Improving conventional or low dose metronomic chemotherapy with targeted antiangiogenic drugs.

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Cancer Res Treat. 2007 Dec;39(4):150-9. Epub 2007 Dec 31.
Improving conventional or low dose metronomic chemotherapy with targeted antiangiogenic drugs.
Kerbel RS.
Sunnybrook Research Institute, Sunnybrook Health Sciences Centre and the University of Toronto, Toronto, Canada.

One
of the most significant developments in medical oncology practice has
been the approval of various antiangiogenic drugs for the treatment of
a number of different malignancies. These drugs include bevacizumab
(Avastin(R)), the anti-VEGF monoclonal antibody. Thus far, bevacizumab
appears to induce clinical benefit in patients who have advanced
metastatic disease only or primarily when it is combined with
conventional chemotherapy. The reasons for the chemo-enhancing effects
of bevacizumab are unknown, and this is a subject that we have been
actively studying along with additional ways that antiangiogenic drugs
may be combined with chemotherapy. In this respect, we have focused
much of our effort on metronomic low dose chemotherapy. We have been
studying the hypothesis that some chemotherapy drugs at maximum
tolerated doses or other cytotoxic- like drugs such as acute "vascular
disrupting agents" (VDAs) can cause an acute mobilization of
proangiogenic cells from the bone marrow which home to and colonize the
treated tumors, thus accelerating their recovery. These cells include
endothelial progenitor cells. This systemic process can be largely
blocked by a targeted antiangiogenic drug, e.g. anti-VEGFR-2
antibodies. In addition, metronomic chemotherapy, i.e., close regular
administration of chemotherapy drugs at low non-toxic doses with no
breaks, over prolonged periods of time not only prevents the acute CEP
bone marrow response, but can even target the cells. This potential
antiangiogenic effect of metronomic chemotherapy can also be boosted by
combination with a targeted antiangiogenic agent. Treatment
combinations of metronomic chemotherapy and an antiangiogenic drug have
moved into phase II clinical trial testing with particularly
encouraging results thus far reported in metastatic breast and
recurrent ovarian cancer. Oral chemotherapy drugs such as
cyclophosphamide (CTX), methotrexate are the main chemotherapeutics
used for such trials. Oral 5-FU prodrugs such as UFT would also appear
to be highly suitable based on long term adjuvant therapy studies in
patients. Recent preclinical results using metronomic cyclophosphamide
and metronomic UFT in models of advanced metastatic breast cancer
suggest that this type of combination might be particularly promising
for metronomic chemotherapy in this indication, particularly when
combined with a targeted antiangiogenic drug.