Metronomic chemotherapy: A relook at its basis and rationale

Rajasekaran, Tanujaa; Ng, Quan‐Sing; Tan, Daniel Shao-Weng; Lim, Darren Wan-Teck; Ang, Mei‐Kim; Toh, Chee-Keong; Chowbay, Balram; Kanesvaran, Ravindran; Tan, Eng‐Huat

doi:10.1016/j.canlet.2016.12.013

Cited by 11 publications

(9 citation statements)

References 48 publications

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“…Furthermore, future head-to-head studies are required to determine which scheme is better. Biomarkers are needed to derive the optimal metronomic dosing of cytotoxic agents (91). Monitoring and evaluating the effect of MCT remains worthy of further investigation.…”

Section: Resultsmentioning

confidence: 99%

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

2020

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Metronomic chemotherapy (MCT) is defined as the rhythmic chemotherapy of low-dose cytotoxic drugs with short or no drug-free breaks over prolonged periods. MCT affects tumor cells and the tumor microenvironment. Particularly, the low-dose schedule impairs the repair process of endothelial cells, resulting in an anti-angiogenesis effect. By stimulating the immune system to eliminate tumor cells, MCT induces immunological activation. Furthermore, combined with targeted therapy, anti-angiogenic drugs enhance the efficacy of MCT. The present review is an overview of phase I, II and III clinical trials focusing on the efficacy, toxicity and mechanism of MCT in patients with non-small cell lung cancer (NSCLC). Furthermore, the prospects of MCT in NSCLC have been discussed. The present review indicated that MCT is an efficacious treatment for selected patients with NSCLC, with acceptable systemic side effects and economic viability for public health. Contents 1. Introduction 2. Preclinical studies of MCT 3. Clinical trials of MCT 4. Mechanism of MCT 5. Conclusion

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Section: Resultsmentioning

confidence: 99%

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

2020

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“…According to the 2014 report of the International Agency for Research on Cancer (IARC), about 1.4 million new cancer patients were added from 2008 to 2012 and it was estimated that the number of cancer cases will increase to 25 million in the next 20 years [ 2 ]. Currently, the primary methods for cancer treatment are surgical resection, radiotherapy, chemotherapy, immunotherapy and so on [ 3 , 4 , 5 , 6 ]. Surgical resection temporarily removes the lesion, which cannot be completely removed due to the strong metastatic characteristic of tumor cells.…”

Section: Introductionmentioning

confidence: 99%

PD-L1 Nanobody Competitively Inhibits the Formation of the PD-1/PD-L1 Complex: Comparative Molecular Dynamics Simulations

Sun

Yan

Zhuo

et al. 2018

IJMS

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The anti-PD-L1 monoclonal antibody (mAb) targeting PD-1/PD-L1 immune checkpoint has achieved outstanding results in clinical application and has become one of the most popular anti-cancer drugs. The mechanism of molecular recognition and inhibition of PD-L1 mAbs is not yet clear, which hinders the subsequent antibody design and modification. In this work, the trajectories of PD-1/PD-L1 and nanobody/PD-L1 complexes were obtained via comparative molecular dynamics simulations. Then, a series of physicochemical parameters including hydrogen bond, dihedral angle distribution, pKa value and binding free energy, and so forth, were all comparatively analyzed to investigate the recognition difference between PD-L1 and PD-1 and nanobody. Both LR113 (the amino acid residues in PD-L1 are represented by the lower left sign of L) and LR125 residues of PD-L1 undergo significant conformational change after association with mAbs, which dominates a strong electrostatic interaction. Solvation effect analysis revealed that solvent-water enhanced molecular recognition between PD-L1 and nanobody. By combining the analyses of the time-dependent root mean squared fluctuation (RMSF), free energy landscape, clustering and energy decomposition, the potential inhibition mechanism was proposed that the nanobody competitively and specifically bound to the β-sheet groups of PD-L1, reduced the PD-L1’s flexibility and finally blocked the formation of PD-1/PD-L1 complex. Based on the simulation results, site-directed mutagenesis of ND99 (the amino acid residues in Nano are displayed by the lower left sign of N) and NQ116 in the nanobody may be beneficial for improving antibody activity. This work offers some structural guidance for the design and modification of anticancer mAbs based on the structure of the PD-1/PD-L1 complex.

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“…In the field of systemic cancer treatment, metronomic chemotherapy is characterized by close, regular administration of chemotherapeutic drugs at relative low, minimally toxic doses for a long period with no extended drug-free break [ 8 ]. Apart from direct antitumor effects, metronomic chemotherapy was shown to have other mechanisms, such as anti-angiogenesis and reverse of immunosuppressive microenvironment [ 9 , 10 ]. Due to better chemotherapeutic tolerability, metronomic treatment strategy has been tested in clinical practice [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Metronomic Cordycepin Therapy Prolongs Survival of Oral Cancer-Bearing Mice and Inhibits Epithelial-Mesenchymal Transition

Chi

et al. 2017

Molecules

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Cordycepin (3′-deoxyadenosine) is a natural compound abundantly found in Cordyceps sinesis in natural and fermented sources. In this study, we examined the effects of cordycepin in a human oral squamous cell carcinoma (OSCC) xenograft model. Cordycepin was administered in a regular, low-dose and prolonged schedule metronomic therapy. Two doses of cordycepin (25 mg/kg, 50 mg/kg) were administrated five days a week for eight consecutive weeks. The tumor volumes were reduced and survival time was significantly prolonged from 30.3 ± 0.9 days (control group) to 56 days (50 mg/kg group, the day of tumor-bearing mice were sacrificed for welfare consideration). The weights of mice did not change and liver, renal, and hematologic functions were not compromised. Cordycepin inhibited the OSCC cell viability in vitro (IC50 122.4–125.2 μM). Furthermore, morphological characteristics of apoptosis, increased caspase-3 activity and G2/M cell cycle arrest were observed. In wound healing assay, cordycepin restrained the OSCC cell migration. Cordycepin upregulated E-cadherin and downregulated N-cadherin protein expression, implying inhibition of epithelial-mesenchymal transition (EMT). The immunohistochemical staining of xenograft tumor with E-cadherin and vimentin validated in vitro results. In conclusion, metronomic cordycepin therapy showed effective tumor control, prolonged survival and low toxicities. Cytotoxicity against cancer cells with apoptotic features and EMT inhibition were observed.

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Metronomic chemotherapy: A relook at its basis and rationale

Cited by 11 publications

References 48 publications

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

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

PD-L1 Nanobody Competitively Inhibits the Formation of the PD-1/PD-L1 Complex: Comparative Molecular Dynamics Simulations

Metronomic Cordycepin Therapy Prolongs Survival of Oral Cancer-Bearing Mice and Inhibits Epithelial-Mesenchymal Transition

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