Diagnostic marker may indicate cancer drug efficacy
could prove useful in gauging the effectiveness of anti-angiogenic
drugs marking the first time that biomarkers have been defined for
this drug class.
Anti-angiogenic drugs inhibit blood vessel development at the tumour by killing the endothelial cells lining tumour blood vessels and/or cutting off the supply of endothelial cells from bone marrow.
These drugs are typically paired with chemotherapy agents. Unlike anti-angiogenic drugs, chemotherapy agents directly assault tumour cells, and a reliable therapeutic biomarker for evaluating these agents is whether there are fewer cells in the tumour, or more, or just the same amount as before the treatment.
Some chemotherapy drugs also have the benefit of being toxic to endothelial cells, providing a possible second biomarker for those agents.
Now researchers at the National Cancer Institute (NCI) have suggested that the anti-angiogenic drugs enhance chemotherapy's ability to kill endothelial cells, as indicated by increases in dead endothelial cells circulating in the patient's blood stream.
The NCI scientists also discovered that anti-angiogenic drugs might combat cancer by preventing immature cells in the bone marrow from developing into endothelial cells.
This research was conducted with four groups of immunodeficient mice in which human prostate cancer cells had been implanted.
Each group received a different treatment: a control agent (no drug); a chemotherapy agent (docetaxel) only; an anti-angiogenic drug (thalidomide) alone; and both chemotherapy and the anti-angiogenic drugs.
Circulating endothelial cell (CEC) levels were measured before all four groups were treated and at specific times during the study.
In the group receiving only chemotherapy, blood levels of dead CECs increased, up to 2.6 fold.
In the animals treated with the two drugs, CEC death was higher - up to 4.3 fold - suggesting that the anti-angiogenic agent may have enhanced chemotherapy's ability to kill the tumour vascular endothelial cells.
Tests conducted later in the study revealed that treatment with the anti-angiogenic drug alone reduced the level of viable CECs by 18 per cent, while treatment with only chemotherapy decreased it by 61 per cent.
The combination of both drugs further diminished the blood levels of viable CECs by 75 per cent, indicating that the anti-angiogenic drug may have inhibited the immature endothelial cells in the bone marrow from reproducing and differentiating into adult cells.
"Many anti-angiogenic drugs may encounter problems during clinical studies, because they can't reduce tumour size rapidly like chemotherapies can," said NCI scientist Haiqing Li, first author of the study.
"Thus, a biomarker is needed for the effectiveness of anti-angiogenic drugs in an early stage," he added.
Li added that in addition to growing them directly from nearby blood vessels, tumours could also signal the body's bone marrow to boost the supply of endothelial cells in the blood circulation.
Results were presented at the first international meeting on Molecular Diagnostics in Cancer Therapeutic Development, organised by the American Association for Cancer Research.
