As the focus of cancer treatments shifts away from conventional chemotherapy to more targeted therapies, a new strategy for
the treatment of cancer has become increasingly popular for both human and veterinary patients. The phrase that has been coined
for this strategy is metronomic chemotherapy or low-dose chemotherapy.
The traditional strategy is to directly target cancer cells with the use of maximally tolerated doses (MTD) of chemotherapy.
As we all know, this strategy can lead to deleterious side effects and a decreased quality of life. Treatments are given intermittently
to allow for normal tissue recovery, which allows for recovery of tumor cells often resulting in re-population of the tumor
with drug-resistant cells and tumor vasculature. As a result, this strategy does not result in cures for many solid tumors
Table 1: Comparison of MTD chemotherapy and etronomic chemotherapy
A different approach is to target normal cells such as endothelial cells and cells of the immune system. Metronomic chemotherapy
still involves the use of chemotherapy drugs, but these drugs are given more frequently at a much lower dose. The targets
of metronomic chemotherapy are circulating endothelial cells and other factors that control angiogenesis. Given that normal
endothelial cells have a more stable genetic makeup, resistance is not likely to be an issue. In addition, this strategy requires
lower doses of chemotherapy that minimize side effects (Table 1).
Review of angiogenesis
In normal tissues, the regulation of angiogenesis is a balance between proangiogenic factors and anti-angiogenic factors.
Most tissues do not require on-going angiogenesis to any significant degree because normal vasculature does not have a high
turnover rate. Exceptions to this would be during growth phases or wound healing.
It has long been recognized that tumor cells rely on angiogenesis to deliver nutrition so that tumors can continue to proliferate.
Without a vascular supply, tumors are not able to grow beyond 1 to 2 mm in size. In order to grow, tumors must have some way
of mobilizing vascular endothelial cells. Many tumors have the ability to secrete potent factors such as vascular endothelial
growth factor (VEGF) and basic fibroblast growth factor (BFGF) that promote angiogenesis.
Potential strategies that can be used to arrest angiogenesis would include targeting the growth factors that promote angiogenesis,
promote the production of anti-angiogenic factors or directly inhibit or kill endothelial cells. Given the limited need for
angiogenesis in mature organisms, it would be expected that significant side effects would be unlikely.
As part of the angiogenic process, endothelial cells are mobilized from the bone marrow into circulation in response to proangiogenic
factors. These circulating endothelial cells are then attracted to the site of active angiogenesis and form tumor vasculature.
Studies have shown that endothelial cells have intrinsic sensitivity to chemotherapy even when used in low doses. The doses
required to inhibit endothelial cells are much lower than those that will inhibit bone marrow and gastrointestinal cells,
thus, limiting side effects. The low doses of chemotherapy used in metronomic chemotherapy directly target endothelial cells
as well as inhibit the release of endothelial cells from the bone marrow.
In addition, metronomic chemotherapy can also induce the production of thrombospondin-1, which is a potent anti-angiogenic
factor. It has been shown that low-dose chemotherapy can selectively remove regulatory T lymphocytes that can lead to enhancement
of immune function.
As is the case with MTD chemotherapy, it is felt that a combination of drugs would be more likely to be effective compared
with a single agent. Metronomic chemotherapy is frequently combined with drugs that have different angiogenic targets. For
example, in human patients, metronomic chemotherapy is combined with drugs such as bevacizumab, which is an antibody against
VEGF. Multiple agents have been shown to have anti-angiogenic activity in vitro so they are logical agents to combine with
metronomic chemotherapy. These agents would include cyclooxygenase-2 (COX-2) inhibitors, doxycycline and thalidomide.