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Epidemiological Studies on Intakers of Panax Ginseng C.A. Meyer:

Epidemiological Studies on Intakers of Panax Ginseng C.A. Meyer: Can This Herb Prevent All Kinds of Cancer? Taik-Koo Yun M.D., Ph D. Korea Institute for Cancer Chemoprevention,

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Epidemiological Studies on Intakers of Panax Ginseng C.A. Meyer:

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  1. Epidemiological Studies on Intakers of Panax GinsengC.A. Meyer: Can This Herb Prevent All Kinds of Cancer? Taik-Koo Yun M.D., Ph D. Korea Institute for Cancer Chemoprevention, Seoul, Korea.

  2. Fresh Ginseng White Ginseng Red Ginseng

  3. Table 3.Effect of red ginseng extract on pulmonary adenoma induced by various chemical carcinogens in long-term in vivo experiments. Sacrifice Weight of Incidence of Diffuse Incidence of (wks) lung lung adenoma infiltration hepatoma DMBA* 48 21% decrease 63% decrease Urethane 28 22% decrease** Aflatoxin B1 56 29% decrease 75% decrease** *: DMBA: 9,10-/dimethyl-1,2-benzanthracene. **: p < 0.05 Yun, Yun, Han: Proc. 3rd Int. Symp. p87-113, 1980.

  4. Fig. Panax ginseng C.A. Meyer: 1.5 yr, 3 yr, 4 yr, 5 yr and 6 yr old roots

  5. Table 5. Incidences of lung adenoma in mice according to type and age of Panax ginseng C.A. Meyer using 9 week medium-term anticarcinogenicity model Incidence of lung adenoma Fresh ginseng White ginseng Red ginseng Age of ginseng (Years) Powder Extract Powder Extract Powder Extract Benzo(a)yrene (BP) 41.3 63.9 45.0 41.3 48.6 47.5 BP + 1.5 31.2 48.3 -- -- 37.9 40.7 BP + 3 30.0 52.5 41.3 32.0 41.7 35.0 BP + 4 31.3 51.8 38.0 46.0 31.7a 30.1a BP + 5 30.3 47.5 31.6a 44.0 28.3b 30.0a BP + 6 27.8a 44.1a25.3c 26.5a25.4c 26.3a BP: Benzo(a)pyrene. Years: Age of ginseng at harvest. a: p < 0.05, b: p < 0.02 and c: p < 0.01. Yun, Lee : Korean J. Ginseng Sci.18: 89-94 & 18: 160-164, 1994 Yun, Lee, Kwon, Choi: Acta Pharmacol. Sinica 17: 293-298, 1996.

  6. Fig. 2. Gross findings of lung tumors inducedby benzo(a)pyrene. There are three whitish-pink nodules in the surface of lung.

  7. Table 8. Studies on anticarcinogenicity of Panax ginseng C.A. Meyer extracts and ginsenosides in vivo Authors Organs Duration of Animals Carcinogens Ginseng Reported year experiments or promotors Yun et al (Korea) Lung 28 wks ICR mice DMBA, Urethane Red G Ex 1980, 1983 Liver 57 wks ICR mice Aflatoxin, AAF Red G Ex 1980,1983 Yun et al (Korea) Lung 9 wks NIH(GP) Benzo(a)pyrene Red G Ex 1987,1994 Wu et al (China) Liver 103 days Wistar rat DEN Extract 1990 Bespalov (Russia) Mammary 28 wks LIO rats MNU Bioginseng 1993 Cervix 22 wks LIO rats DMBA Bioginseng 1993 Nervous 12 mos LIO rats ENU Bioginseng 1993 Konoshima (Japan) Skin Two-stage Rats 4NQ-oxide Extract 1994 Surh et al (Korea) Skin Two-stage Rats TPA Rg3 1999 Wanibuchi(Japan) Colon 12 wks F-344 rats DMH Extract 2000 Nishino (Japan) Liver 40 wks C3H/He Spontaneous Extract 2000 Yun et al (Korea) Lung 9 wks ICR mice BP Rg3, Rg5, Rh2 ,Rh1 2001 Wargovich (U.S.A) Colon 8 wks F-344 rats AOM Red G Ex 2001 Yun (Korea) Lung 9 wks ICR mice BP Enzy.produced Rg3, Rg5, Rh2 2004 You(U.S.A.) Lung 20-26 wks A/J mice BP Red G Ex 2006

