TY - JOUR
T1 - Metronomic activity of CD44-targeted hyaluronic acid-paclitaxel in ovarian carcinoma
AU - Lee, Sun Joo
AU - Ghosh, Sukhen C.
AU - Han, Hee Dong
AU - Stone, Rebecca L.
AU - Bottsford-Miller, Justin
AU - Shen, De Yue
AU - Auzenne, Edmond J.
AU - Lopez-Araujo, Alejandro
AU - Lu, Chunhua
AU - Nishimura, Masato
AU - Pecot, Chad V.
AU - Zand, Behrouz
AU - Thanapprapasr, Duangmani
AU - Jennings, Nicholas B.
AU - Kang, Yu
AU - Huang, Jie
AU - Hu, Wei
AU - Klostergaard, Jim
AU - Sood, Anil K.
PY - 2012/8/1
Y1 - 2012/8/1
N2 - Purpose: Most primary human ovarian tumors and peritoneal implants, as well as tumor vascular endothelial cells, express the CD44 family of cell surface proteoglycans, the natural ligand for which is hyaluronic acid. Metronomic dosing, the frequent administration of chemotherapeutics at substantially lower than maximum tolerated doses (MTD), has been shown to result in reduced normal tissue toxicity and to minimize "off-treatment" exposure resulting in an improved therapeutic ratio. Experimental Design: We tested the hypothesis that hyaluronic acid (HA) conjugates of paclitaxel (TXL; HA-TXL) would exert strong antitumor effects with metronomic (MET) dosing and induce antiangiogenic effects superior to those achieved with MTD administration or with free TXL. Female nude mice bearing SKOV3ip1 or HeyA8 ovarian cancer cells were treated intraperitoneally (i.p.) withMETHA-TXL regimens (or MTD administration) to determine therapeutic and biologic effects. Results: All MET HA-TXL-treated mice and the MTD group revealed significantly reduced tumor weights and nodules compared with controls (all P values < 0.05) in the chemotherapy-sensitive models. However, the MTD HA-TXL-treated mice showed significant weight loss compared with control mice, whereas body weights were not affected in the metronomic groups in HeyA8-MDR model, reflecting reduced toxicity. In the taxane-resistant HeyA8-MDRmodel, significant reduction in tumor weight and nodule counts was noted in the metronomic groups whereas the response of the MTD group did not achieve significance. While both MTD and metronomic regimens reduced proliferation (Ki-67) and increased apoptosis (TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling), only metronomic treatment resulted in significant reductions in angiogenesis (CD31, microvessel density). Moreover, metronomic treatment resulted in substantial increases in thrombospondin-1 (Tsp-1), an inhibitor of angiogenesis. Conclusions: This study showed that MET HA-TXL regimens have substantial antitumor activity in ovarian carcinoma, likely via a predominant antiangiogenic mechanism.
AB - Purpose: Most primary human ovarian tumors and peritoneal implants, as well as tumor vascular endothelial cells, express the CD44 family of cell surface proteoglycans, the natural ligand for which is hyaluronic acid. Metronomic dosing, the frequent administration of chemotherapeutics at substantially lower than maximum tolerated doses (MTD), has been shown to result in reduced normal tissue toxicity and to minimize "off-treatment" exposure resulting in an improved therapeutic ratio. Experimental Design: We tested the hypothesis that hyaluronic acid (HA) conjugates of paclitaxel (TXL; HA-TXL) would exert strong antitumor effects with metronomic (MET) dosing and induce antiangiogenic effects superior to those achieved with MTD administration or with free TXL. Female nude mice bearing SKOV3ip1 or HeyA8 ovarian cancer cells were treated intraperitoneally (i.p.) withMETHA-TXL regimens (or MTD administration) to determine therapeutic and biologic effects. Results: All MET HA-TXL-treated mice and the MTD group revealed significantly reduced tumor weights and nodules compared with controls (all P values < 0.05) in the chemotherapy-sensitive models. However, the MTD HA-TXL-treated mice showed significant weight loss compared with control mice, whereas body weights were not affected in the metronomic groups in HeyA8-MDR model, reflecting reduced toxicity. In the taxane-resistant HeyA8-MDRmodel, significant reduction in tumor weight and nodule counts was noted in the metronomic groups whereas the response of the MTD group did not achieve significance. While both MTD and metronomic regimens reduced proliferation (Ki-67) and increased apoptosis (TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling), only metronomic treatment resulted in significant reductions in angiogenesis (CD31, microvessel density). Moreover, metronomic treatment resulted in substantial increases in thrombospondin-1 (Tsp-1), an inhibitor of angiogenesis. Conclusions: This study showed that MET HA-TXL regimens have substantial antitumor activity in ovarian carcinoma, likely via a predominant antiangiogenic mechanism.
UR - http://www.scopus.com/inward/record.url?scp=84864454025&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84864454025&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-11-3250
DO - 10.1158/1078-0432.CCR-11-3250
M3 - Article
C2 - 22693353
AN - SCOPUS:84864454025
SN - 1078-0432
VL - 18
SP - 4114
EP - 4121
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 15
ER -