Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice

Emmenegger, Urban; Shaked, Yuval; Man, Shan; Bocci, Guido; Spasojević, Ivan; Francia, Giulio; Kouri, Andrew; Coke, Robert; Cruz‐Muñoz, William; Ludeman, Susan M.; Colvin, O. Michael; Kerbel, Robert S.

doi:10.1158/1535-7163.mct-07-0181

Cited by 43 publications

(25 citation statements)

References 47 publications

(61 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The low 4-HC concentrations up to 0.1 mmol/L were similar to concentrations measured in vivo during metronomic CTX treatment (34). Cell viability was measured after both 24 and 144 hours of exposure to 4-HC to assess the effects of direct treatment and prolonged exposure, respectively.…”

Section: Enmd-1198 Reduces Mda-bo2 Cell Viability In Vitromentioning

confidence: 53%

2-Methoxyestradiol Analogue ENMD-1198 Reduces Breast Cancer-Induced Osteolysis and Tumor Burden BothIn VitroandIn Vivo

Snoeks

Mol²,

Que³

et al. 2011

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

It has been estimated that 70% of advanced breast cancer patients will face the complication of bone metastases. Three processes are pivotal during bone metastatic growth of breast cancer, namely, tumor cell proliferation, angiogenesis, and osteolysis. During tumor-induced osteolysis, a number of cytokines and growth factors are released from the degraded bone matrix. These factors stimulate further tumor growth, tumor angiogenesis, and tumor-induced osteolysis. New therapies should target all relevant processes to halt this powerful feedback loop. Here, we characterized the new 2-methoxyestradiol analogue ENMD-1198 and showed that it is cytotoxic to tumor cells. Moreover, ENMD-1198 showed both antiangiogenic and vascular disruptive properties and was capable of protecting the bone against tumor-induced osteolysis. We confirmed the in vitro data with a series of in vivo experiments showing the beneficial effects of ENMD-1198 and ENMD-1198-based combination treatments of metastatic breast cancer in bone both on tumor progression and on survival with long-term ENMD-1198 treatment. We confirmed the in vivo relevance of the ENMD-1198 protective effect on bone both with X-ray radiographs and microcomputed tomography. In addition, we combined ENMD-1198 treatment with low-dose metronomic cyclophosphamide and the bisphosphonate risedronic acid, leading to a mild increase in treatment efficacy. Mol Cancer Ther; 10(5); 874-82. Ó2011 AACR.

show abstract

Section: Enmd-1198 Reduces Mda-bo2 Cell Viability In Vitromentioning

confidence: 53%

2-Methoxyestradiol Analogue ENMD-1198 Reduces Breast Cancer-Induced Osteolysis and Tumor Burden BothIn VitroandIn Vivo

Snoeks

Mol²,

Que³

et al. 2011

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…Grade 3 neuropathy was more common with weekly dosing (24 vs. 12%; p = 0.0003). This large phase III trial confirmed the superior effiSchmidt Breast Care 2016;11:22-26 24 cacy of dose-dense weekly paclitaxel with neurotoxicity as treatment-limiting toxicity.…”

Section: Weekly Schedulesmentioning

confidence: 60%

“…Because of this, it could be suspected that altered pharmacokinetic characteristics due to long-term drug exposure might potentially result in acquired resistance and increased risk of unfavorable drug interactions. However, it was shown in a comprehensive preclinical pharmacokinetic and pharmacodynamic study that exposure of mice for 8 weeks did not compromise subsequent activity of metronomic chemotherapy [24].…”

Section: Metronomic Schedulesmentioning

confidence: 99%

Dose-Dense Chemotherapy in Metastatic Breast Cancer: Shortening the Time Interval for a Better Therapeutic Index

