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Antiangiogenic
scheduling of chemotherapy improves efficacy against experimental drug-resistant
cancer
Browder T, Butterfield CE, Kraling BM, Shi B, Marshall B, O'Reilly MS,
Folkman J
Children's Hospital, Department of Pediatric Oncology,
Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
To reveal the antiangiogenic capability of cancer chemotherapy, we
developed an alternative antiangiogenic schedule for administration of
cyclophosphamide.
We show here that this antiangiogenic schedule avoided drug resistance and
eradicated Lewis lung carcinoma and L1210 leukemia, an outcome not possible with
the conventional schedule.
When Lewis lung carcinoma and EMT-6 breast cancer were made drug resistant
before therapy, the antiangiogenic schedule suppressed tumor growth 3-fold more
effectively than the conventional schedule.
When another angiogenesis inhibitor, TNP-470, was added to the antiangiogenic
schedule of cyclophosphamide, drug-resistant Lewis lung carcinomas were
eradicated.
Each dose of the antiangiogenic schedule of cyclophosphamide induced the
apoptosis of endothelial cells within tumors, and endothelial cell apoptosis
preceded the apoptosis of drug-resistant tumor cells.
This antiangiogenic effect was more pronounced in p53-null mice in which the
apoptosis of p53-null endothelial cells induced by cyclophosphamide was so
vigorous that drug-resistant tumors comprising 4.5% of body weight were
eradicated.
Thus, by using a dosing schedule of cyclophosphamide that provided more
sustained apoptosis of endothelial cells within the vascular bed of a tumor, we
show that a chemotherapeutic agent can more effectively control tumor growth in
mice, regardless of whether the tumor cells are drug resistant.
PMID: 10766175 [PubMed - indexed for MEDLINE]
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