Influence of formulation vehicle on metronomic taxane chemotherapy: albumin-bound versus cremophor EL-based paclitaxel.
OBJECTIVE
Low-dose metronomic chemotherapy treatments, especially when combined with 'dedicated' antiangiogenic agents, can induce significant antitumor activity without serious toxicity in various preclinical models. It remains unclear, however, whether some cytotoxic drugs are better suited for metronomic regimens than others. Paclitaxel appears to be a strong candidate for metronomic chemotherapy given its ability to inhibit endothelial cell functions relevant to angiogenesis in vitro at extraordinarily low concentrations and broad-spectrum antitumor activity. Clinically relevant concentrations of the formulation vehicle cremophor EL in Taxol, however, were previously reported to nullify the antiangiogenic effect of paclitaxel, the result of which would hamper its usefulness in metronomic regimens. We hypothesized that ABI-007, a cremophor EL-free, albumin-bound, 130-nm form of paclitaxel, could potentially alleviate this problem.


METHODS
The antiangiogenic activity of ABI-007 was assessed by multiple in vitro assays. The in vivo optimal dose of ABI-007 for metronomic chemotherapy was determined by measuring circulating endothelial progenitors in peripheral blood. The antitumor effects of metronomic and maximum tolerated dose ABI-007 and Taxol were then evaluated and compared in severe combined immunodeficient mice bearing human MDA-MD-231 breast cancer and PC3 prostate cancer xenografts.


RESULTS
ABI-007 significantly inhibited rat aortic microvessel outgrowth, human endothelial cell proliferation, and tube formation. The optimal metronomic dose of ABI-007 was determined to be between 3 and 10 mg/kg. Metronomic ABI-007 but not Taxol, significantly suppressed tumor growth in both xenograft models. Furthermore, the antitumor effect of minimally toxic metronomic ABI-007 approximated that of the maximum tolerated dose of Taxol.


CONCLUSIONS
Our results underscore the influence of formulation vehicles on the selection of cytotoxic drugs for metronomic chemotherapy.
Ng
Sylvia S W
SS
Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
Sparreboom
Alex
A
Shaked
Yuval
Y
Lee
Christina
C
Man
Shan
S
Desai
Neil
N
Soon-Shiong
Patrick
P
Figg
William D
WD
Kerbel
Robert S
RS
D000418:Albumins / Q000378:metabolism*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001011:Aorta / Q000378:metabolism; D001952:Bridged-Ring Compounds / Q000008:administration & dosage*; D049109:Cell Proliferation; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D051381:Rats; D013501:Surface-Active Agents / Q000008:administration & dosage*; D043823:Taxoids / Q000008:administration & dosage*
D000418:Albumins; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D013501:Surface-Active Agents; D043823:Taxoids; C080625:taxane; C022131:cremophor; D011092:Polyethylene Glycols; D017239:Paclitaxel