Schmidt¹

2015

Breast Care

View full text Add to dashboard Cite

factor receptor 2 (HER2)-positive advanced breast cancer. Still, despite these advances in targeted therapies, cytotoxic chemotherapy remains a cornerstone in the treatment of advanced disease.Clearly, chemotherapy has an essential role in rapidly progressive life-threatening disease. In these situations, it is sometimes prudent to sacrifice toxicity for improved efficacy leading to rapid responses which in turn should improve the quality of life of the patient.This goal can be achieved by combining chemotherapy with targeted agents like bevacicumab [2] and trastuzumab [3]. Another possibility to achieve a fast response is to combine several chemotherapeutic agents. Even though this approach does not lead to improved survival compared to sequential single-agent chemotherapy, it is sometimes necessary for prompt symptom control. In a meta-analysis of 12 trials with 2,317 patients randomized to combination chemotherapy compared to the same drugs used sequentially, the authors showed that combination chemotherapy led to a higher risk ratio (RR) of 1.13 (95% confidence interval (CI) 1.03-1.24; p = 0.008) at the cost of a higher rate of febrile neutropenia (RR 1.32, 95% CI 1.06-1.65; p = 0.01). Despite the higher response rate, there was no difference in overall survival (OS) between these treatment strategies (hazard ratio (HR) 1.04, 95% CI 0.93-1.16; p = 0.45). Furthermore, combination chemotherapy led to a higher risk of progression (HR 1.16, 95% CI 1.03-1.31; p = 0.01). This high-level evidence further supports the recommendations to use sequential monotherapy unless there is rapid disease progression [4].However, it is in this very situation that the concept of dose density can come into play, including in advanced and metastatic breast cancer. Dose-Dense ChemotherapyIn an attempt to increase the efficacy of anthracycline-and taxane-containing regimens originally used in the adjuvant treatment Keywords Dose-dense · Metastatic · Breast cancer · Weekly · Metronomic Summary Despite the advancement of targeted therapies in metastatic breast cancer, chemotherapy is still of pivotal importance. The concept of dose density is known to increase the efficacy of chemotherapy. In metastatic disease, preservation of the quality of life is equally important. Because of this, weekly regimens are a cornerstone in metastatic disease. Taxanes like paclitaxel or nab-paclitaxel as well as antracyclines are often used in palliative treatment. Further advances to increase dose density have led to the concept of daily metronomic schedules with oral chemotherapeutic drugs like cyclophosphamide, capecitabine, or vinorelbine. Metronomic chemotherapy affects tumor angiogenesis and also weakens immunosuppressive regulatory T cells, promoting better control of tumor progression. Weekly or daily dose-dense regimens are a reasonable compromise between efficacy and toxicity to improve the therapeutic index. This is most important for the treatment of chronic disease where palliation and preservation of quality of life are vital.

show abstract

“…Preclinical studies are reassuring in a number of ways. As an example, metronomic cyclophosphamide administered to mice results in circulating drug levels that have been shown to have antiendothelial cell effects in vitro [54]. Furthermore, circulating drug levels were maintained over prolonged periods of time, and thus altered cyclophosphamide metabolism is an unlikely cause for acquired resistance to metronomic cyclophosphamide.…”

Section: Mechanisms Of Resistance To Metronomic Chemotherapymentioning

confidence: 99%

Resistance to metronomic chemotherapy and ways to overcome it

et al. 2017

Self Cite

View full text Add to dashboard Cite

Therapeutic resistance is amongst the major determinants of cancer mortality. Contrary to initial expectations, antivascular therapies are equally prone to inherent or acquired resistance as other cancer treatment modalities. However, studies into resistance to vascular endothelial growth factor pathway inhibitors revealed distinct mechanisms of resistance compared to conventional cytotoxic therapy. While some of these novel mechanisms of resistance also appear to be functional regarding metronomic chemotherapy, herein we summarize available evidence for mechanisms of resistance specifically described in the context of metronomic chemotherapy. Numerous preclinically identified molecular targets and pathways represent promising avenues to overcome resistance and enhance the benefits achieved with metronomic chemotherapy eventually. However, there are considerable challenges to clinically translate the preclinical findings.

show abstract

Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice

Cited by 43 publications

References 47 publications

2-Methoxyestradiol Analogue ENMD-1198 Reduces Breast Cancer-Induced Osteolysis and Tumor Burden BothIn VitroandIn Vivo

2-Methoxyestradiol Analogue ENMD-1198 Reduces Breast Cancer-Induced Osteolysis and Tumor Burden BothIn VitroandIn Vivo

Dose-Dense Chemotherapy in Metastatic Breast Cancer: Shortening the Time Interval for a Better Therapeutic Index

Resistance to metronomic chemotherapy and ways to overcome it

Contact Info

Product

Resources

About