Metronomic chemotherapy in non‑small cell lung cancer (Review)

Shu, Yefei; Weng, Shanshan; Zheng, Shu

doi:10.3892/ol.2020.12170

Cited by 14 publications

(16 citation statements)

References 95 publications

(95 reference statements)

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“…During the last decade, numerous clinical trials have been performed to explore MC in first-and second-line treatment, and to investigate the maintenance of treatment for metastatic NSCLC [27][28][29][30]. Due to lower toxicity, higher tolerability and acceptable safety, MC could be a better option for patients with NSCLC cancer [31]. In our study, the same impact of MTD and MC schedules on in vivo NSCLC tumor growth was reported.…”

Section: Discussionsupporting

confidence: 68%

Metronomic Chemotherapy Modulates Clonal Interactions to Prevent Drug Resistance in Non-Small Cell Lung Cancer

Bondarenko

Grand

Shaked

et al. 2021

Cancers

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Despite recent advances in deciphering cancer drug resistance mechanisms, relapse is a widely observed phenomenon in advanced cancers, mainly due to intratumor clonal heterogeneity. How tumor clones progress and impact each other remains elusive. In this study, we developed 2D and 3D non-small cell lung cancer co-culture systems and defined a phenomenological mathematical model to better understand clone dynamics. Our results demonstrated that the drug-sensitive clones inhibit the proliferation of the drug-resistant ones under untreated conditions. Model predictions and their experimental in vitro and in vivo validations indicated that a metronomic schedule leads to a better regulation of tumor cell heterogeneity over time than a maximum-tolerated dose schedule, while achieving control of tumor progression. We finally showed that drug-sensitive and -resistant clones exhibited different metabolic statuses that could be involved in controlling the intratumor heterogeneity dynamics. Our data suggested that the glycolytic activity of drug-sensitive clones could play a major role in inhibiting the drug-resistant clone proliferation. Altogether, these computational and experimental approaches provide foundations for using metronomic therapy to control drug-sensitive and -resistant clone balance and highlight the potential of targeting cell metabolism to manage intratumor heterogeneity.

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Section: Discussionsupporting

confidence: 68%

Metronomic Chemotherapy Modulates Clonal Interactions to Prevent Drug Resistance in Non-Small Cell Lung Cancer

Bondarenko

Grand

Shaked

et al. 2021

Cancers

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“…To compare different treatment schemes, we simulated various single and combination therapy schedules based on clinical protocols of MTD and M treatments with short half-life anti-cancer drugs [ 89 ] ( Fig 4 ). A major consideration for treatment design is to limit toxicity to normal tissue, so a hypothetical toxic dose level is indicated by a normalized value equal to 1 in the plots.…”

Section: Resultsmentioning

confidence: 99%

Computational simulations of tumor growth and treatment response: Benefits of high-frequency, low-dose drug regimens and concurrent vascular normalization

2023

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Implementation of effective cancer treatment strategies requires consideration of how the spatiotemporal heterogeneities within the tumor microenvironment (TME) influence tumor progression and treatment response. Here, we developed a multi-scale three-dimensional mathematical model of the TME to simulate tumor growth and angiogenesis and then employed the model to evaluate an array of single and combination therapy approaches. Treatments included maximum tolerated dose or metronomic (i.e., frequent low doses) scheduling of anti-cancer drugs combined with anti-angiogenic therapy. The results show that metronomic therapy normalizes the tumor vasculature to improve drug delivery, modulates cancer metabolism, decreases interstitial fluid pressure and decreases cancer cell invasion. Further, we find that combining an anti-cancer drug with anti-angiogenic treatment enhances tumor killing and reduces drug accumulation in normal tissues. We also show that combined anti-angiogenic and anti-cancer drugs can decrease cancer invasiveness and normalize the cancer metabolic microenvironment leading to reduced hypoxia and hypoglycemia. Our model simulations suggest that vessel normalization combined with metronomic cytotoxic therapy has beneficial effects by enhancing tumor killing and limiting normal tissue toxicity.

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“…The concept of MC, and its therapeutic use, have been extensively reviewed [19][20][21][22][23]25] as regards the treatment of breast cancer [34,35], non-small-cell lung cancer (NSCLC) [36], and high-risk pediatric malignancies [37]. A systematic review on MC compiles the clinical experience in different cancers such as breast, castration-resistant prostate, ovarian, glial, renal, lung, gastrointestinal, hepatocellular, multiple myeloma, melanoma, and head and neck [38].…”

Section: Metronomic Chemotherapy: a Multimodal Therapymentioning

confidence: 99%

Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment

Muñoz

Girotti

Hileeto

et al. 2021

Cancers

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The concept of cancer as a systemic disease, and the therapeutic implications of this, has gained special relevance. This concept encompasses the interactions between tumor and stromal cells and their microenvironment in the complex setting of primary tumors and metastases. These factors determine cellular co-evolution in time and space, contribute to tumor progression, and could counteract therapeutic effects. Additionally, cancer therapies can induce cellular and molecular responses in the tumor and host that allow them to escape therapy and promote tumor progression. In this study, we describe the vascular network, tumor-infiltrated immune cells, and cancer-associated fibroblasts as sources of heterogeneity and plasticity in the tumor microenvironment, and their influence on cancer progression. We also discuss tumor and host responses to the chemotherapy regimen, at the maximum tolerated dose, mainly targeting cancer cells, and a multimodal metronomic chemotherapy approach targeting both cancer cells and their microenvironment. In a combination therapy context, metronomic chemotherapy exhibits antimetastatic efficacy with low toxicity but is not exempt from resistance mechanisms. As such, a better understanding of the interactions between the components of the tumor microenvironment could improve the selection of drug combinations and schedules, as well as the use of nano-therapeutic agents against certain malignancies.

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Metronomic chemotherapy in non‑small cell lung cancer (Review)

Cited by 14 publications

References 95 publications

Metronomic Chemotherapy Modulates Clonal Interactions to Prevent Drug Resistance in Non-Small Cell Lung Cancer

Metronomic Chemotherapy Modulates Clonal Interactions to Prevent Drug Resistance in Non-Small Cell Lung Cancer

Computational simulations of tumor growth and treatment response: Benefits of high-frequency, low-dose drug regimens and concurrent vascular normalization

Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment

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