  8. Table 9. Epidemiological studies on ginseng intakers 1. Purposes: The aim of the epidemiological study is to investigate whether ginseng intake is related to the morbidity and mortality of various human cancers. 2. Studies: A. Case Cotrol Studies 1. 905 Case-control study Cases: 905 cancer patients who were in Korea Cancer Center Hospital since 1987. Controls: 905 patients with non-cancerous diseases. Patients with diseases known to be associated with smoking or alcohol consumption were excluded. Matching: One to one matching: Age, sex and date of admission Total: 1,810 patients Questionaire:Demographic variable, Ginseng intake information, Cigarette and alcohol consumption Statistical analysis: Relative risk and 95 percent confidence interval, Chi-square and Chi-square homogeneity test, Linear trend test, Dose-response relationship evaluation, Kappa value. 2. 1987 Case-control study (Total: 3974 participants) B. Cohort study Kangwha-eup, Inchon city (4,675 participants)

  9. Table 10. Distribution of cancer sites in 905 case subjects Case(cancer) subjects Site of cancer Male Female Liver 101 13 Lung 82 29 Stomach 80 42 Larynx 14 3 Cervix 0 178 Breast 0 84 Thyroid 0 27 Others 135 92 Total 436 469 T-K. Yun, S-Y. Choi : Int. J. Epidemiol. 19: 871-876, 1990.

  10. Table 11. Odd ratios of cancer and 95% confidence interval (CI) by ginseng intake in 905 pairs Measures Cases Controls Odds ratio (%) (%) (95% CI) No intake of ginseng 343 231 1.00 Intake of ginseng 562 (62) 674 (74) 0.56 (0.46 - 0.69) Fresh ginseng Fresh slice 103 94 0.74 (0.53 - 1.04) Juice 39 34 0.77 (0.46 - 1.30) Extract* 13 64 0.14 (0.07 - 0.26) Extract and powder* 13 26 0.34 (0.16 - 0.70) Extract and slice* 6 22 0.18 (0.07 - 0.49) White ginseng Extract* 247 261 0.64 (0.50 - 0.82) Extract and fresh slice 54 61 9.59 (0.39 - 0.91) Powders* 28 43 0.44 (0.26 - 0.75) Powder and fresh slice 10 14 0.48 (0.19 - 1.17) Tea 37 27 0.93 (0.53 - 1.51) Red ginseng Extract 2 3 0.45 (0.05 - 3.32) Others 10 25 0.27 (0.13 - 0.53) * P < 0.01 Yun, T-K. and Choi, S-Y.: Int. J. Epidemiol. 19: 871-876, 1990.

  11. Table 12. Dose response relation by frequency of ginseng intake in 905 pairs case-control study Frequency of ginseng intake Relative risks(RRs) Male Female No intake 1.00 1.00 1 - 3 times / year 0.58 0.81 4 - 11 times / year 0.43 0.56 1 time/month < 0.25 0.52 RR: Relative risks, adjusted for age, sex, education, smoking and alcohol consumption. T-K. Yun, S-Y. Choi : Int. J. Epidemiol. 19: 871-876, 1990.

