They may help block tumor regrowth following chemotherapy
SCIENTISTS HAVE GAINED new insight into a mechanism in which chemotherapy may actually assist rapid tumor regrowth after treatment. The research also helps to explain why a combination of traditional chemotherapy with drugs that block formation of new blood vessels might impede tumor recovery that can often follow cancer therapy.
"Chemotherapy remains the most commonly employed form of systemic cancer treatment. However, although partial or complete shrinkage of tumor mass is frequently induced in chemotherapy-responsive tumors, survival benefits of such responses can be compromised by rapid regrowth of the drug-treated tumors," senior study author Robert S. Kerbel, PhD, said in a statement. Dr. Kerbel is in the department of medical biophysics at the University of Toronto; the study was published in the journal Cancer Cell.
Clinical trials have indicated that antiangiogenic drugs can sometimes enhance the effectiveness of traditional chemotherapy. One example of this is coadministration of the antiangiogenic drug bevacizumab with the chemotherapeutic agent paclitaxel, a combination that has been found to improve survival benefits for metastatic breast cancer and small cell lung cancer. In contrast, coadministration of bevacizumab with gemcitabine for treatment of pancreatic cancer does not increase the effectiveness of chemotherapy alone.
"Several hypotheses have been proposed to explain how antiangiogenic drugs enhance the treatment efficacy of cytotoxic chemotherapy, including impairing the ability of chemotherapy-responsive tumors to regrow after therapy," said co-author Yuval Shaked, PhD, also of the University of Toronto. Their research group had previously shown that treatment with a type of cytotoxic-like agent known as a vascular disrupting agent (VDA) induces rapid mobilization of cells called circulating endothelial progenitors (CEPs) from the bone marrow compartment that helps the tumor to regrow blood vessels and thereby recover from treatment.
Our results provide a new perspective regarding the impact that conventional chemotherapy can have on tumor angiogenesis and hence how combination with antiangiogenic drugs may amplify the antitumor effects of chemotherapy.
-Yuval Shaked, PhD, University of Toronto
The researchers built on this earlier observation by analyzing whether different, conventional chemotherapeutic drugs had variable abilities to interfere with CEP mobilization and whether antiangiogenic drugs could block chemotherapy-induced CEP responses and hence amplify their effectiveness. They found that paclitaxel rapidly induced CEP mobilization whereas gemcitabine did not. They went on to show that pharmacological inhibition of CEP mobilization by combination treatment with an antiangiogenic drug or treatment of mutant mice deficient in CEPs resulted in enhanced antitumor effects mediated by paclitaxel but not gemcitabine.
"Our results provide a new perspective regarding the impact that conventional chemotherapy can have on tumor angiogenesis and hence how combination with antiangiogenic drugs may amplify the antitumor effects of chemotherapy," Dr. Kerbel said. "Further, our findings provide a potential explanation of why not all chemotherapy drugs will necessarily have their efficacy enhanced by the addition of an antiangiogenic agent when the mechanism involves blunting CEP mobilization acutely induced by the chemotherapy drug."
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