Metronomic activity of CD44-targeted hyaluronic acid-paclitaxel in ovarian carcinoma.
OBJECTIVE
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.


METHODS
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.) with MET HA-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-MDR model, 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.
Department of Gynecologic Oncology and Reproductive Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Sun Joo
SJ
Lee
Sukhen C
SC
Ghosh
Hee Dong
HD
Han
Rebecca L
RL
Stone
Justin
J
Bottsford-Miller
De Yue
DY
Shen
Edmond J
EJ
Auzenne
Alejandro
A
Lopez-Araujo
Chunhua
C
Lu
Masato
M
Nishimura
Chad V
CV
Pecot
Behrouz
B
Zand
Duangmani
D
Thanapprapasr
Nicholas B
NB
Jennings
Yu
Y
Kang
Jie
J
Huang
Wei
W
Hu
Jim
J
Klostergaard
Anil K
AK
Sood
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D019700:Thrombospondin 1 / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D016207:Cytokines; D018960:Hyaluronan Receptors; D019394:Ki-67 Antigen; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019700:Thrombospondin 1; D006820:Hyaluronic Acid; D017239:Paclitaxel