Metronomic activity of CD44-targeted hyaluronic acid-paclitaxel in ovarian carcinoma - PubMed (original) (raw)

. 2012 Aug 1;18(15):4114-21.

doi: 10.1158/1078-0432.CCR-11-3250. Epub 2012 Jun 12.

Sukhen C Ghosh, Hee Dong Han, Rebecca L Stone, Justin Bottsford-Miller, De Yue Shen, Edmond J Auzenne, Alejandro Lopez-Araujo, Chunhua Lu, Masato Nishimura, Chad V Pecot, Behrouz Zand, Duangmani Thanapprapasr, Nicholas B Jennings, Yu Kang, Jie Huang, Wei Hu, Jim Klostergaard, Anil K Sood

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

Sun Joo Lee et al. Clin Cancer Res. 2012.

Abstract

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.) 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.

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Figures

Figure 1

Figure 1

Effects of metronomic (MET) dosing and maximal tolerated dosing (MTD) of HA-TXL on tumor growth in SKOV3ip1 (A), HeyA8 (B) and HeyA8-MDR (C) models of ovarian cancer. Mice were randomly allocated to five groups and underwent treatment with intraperitoneal injection as follows for the SKOV3ip1 model: 1) Control PBS, 2) MET HA-TXL, 10 mg/kg, 3) MET HA-TXL, 20 mg/kg, 4) MET HA-TXL, 30 mg/kg, 5) MTD HA-TXL 180 mg/kg, all HA-TXL doses being given as TXL equivalents. For the HeyA8 and HeyA8-MDR studies, the MET groups were lowered to 5, 10 and 20 mg/kg. For comparison of HA-TXL to TXL, the HeyA8-MDR model was used (D) according to the following groups: 1) Control, 2) HA-TXL MTD (180 mg/kg), 3) HA-TXL MET (20 mg/kg), 4) TXL MTD (10mg/kg), 5) TXL MET (0.5 mg/kg), 6) Free HA, 7) HA-TXL MET + free HA. Effects of TXL-MET or HA-TXL MET were assessed on animal survival in the HeyA8-MDR model (E). Values are means + SEM. *p<0.01; **p<0.001.

Figure 2

Figure 2

Effects of MET and MTD HA-TXL treatment in the SKOV3ip1 model on biological endpoints, including (A) cell proliferation (Ki67); (B) MVD (CD31); (C) apoptosis (TUNEL) and (D) TSP-1. Tumors harvested following 3–4 weeks of therapy were stained for Ki67, CD31, TSP-1 and TUNEL. All pictures were taken at original magnification × 200. The error bars represent SEM. *p<0.05; **p<0.001

Figure 3

Figure 3

Effects of HA-TXL therapy on systemic cytokine production. Plasma was collected from HeyA8 model at day 7 post-tumor implantation (basal), day 14 (7 days after startingtreatment) and at the time of euthanasia. Multiplex ELISA was carried out based on the manufacturer’s instruction for detecting human and mouse IL-6 (A), G-CSF (B), and VEGF (C) in plasma obtained from the control and treated groups. There was a progressive increase in these cytokines in the untreated controls; however, the cytokine levels remained lower throughout in the MET dosing groups compared to the MTD treatment group. *p<0.05. Error bars represent SEM.

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