  12. Table 13. Case-control study on 1987 pairs Purpose of study In order to explore further 1. The types of ginseng products that have the most prominent cancer preventive effect. 2. The reproducibility of the dose-response relationship. 3. The duration of ginseng consumption that has a significant preventive effect. 4. The types of cancer which can be prevented by ginseng. 5. The effect of ginseng on cancers associated with smoking. Yun, T-K. and Choi, S-Y.: Cancer Epidemiol. Biomarkers Prev. 4: 401-408, 1995.

  13. Table l4. Odds ratios and 95% confidence intervals for cancers by ginseng intake in 1987 pairs case-control study. Cancer Type of ginseng patients Controls Odd ratios 95% CI (%) (%) No intake of ginseng 921 605 1.00 Reference Intake of ginseng 1066(53.6) 1382(69.6) 0.50 0.44-0.58 Fresh ginseng Slice 210 172 0.79 0.63 - 1.01 Juice 69 63 0.71 0.49 - 1.03 Extract 146 255 0.37 0.29 - 0.46 White ginseng Powder 60 129 0.30 0.22 - 0.41 Extract 373 442 0.57 0.48 - 0.68 Tea 43 41 0.69 0.45 - 1.07 Red ginseng Extract 6 17 0.20 0.08 - 0.50 Combination 22 58 0.16 0.10 - 0.25 Adjusted for age, sex, marital status, educations, smoking, and alcohol consumption. Yun and Choi: Cancer Epidemiol. Biomarkers Prev. 4: 402-408, 1995.

  14. Table 15. Odds ratios for various cancers according to ginseng intakers in case-control study on 1987 pairs Site of cancer Cancer Control OR 95% CI Never taken/ Never taken/ ever taken ever taken Lip, oral cavity, and pharynx 67 / 92 40 / 119 0.47 0.29 ± 0.76 Esophagus 40 / 47 14 / 73 0.20 0.09 ± 0.38 Stomach 142 / 158 7 6 / 224 0.36 0.09 ± 0.52 Colon and rectum 55 / 63 3 2 / 86 0.42 0.24 ± 0.74 Liver 108 / 156 67 / 197 0.48 0.33 ± 0.70 Pancreas 12 / 11 5 / 18 0.22 0.05 ± 0.95 Larynx 21 / 19 8 / 32 0.18 0.06 ± 0.54 Lung 120 / 156 81 / 195 0.55 0.38 ± 0.79 Female breast 82 / 92 70 / 109 0.63 0.40 ± 1.05 Cervix uteri 156 / 146 312 / 170 0.72 0.52 ± 1.01 Ovary 17 / 5 8 / 14 0.15 0.04 ± 0.60 Urinary bladder 23 / 40 16 / 47 0.64 0.28 ± 1.47 Thyroid gland 16 / 24 14 / 26 0.96 0.38 ± 2.44 Other 53 / 61 35 / 79 0.48 0.27 ± 0.85 Adjusted for age, sex, marital status, education, smoking, and alcohol consumption. OR: Odd ratios CI: Confidence interval Yun, T.K.and S.Y. Choi: Cancer Epidemiol. Bipmarkers & Prev. 4: 401-408, 1995.

  15. Table 16. Odds ratios of cancer and 95% CI in case-control study on 1987 pairs. Frequency of Male Female ginseng intake Cancer Contr OR 95% CI Cancer Contr OR 95% CI None 409 234 1.00 Reference 512 371 1.00 Reference 1 - 3 times / year 246 231 0.62 0.49-0.79 171 209 0.60 0.47-0.76 4 - 11 times / year 197 223 0.48 0.37-0.62 127 171 0.54 0.42-0.71 1 time / month or more 220 384 0.31 0.25-0.39 105 164 0.47 0.39-0.62 Total lifetime consumption of ginseng None 409 452 1.00 Reference 512 371 1.00 Reference 1 - 50 452 501 0.51 0.42-0.63 322 402 0.58 0.48-0.71 51 - 100 75 100 0.41 0.29-0.58 28 39 0.56 0.34-0.93 101 - 300 80 131 0.32 0.23-0.44 29 54 0.39 0.25-0.61 301 - 500 20 29 0.33 0.18-0.62 8 21 0.29 0.14-0.63 500 - 36 77 0.25 0.16-0.38 16 28 0.42 0.23-0.79 Yun, T-K. and Choi, S-Y.: Cancer Epiddemiol. Biomarkers Prev. 4: 401-408, 1995.

