Metronomic oral paclitaxel shows anti-tumor effects in an orthotopic mouse model of ovarian cancer

다국어 초록 (Multilingual Abstract)

Objective: The purpose of this study was to compare the in vivo anti-tumor efficacy of a mucoadhesive, lipid-based, oral paclitaxel formulation (DHP107) with traditional, intraperitoneal (IP) paclitaxel using an orthotopic mouse model of chemotherapy-sensitive SKOV3ip1 ovarian cancer.
Methods: To determine the optimal therapeutic dose of oral paclitaxel, DHP107 was administered per os to female athymic nude mice at 0, 25, or 50 mg/kg twice per week. Control mice received 100 μL saline once per week. IP injections of paclitaxel at 5 mg/kg once per week were used for comparison. To evaluate the potential therapeutic effect of metronomic DHP107 chemotherapy, mice received DHP107 50 mg/kg once per week per os, which was compared with 25 mg/kg twice per week and with vehicle-treated controls.
Results: Low-dose DHP107 (25 mg/kg) twice per week was as effective as IP paclitaxel (5 mg/kg once a week) but high-dose DHP107 (50 mg/kg once per week) was less effective at inhibiting tumor growth in an orthotopic mouse model (88%, 82%, and 36% decrease in tumor weight, respectively). Mice that received 25 mg/kg DHP107 twice per week or 50 mg/kg DHP107 once per week per os had a significant decrease in tumor weight compared with vehicle-treated controls (p<0.01, both doses).
Conclusion: Metronomic oral chemotherapy with DHP107 showed anti-tumor efficacy in vivo similar to IP paclitaxel in an orthotopic mouse model.

참고문헌 (Reference)

1 Landen CN, "Tumor-selective response to antibody-mediated targeting of alphavbeta3 integrin in ovarian cancer" 10 : 1259-1267, 2008

2 김민규, "The relationship between cisplatin resistance and histone deacetylase isoform overexpression in epithelial ovarian cancer cell lines" 대한부인종양학회 23 (23): 182-189, 2012

3 Kerbel RS, "The anti-angiogenic basis of metronomic chemotherapy" 4 : 423-436, 2004

4 Liggins RT, "Solid-state characterization of paclitaxel" 86 : 1458-1463, 1997

5 Birner A, "Safe administration of oral chemotherapy" 7 : 158-162, 2003

6 Seidman AD, "Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors:final results of Cancer and Leukemia Group B protocol 9840" 26 : 1642-1649, 2008

7 Di Leo A, "Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer" 26 : 5544-5552, 2008

8 Sandler A, "Paclitaxel-carboplatin alone or with bevacizumab for nonsmall-cell lung cancer" 355 : 2542-2550, 2006

9 Britten CD, "Oral paclitaxel and concurrent cyclosporin A: targeting clinically relevant systemic exposure to paclitaxel" 6 : 3459-3468, 2000

10 Veltkamp SA, "Novel paclitaxel formulations for oral application: a phase I pharmacokinetic study in patients with solid tumours" 60 : 635-642, 2007

11 Vergote I, "Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer" 363 : 943-953, 2010

12 Kamat AA, "Metronomic chemotherapy enhances the efficacy of antivascular therapy in ovarian cancer" 67 : 281-288, 2007

13 Myung Joo Kim, "Intraoperative intraperitoneal chemotherapy with cisplatin in epithelial ovarian cancer" 대한부인종양학회 23 (23): 91-97, 2012

14 Robert S. Kerbel, "Improving Conventional or Low Dose Metronomic Chemotherapy with Targeted Antiangiogenic Drugs" 대한암학회 39 (39): 150-159, 2007

15 Weiss RB, "Hypersensitivity reactions from taxol" 8 : 1263-1268, 1990

16 Shin BS, "Enhanced absorption and tissue distribution of paclitaxel following oral administration of DHP 107, a novel mucoadhesive lipid dosage form" 64 : 87-94, 2009

17 Hong JW, "Efficacy and tissue distribution of DHP107, an oral paclitaxel formulation" 6 (6): 3239-3247, 2007

18 Gao P, "Development of a supersaturable SEDDS (S-SEDDS)formulation of paclitaxel with improved oral bioavailability" 92 : 2386-2398, 2003

19 Gelderblom H, "Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation" 37 : 1590-1598, 2001

20 Liebmann J, "Cremophor EL, solvent for paclitaxel, and toxicity" 342 : 1428-, 1993

21 Meerum Terwogt JM, "Coadministration of oral cyclosporin A enables oral therapy with paclitaxel" 5 : 3379-3384, 1999

22 Malingre MM, "Co-administration of GF120918 significantly increases the systemic exposure to oral paclitaxel in cancer patients" 84 : 42-47, 2001

23 Paine MF, "Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism" 283 : 1552-1562, 1997

24 Yap TA, "Beyond chemotherapy: targeted therapies in ovarian cancer" 9 : 167-181, 2009

25 Browder T, "Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer" 60 : 1878-1886, 2000

26 Kang HJ, "A phase II study of paclitaxel and capecitabine as a first-line combination chemotherapy for advanced gastric cancer" 98 : 316-322, 2008