Carboxymethylpachymaran CMP Pachyman 1 1 3 70 National Cancer Center Research Institute( Tsukijin Tokyo 4 1979 CMP CMP CMP CMP 1
1. CMP S180 H22 50 mg/kg, 100mg/kg, 200mg/kg 5mg/kg, 10mg/kg, 100mg/kg H 22 55.5%, 42.7% 62.4% S 180 35.5%, 69.7% 71.8% H 22 23.3%, 41.3% 43.3% S 180 41.2%, 52.2% 50.5% 2. CMP(0.5µg/ml-250µg/ml) S180 H22 24 3. CMP 4. CMP ConA LPS 1. CMP 5 10 50mg/kg iv ConA LPS 2. CMP 5 10 50mg/kg iv ConA 3. CMP 50 100 200mg/kg iv 4. CMP 0.1~250 ug/ml 5. CMP 0.05~50 ug/ml 6. CMP 0.1~250 ug/ml ConA LPS 7. CMP 0.5~50 ug/ml 8. CMP 50~100 ug/ml TNF-α 2
CMP TNF 3
ABSTRACT Anti-tumor effect of Carboxymethylpachymaran and analysis of the mechanism of actions Postgraduate: Zhang Xiujun Supervisor: Professsor Zhibin Lin Department of Pharmacology Peking University Health Sciense Center Carboxymethylpachymaran (CMP) was synthesized from pachymaran by Carboxymethylates. Pachymaran was obtained by chemical modification of Pachyman, which was extracted from Poria cocos Wolf. It was demonstrated in many studies that CMP showed strong anti-tumor effect and strengthed immonological fanction. Investigators suggested that the anti-tumor effect of CMP might be mediated by host immune responses, which means that the effect was associated with their enhancement of immune function. All the above study were mainly based on nongastro-intestinal administration which could be done as an initial research but will mislead the further development as a new drug. In order to investigate the anti-tumor effect of CMP and the route of administration, to elucidate the relationship between the immuno-modulating effect and the anti-tumor activity, a series of experiments, from in vivo to in vitro, were designed to investigate the action of CMP. The main results are as the following: in vivo, CMP inhibited significantly the growth of Sarcoma 180 and H22 in a dose-dependant manner in Kunming Mice by gastro-intestinal oral 4
and venous administration. The highest anti-tumor ratio for H 22 in vivo is 55.5%, 42.7%, 62.4% respectively; for S 180 is 35.5%, 69.7%, 71.8% respectively by gastro-intestinal administration of once two-day with dosage 50mg/kg, 100mg/kg 200mg/kg. The dosage is 5mg/kg, 10mg/kg, 100mg/kg by iv once two-day with the highest anti-tumor ratio 23.3%, 41.3%, 43.3% for H 22 ; and 41.2%, 52.2%, 50.5% for S 180. 2. CMP could inhibit moderately /of both S180 and H22 cell proliferation within concentration range of 0.1µg/ml-250µg/ml in vitro. 3. The splcen lymphocytc culture mediam with CMP in vitro didn t inhibit S180 cell proliferation. 4. The peritoneal macrophages culture mediam with CMP in vitro strongly inhibited S180 cell proliferation. 5. CMP could not influence T lymphocyte proliferation induced by ConA or ly LPS in vivo, But can promote phagositosis of peritoneal macrophages on neutral red in vivo. 6. CMP significantly increased delayed type hypersesitivity DTH in mice. 7. CMP promoted T lymphocyte proliferation both directly as well as induced by ConA or LPS in vitro. 8. CMP promoted markedly mixed lymphocyte reaction (MLR) in vitro. 9. CMP increased phagositosis of peritoneal macrophages on neutral red in vitro. 10. CMP increased TNF-α secretion by mouse peritoneal macrophages both in vitro and in vivo. The results show that CMP has effect of antitumor activity both in vivo and in vitro. Moreover, as an immunomodulator, CMP enhance the proliferation of splenic lymphocyte, phagocytosis and TNF-α secretion of peritoneal macrophage, strenth the DTH response to DNFB. Present data provide significant support for further development of CMP as an anti-tumor 5
drug. 6
100083 Poria cocos wolf 1 pentose pectin pachymose C 10H 24O 14 -pachyman [C 6H 10O 5] n - - 93% letanin - 1 3 1 3-1 6-1 6-1 3 2 pachyman 80% 1 90% 7
1979 Carboxymethylpachymaran 2 SNPCP 3 Humuro 1976 hydroxyethyl-pachyman 5 1976 8M 4 U-pachyman 6 8
. Humuro 1976 S180 ICR/JCL 24 5mg/kg 10 5 95% 73% -1 9% -2 61% -3 99% 100% 5 90 ICR/ICJ S180, 250mg/kg/d 6 8 Pachyman Polysaccharides 96 24 S180 2mg/l 93.7% K562 46.92% S180,,, 20mg/L S180 24 C/P S180 9
2.6 (, ),,,,, (1-6). 10, 43.2% 3. 4 Hamuro 1971 S180 Ehrlich MM-102 CCM 50mg 10 5 S180 MM-102 SWM/Ms 90.1%, 500mg ICR/JCL 96.1% 50mg 90.1% 50mg Swiss albino 99.1%,. 2 ICR/ICL U-14,,, ( ),, 10, 8,, 100mg/kg 92.7%. 1991 U14. 615 U14, 250mg/kg,, 25, 23.5% 94%, 64% 10
(P<0.01) 5.88 9.53, 1.43 1.74 (P<0.01) 75.68% 10 615 U14 1983 100mg/kg/d, 23.49% (P<0.01), 71.53%(P<0.05), 139.2%(P<0.01),, C57 Lewis 24, 100mg/kg/d, 4, 0.25% 0.5%, 54.7% 61.7%,, S180 ( 30% ) 11., YUKIKO 1973 ICR/JCL (TX ) S180, 24 (25mg/kg/d)10,, TX 12 99% 6.6%, TX Hamuro 1978 13 1983 50mg/kg 35.5%(P<0.05), 58.0%(P<0.01)., ( 37.9%, 42.3%),, 85.4% 110.0%.,, 11
,., 14 15 1985, 4 IL-2 IL-2 3.5 15 1997 S180 S7811, 12.5-100ug/ml,, 48-96x103IU/ml, 9.6x103IU/ml,. IL-2, IFN-r, TNF-, IL-6. A B, 12, (PHA) A(ConA), 24, 36, 48, 72,,, 50 g/ml, 100 g/ml, 150 g/ml, 100 g/ml, 36., 16 17 (PHA) A(ConA). 1997 16 - GM-CSF. - GM-CSF T,,,,,. GM-CSF,,. 48 GM-CSF,, 168 80,000U/ml. GM-CSF,,,,. 12
GM-CSF 20 1988 LD 50 3.13g/kg,,,,, 1-2. 15g/kg, 7,,, (627mg/kg) 3 4/16,, T (448mg/kg) (313mg/kg), 0.3kg 0.5kg,,,.,, 3 - (SGPT), ; (BUN) ;,, (P<0.001), (P<0.01),, 313mg/kg, 159mg/kg, 3,,,,,,,.. 50-100. 1994 50 1 5g 3 LCT E T IgG IgA IgM C3 13
1 3 21 60 30 2 5 22 2ml/30mg 2 60mg 30 2 2 60mg 120mg-150mg 10% 23 30 2 30 54.28% 54.28% 88.57% 30 36.67% 90% 30 30% 90% (PHA), IgA IgG, IgM, 66, - 86.36%, 14
biological response modifier BMP BMP, 70 20 CMP CMP CMP CMP TNF-α CMP 15
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