  16. Table 17. Odds ratios for cancers according to ginseng intake and smoking in case-control study on 1987 pairs. Nonsmokers Smokers Cancers Ginseng intake OR 95% CI OR 95% CI Lung Ever taken 1.00 (27) Reference 1.99 (81) 1.25 - 3.19 Never taken 2.11 (40) 1.08 - 4.15 4.13 (128) 1.90 - 9.03 Lip, oral cavity, and pharynx Ever taken 1.00 Reference 2.36 (43) 1.23 - 4.51 Never taken 2.13 (24) 0.95 - 4.79 4.41 (69) 1.29 - 15.04 Esophagus Ever taken 1.00 ( 5) Reference 0.13 (35) 0.06 - 0.31 Never taken 0.51 ( 5) 0.10 - 2.69 0.38 (42) 0.09 - 1.62 Stomach Ever taken 1.00 Reference 2.90 (62) 1.79 - 4.70 Never taken 2.73 (80) 1.61 - 4.64 1.90 (101) 0.84 - 4.28 Colorectum Ever taken 1.00 (31) Reference 3.25 (20) 1.25 - 8.44 Never taken 2.11 (35) 1.03 - 4.34 2.45 (31) 0.60 - 10.13 Liver Ever taken 1.00 (31) Reference 2.09 (81) 1.33 - 3.29 Never taken 1.68 (27) 0.79 - 3.57 2.50 (125) 1.06 - 5.92 Adjusted for age, sex, education, and alcohol consumption. Numbers in parentheses, nubmber of cancer patients. Yun, T-K. and Choi, S-Y.: Cancer Epiddemiol. Biomarkers Prev. 4: 401-408, 1995.

  17. Table 18. Population and methods of cohort Participants and methods 1. Ginseng cultivation area: Kangwha-eup, Inchon city 4,675 persons 2. Selection of study population: Selected from resident’s list registered in the government. associated with smoking or alcohol consumption were excluded. 3. Interviews: First interview: since August 1987. Standard questionaire Demographic characteristics Past history of disease Ginseng intake information Smoking and drinking habbits Life long occupation 4. Identifgication of cancers: Hospital records Medical insurance data Deaths certificate of government Second interviews: since 1992 5. Statistical analysis Proportional hazard model Cox for relative risks and 95% C. interval. Adjusted for age, sex, education, smoking and alcohol consumption, Dose-response relationship evaluation. PROC OHREG procedure in the SAS statistical package. Yun, T-K. and Choi, S-Y.: Int. J. Epidemiology, 27: 359-364, 1998

  18. Table 19. Relative risks of cancer by ginseng intake in cohort study Kinds of ginseng No. of subjects No. cancer cases RR1 95% CI RR2 95% CI (%) No intake 1283(29.8) 62 1.00 - 1.00 - Ginseng intake 3167(71.2) 75 0.480.34 - 0.67 0.40 0.28 - 0.56 Fresh ginseng Slices & juice 236 8 0.66 0.32 - 1.39 0.67 0.33 - 1.32 Extract 296 3 0.23 0.08 - 0.63 0.31 0.13 - 0.74 White ginseng Powder 147 5 0.59 0.22 - 1.62 0.49 0.19 - 1.23 Extract 68 1 0.62 0.15 - 2.53 0.50 0.12 - 2.07 Tea 442 18 0.89 0.52 - 1.52 0.65 0.37 - 1.12 Red ginseng Extract 24 - - - - - Boiled chicken with 381 12 0.77 0.40 - 1.23 0.71 0.38 - 1.21 young ginseng root Multiple combination 1573 28 0.37 0.24 - 0.57 0.34 0.20 - 0.53 RR1: Adjusted for age and sex. RR2: Adjusted for age, sex, education, smoking and alcohol consumption ( )a: Person-years of follow-up. ( )b: Incident rate for 1000 person-years. Yun, T-K. and Choi, S-Y.: Int. J. Epidemiology, 27: 359-364, 1998

