Metronomic dosing — long-term, low-dose, frequent administration of chemotherapeutic drugs — reduces the toxic side effects of traditional chemotherapy. Rather than directly killing cancer cells, it prevents blood-vessel formation by blocking endothelial-cell growth. Why the endothelial cells of new blood vessels are specifically targeted by this dosing strategy is a mystery that Guido Bocci, Robert Kerbel and colleagues are on the way to solving — the angiogenesis inhibitor thrombospondin-1 (TSP1) thinks less is best.
Bocci et al. began by analysing gene-expression profiles of microvascular endothelial cells and found that long-term exposure to the antitumour agent BAL-9504 increased TSP1 expression. Further in vitro investigations confirmed this observation, showing that TSP1 expression increased in the drug-treated cells, which also secreted the protein into the culture medium. The effects of the metronomic chemotherapy — blocked proliferation and reduced cell survival — were partially reversed by TSP1-neutralizing antibodies, indicating that TSP1 regulates the metronomic dosing response in vitro. But does it have a similar effect in vivo?
They administered a previously well-characterized, low-dose, daily cyclophosphamide treatment to wild-type and Tsp1-null mice and assessed in vivo angiogenesis. After 7 days, the cyclophosphamide treatment had significantly reduced neovascularization in the wild-type mice, but not in the Tsp1-null mice, indicating that Tsp1 is required to mediate the anti-angiogenic effects of the metronomic dosing regimen in vivo. To establish whether lack of Tsp1 also affected tumour growth, fast-growing tumour cells were injected into wild-type and Tsp1-null mice. The mice were initially treated with the maximum-tolerated dose of cyclophosphamide, which slowed growth of the tumours in both mice strains. This was followed by low-dose cyclophosphamide treatment, which reduced tumour growth in only wild-type mice. So, although lack of Tsp1 does not affect the response to the maximum-tolerated dose of cyclophosphamide, it does prevent the effects of metronomic chemotherapy.
As soluble, circulating TSP1 was observed after in vitro metronomic dosing, it might be a useful surrogate marker for monitoring the clinical outcome of metronomic chemotherapy treatments. Human-tumour-bearing immunodeficient mice were treated with various metronomic regimens and after 20 days antitumour effects were seen in all treated animals. This antitumour response correlated with a 2–6-fold increase in Tsp1/tumour volume ratio, indicating that increased Tsp1 coincides with a decrease in tumour size.
This work provides an initial insight into the mechanisms that regulate the antitumour and anti-angiogenesis effects of metronomic therapies. TSP1 might also be a useful clinical tool for monitoring how patients are responding to this treatment strategy.
ORIGINAL RESEARCH PAPER
Bocci, G. et al. Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc. Natl Acad. Sci. USA 100, 12917–12922 (2003)
Related links
Rights and permissions
About this article
Cite this article
Croager, E. Less is best?. Nat Rev Cancer 3, 892 (2003). https://doi.org/10.1038/nrc1241
Issue Date:
DOI: https://doi.org/10.1038/nrc1241