chemotherapeutic drugs are, without a doubt, potent cytotoxic agents. However, they often fail to cure cancer due to the fact that they are unable to reach cancer cells within the tumor in sufficient amounts [5,6]. Hence, the discovery of more efficient approaches to enhance tumor drug delivery is imperative. Here, the main obstacles in drug delivery to the tumor are presented along with the approaches currently used to overcome them. Furthermore, the use of anti-inflammatory agents is proposed as a promising alternative approach to normalize vessels and improve therapy. Europe PMC Funders Group Causes of insufficient drug delivery to tumorsInefficient drug delivery may arise due to barriers posed by abnormal structure and function of tumor stroma, known as desmoplasia. Desmoplastic tumors are characterized by a dense ECM, containing increased levels of total fibrillar collagen, hyaluronan, fibronectin, proteoglycans and tenascin C [4], which also provides the tumor with a reservoir of growth factors eventually promoting its growth. The dense ...

show abstract

Metronomics: towards personalized chemotherapy?

Cited by 277 publications

References 194 publications

Role of vascular normalization in benefit from metronomic chemotherapy

Role of vascular normalization in benefit from metronomic chemotherapy

Nanomedicine-based intraperitoneal therapy for the treatment of peritoneal carcinomatosis — Mission possible?

Targeting Inflammation to Improve Tumor Drug Delivery

Contact Info

Product

Resources

About