Dominant effect of antiangiogenesis in combination therapy involving cyclophosphamide and axitinib.

Abstract

PURPOSE:

Antiangiogenic drug treatment inhibits tumor growth by decreasing blood supply, which can also reduce the delivery of other therapeutic agents. Presently, we investigated the effect of the vascular endothelial growth factor receptor tyrosine kinase inhibitor axitinib (AG-013736) on tumor vascular patency and chemotherapeutic drug uptake. Furthermore, the effect of axitinib on the antitumor activity of combination treatments with cyclophosphamide was examined.

EXPERIMENTAL DESIGN:

Prostate cancer PC-3 xenografts were used to evaluate the effect of axitinib treatment on tumor vascular morphology, fluorescent dye perfusion, hypoxia, and uptake of 4-hydroxycyclophosphamide, the active metabolite of the chemotherapeutic prodrug cyclophosphamide. Sequential or simultaneous schedules for axitinib and cyclophosphamide administration were evaluated in both PC-3 tumors and 9L gliosarcoma xenograft models.

RESULTS:

Axitinib monotherapy induced sustained growth stasis in PC-3 tumors in association with extensive apoptotic cell death. A substantial decrease in tumor vascular patency was observed, exemplified by a near complete loss of Hoechst 33342 perfusion and the absence of pimonidazole staining in the increasingly hypoxic tumors. Antitumor activity was significantly enhanced in both PC-3 and 9L tumors treated using an optimized schedule of sequential, intermittent axitinib-cyclophosphamide combination therapy despite a 40% to 70% decrease in tumor tissue uptake of 4-hydroxycyclophosphamide.

CONCLUSIONS:

In axitinib-cyclophosphamide combination therapy, enhanced anticancer activity can be achieved when the reduced tumor cell exposure to the cancer chemotherapeutic agent is compensated by antiangiogenesis-induced tumor cell starvation. This intrinsic antitumor effect was particularly evident in PC-3 tumor xenografts, where tumor blood flow deprivation dominates the overall therapeutic response.

• Authors: Jie Ma, David J Waxman
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 2 Pg. 578-88 (Jan 15 2009) ISSN: 1078-0432 [Print] United States
• PMID: 19147763 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Angiogenesis Inhibitors
• Benzimidazoles
• Imidazoles
• Indazoles
• 4-hydroxycyclophosphamide
• Cyclophosphamide
• Axitinib
• bisbenzimide ethoxide trihydrochloride

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Axitinib
• Benzimidazoles (pharmacology)
• Cell Line, Tumor
• Cyclophosphamide (administration & dosage, analogs & derivatives, metabolism, pharmacology)
• Genes, Dominant
• Humans
• Imidazoles (administration & dosage)
• Indazoles (administration & dosage)
• Male
• Mice
• Mice, Inbred ICR
• Mice, SCID
• Neoplasm Transplantation
• Prostatic Neoplasms (drug therapy)