The anti-angiogenic basis of metronomic chemotherapy

  title={The anti-angiogenic basis of metronomic chemotherapy},
  author={Robert S. Kerbel and Barton A. Kamen},
  journal={Nature Reviews Cancer},
In addition to proliferating cancer cells and various types of normal cells, such as those of the bone marrow, conventional cytotoxic chemotherapeutics affect the endothelium of the growing tumour vasculature. The anti-angiogenic efficacy of chemotherapy seems to be optimized by administering comparatively low doses of drug on a frequent or continuous schedule, with no extended interruptions — sometimes referred to as 'metronomic' chemotherapy. In addition to reduced acute toxicity, the… 
Upregulation of endogenous angiogenesis inhibitors: A mechanism of action of metronomic chemotherapy
In the March 2004 issue of Cancer Research, Hamano et al. demonstrated that low-dose cyclophosphamide inhibits tumor growth by upregulating the endogenous angiogenesis inhibitor thrombospondin-1 in tumor and perivascular cells.
[Metronomic chemotherapy in pediatric oncology: hype or hope?].
Metronomic chemotherapy: an antiangiogenic scheduling
  • B. Laquente, F. Viñals, J. Germà
  • Biology
    Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico
  • 2007
The possible antiangiogenesis basis of this therapeutic strategy, the experimental studies published and the recent clinical studies that explore this less toxic schedule of cytotoxic drugs are described.
Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity.
The results suggest that CEPs may serve as a pharmacodynamic biomarker to determine the OBD of metronomic chemotherapy regimens, and the advantages of reduced toxicity, increased efficacy in some cases, and ability to combine chemotherapy administered long term with targeted therapies can be compromised.
Metronomic Low-Dose Antiangiogenic Chemotherapy in Mice and Man
Metronomic chemotherapy, because of its relatively nontoxic nature, is ideal for combination therapy using various targeted biologic agents, especially antiangiogenic drugs.
Metronomic chemotherapy in non-small cell lung cancer.
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.
Tumor endothelial cells as a potential target of metronomic chemotherapy
Here, the evidence regarding the anti-angiogenic potential of MCT as a crucial determinant of tumor dormancy and cancer treatment is systematically reviewed.


Metronomic therapy for breast cancer
The effectiveness of metronomic chemotherapy regimens can be improved significantly by concurrent administration of antiangiogenic, endothelial-specific drugs and further confirmation is required with randomized, controlled clinical trials.
Metronomic scheduling: the future of chemotherapy?
Continuous low-dose anti-angiogenic/ metronomic chemotherapy: from the research laboratory into the oncology clinic.
Many cancers are intrinsically resistant to chemotherapy and most of the remainder, which are initially responsive, usually acquire resistance afterwards, so the hypothetical beneficial anti-angiogenic side effect of chemo-therapy would seem negligible, or minimal, at best.
Antiangiogenic scheduling of lower dose cancer chemotherapy.
It would be beneficial to initiate clinical trials to evaluate the antiangiogenic scheduling of chemotherapy expeditiously, because appropriate chemotherapeutic agents and commercially available compounds that inhibit angiogenesis are readily available.
Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice.
Two studies suggest a potentially complementary strategy of rescheduling the administration of classical cytotoxic drugs in order to target tumor endothelial cells, and each presents data suggesting that “metronomic” dosing regimens—either continuous infusion or frequent administration without extended rest periods—could have real value in the clinic.
Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy
The results implicate TSP-1 as a secondary mediator of the antiangiogenic effects of at least some low-dose metronomic chemotherapy regimens, suggesting a marked and selective sensitivity of activated endothelial cells.
Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer.
Using a dosing schedule of cyclophosphamide that provided more sustained apoptosis of endothelial cells within the vascular bed of a tumor, it is shown that a chemotherapeutic agent can more effectively control tumor growth in mice, regardless of whether the tumor cells are drug resistant.
Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity.
A combination therapy with DC101 and low-dose vinblastine resulted in full and sustained regressions of large established tumors, without an ensuing increase in host toxicity or any signs of acquired drug resistance during the course of treatment, which lasted for >6 months.
Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs.
The results are consistent with the possibility that continuous low-dose therapy with various chemotherapeutic drugs may have a highly selective effect against cycling vascular endothelial cells, and may be relevant to the use of continuous or frequent administration of low doses of certain types of drugs as an optimal way of delivering antiangiogenic therapy.
Differences in therapeutic indexes of combination metronomic chemotherapy and an anti-VEGFR-2 antibody in multidrug-resistant human breast cancer xenografts.
  • G. Klement, Ping Huang, R. Kerbel
  • Biology, Medicine
    Clinical cancer research : an official journal of the American Association for Cancer Research
  • 2002
It is concluded that vascular-targeting protocols involving frequent administration of very low doses of certain chemotherapeutic drugs can provide a stable and safe way to circumvent multidrug resistance in established orthotopically growing tumors, as long as these are used in combination with a second anti-VEGFR-2 blocking antibodies.