Abstract
We have recently reported that red ginseng acidic polysaccharide (RGAP), isolated from Korean red ginseng (Panax ginseng C. A. Meyer), shows immunomodulatory and antitumor activities, mainly mediated by the nitric oxide (NO) production of macrophages. This compound may be used in cancer therapy alone or in combination with other chemotherapeutic agents. The synergistic effect of RGAP and paclitaxel (taxol) was evaluated to develop new biological response modifiers in cancer therapy. The present study demonstrates a synergistic antitumor effect of RGAP and paclitaxel in mice transplanted with sarcoma 180 and B16 melanoma. Combined treatment with paclitaxel (5 or 15 mg/kg) and RGAP (25 mg/kg) resulted in a 28.6 or 42.8 % increase in the life span of ICR mice bearing sarcoma 180 tumor cells, while no obvious effect was seen on sole paclitaxel treatment. When a combination of paclitaxel (10 mg/kg) and RGAP (100 mg/kg) was administered to C57BL/6 mice implanted with B16 melanoma, the tumor weight per mouse also decreased by 76.3 %, suggesting that RGAP may be used as an adjuvant in medicinal applications of paclitaxel. The augmented antitumor effect of paclitaxel is supposed to be the result of the immunomodulating antitumor effect of RGAP. RGAP, having B cell specific mitogenic activity, induced the secretion of interleukin-6 (IL-6) in spleen cells in a concentration-dependent manner (5 to 500 μg/μL). RGAP also restored the proliferation of splenocytes and NK cell activity suppressed by paclitaxel. Flow cytometric analysis of splenocytes in mice treated with paclitaxel showed a significant increase of CD11b+ cells. Additionally, a synergistic effect of RGAP and paclitaxel was found to effect an increased tumoricidal activity of macrophages. The above results suggest that clinical trials of RGAP as an adjuvant in cancer chemotherapy of paclitaxel are highly feasible.
Key words
Panax ginseng
- Araliaceae - red ginseng acidic polysaccharide (RGAP) - paclitaxel - antitumor effect - macrophages - synergism
References
-
1
Wani M C, Taylor H L, Wall M E, Coggon P, Mcphail A T.
Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia
.
J Am Chem Soc.
1971;
93
2325-7
-
2
Schiff P B, Faut J, Horwitz S B.
Promotion of microtubule assembly in vitro by taxol.
Nature.
1979;
277
665-7
-
3
Donaldson K L, Goolsby G L, Wahl A F.
Cytotoxicity of the anticancer agents cisplatin and taxol during cell proliferation and the cell cycle.
Int J Cancer.
1994;
57
847-55
-
4
Brahn E, Tang C, Banquerigo M L.
Regression of collagen-induced arthritis with taxol, a microtubule stabilizer.
Arthritis Rheum.
1994;
37
839-45
-
5
Ding A H, Porteu F, Sanchez E, Nathan C F.
Down-regulation of tumor necrosis factor receptors on macrophages and endothelial cells by microtubule depolymerizing agents.
J Exp Med.
1990;
171
715-27
-
6
Rowinsky E K, Donehower R C.
The clinical, pharmacology and use of antimicrotubule agents in cancer chemotherapeutics.
Pharmacol Ther.
1991;
52
35-84
-
7
Martello L A, Mcdaid H M, Regl D L, Yang C PH, Meng D.
Taxol and discodermolide represent a synergistic drug combination in human carcinoma cell lines.
Clin Cancer Res.
2000;
6
1978-87
-
8
Park K M, Jeong T C, Kim Y S, Shin H J, Nam K Y, Park J D.
Immunomodulatory effect of acidic polysaccharide fraction from Korean red ginseng (Panax ginseng).
Nat Prod Sci.
2000;
6
31-35
-
9
Park K M, Kim Y S, Jeong T C, Joe C O, Shin H J, Park J D.
Nitric oxide is involved in the immunomodulating activities of acidic polysaccharide from Panax ginseng
.
Planta Medica.
2001;
67
122-6
-
10
Kim Y S, Park K M, Shin H J, Song K S, Nam K Y, Park J D.
Anticancer activities of red ginseng acidic polysaccharide by activation of macrophages and natural killer cells.
Yakhak Hoeji.
2002;
46
113-9
-
11 Hudson L, Hay F C. Practical Immunology. 3rd edition London; Blackwell Scientific Publications 1989: pp 172-74
-
12 Conrad R E. Induction and collection of peritoneal exudate macrophages. In: Manual of Macrophage Methodology. New York; Marcel Dekker 1981: pp 5-11
-
13
Chuang L T, Lotzova E, Heath J, Cook K R, Munkarah A.
Alteration of lymphocyte microtubule assembly, cytotoxicity, and activation by the anticancer drug taxol.
Cancer Res.
1994;
54
1286-91
-
14
Goldspiel B R.
Clinical overview of the taxanes.
Pharmacotherapy.
1997;
17
110S-125
-
15
Chan O TM, Yang L X.
The immunological effects of taxanes.
Cancer Immunol Immunother.
2000;
49
181-5
-
16
Kirikae T, Ojima I, Kirikae F, Ma Z, Kuduk S D.
Structural requirements of taxoids for nitric oxide and tumor necrosis factor production by murine macrophages.
Biochem Biophys Res Commun.
1996;
227
227-35
-
17
Bogdan C, Ding A.
Taxol, a microtubule-stabilizing antineoplastic agent, induces expression of tumor necrosis factor alpha and interleukin-1 in macrophages.
J Leukocyte Biol.
1992;
52
119-21
-
18
Ting J P, White C M, Martin B K, Haskill J S.
Taxol-dependent transcriptional activation of IL-8 expression in a subset of human ovarian cancer.
Cancer Res.
1996;
56
1303-8
-
19
Mullins D W, Burger C J, Elgert K D.
Paclitaxel enhances macrophage IL-12 production in tumor-bearing hosts through nitric oxide.
J Immunol.
1999;
162
6811-8
-
20
Manthey C L, Perera P Y, Salkowski C A, Vogel S N.
Taxol provides a second signal for murine macrophage tumoricidal activity.
J Immunol.
1994;
152
825-31
Dr. Jong-Dae Park
KT&G Central Research Institute
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