  19. Table 20. Relative risks of selected cancers by ginseng intake Cancers (n) No. of Stomach (42) Lung (24) Liver (14) Ginseng intake subjects No. RR 95% CI No. RR. 95% CI No. RR 95% CI No intake 1283 23 1.00 - 14 1.00 - 4 1.00 - Ginseng intake 3167 19 0.33 0.18 - 0.57 10 0.30 0.14 - 0.65 10 0.86 0.25 - 2.9 Fresh ginseng Slices & juice 236 2 0.57 0.17 - 1.94 1 0.67 0.15 - 3.43 2 1.97 0.34 - 2.95 Extract 296 1 0.33 0.12 - 0.88 1 0.28 0.04 - 2.17 - - - White ginseng Powder 147 1 0.24 0.03 - 1.84 - - - - - - Extract 68 2 1.34 0.30 - 5.97 - - - - - - Tea 442 6 0.64 0.26 - 1.61 4 0.80 0.26 - 2.44 2 1.72 0.15 - 4.87 Red ginseng Extract 24 - - - - Boiled chicken with 381 5 0.43 0.12 - 1.43 1 0.35 0.08 - 1.95 1 0.85 0.15 - 4.87 young ginseng root RR: Relative risks, adjusted for age, sex, education, smoking and alcohol consumption CI: Confidence interval Value in parentheses indicate number of cancer cases. Yun, T-K. and Choi, S-Y.: Int. J. Epidemiology, 27: 359-364, 1998

  20. Table 21. Comparison of relative risks for cancer by type of ginseng intake between medium-term experiment, case-control studies and cohort Studies. Medium-term Case-control Cohort experiment in mice studies studies Kind of ginseng Anticarcinogenicity 905 pairs 1987 pairs 5 years 7 years 10 years Positive (RR) (RR) (RR) (RR) (RR) Ginseng intake - 0.56 0.50 0.40 0.38 0.48 Fresh ginseng - less than 5 year old fresh ginseng - Slices 6 year-old onlyNegative Negative Negative Negative Negative Extract 6 year-old only0.14 0.37 0.31 0.52Negative White ginseng - less than 5 yrar white ginseng - Powder 5 and 6 year-old 0.64 0.57Negative Negative Negative Extract 5 and 6 year-old 0.44 0.30Negative Negative Negative Red ginseng Powder 4,5 and 6 year-old Extract 4,5 and 6 year-old 0.45 0.20 24 persons (no cancer death) Combination - 0.27 0.16 0.34 0.47 0.36 RR: Adjusted for age, sex, education, smoking, alcohol consumption

  21. Table 21. Comparison of dose response relation by frequency of ginseng intake between two case-control studies and cohort study Relative risks (RR) for cancer Frequency of Case-control studies Cohort study ginseng intake Patients Population bases 905 pairs 1987 pairs 4553 persons /5 years Male Female Both sex Both sex No intake 1.00 1.00 1.00 1.00 1 - 3 times / year 0.58 0.81 0.60 0.46 4 - 11 times / year 0.43 0.56 0.51 0.35 1 time/month < 0.25 0.52 0.36 0.34 RR: Relative risks, adjusted for age, sex, education, smoking and alcohol consumption. T-K. Yun, S-Y. Choi : Int. J. Epidemiol. 19: 871-876, 1990, Cancer Epidemiol. Biomarkers & Prev. 4: 402-408, 1995 Int. J. Epidemiol. 27: 359-364, 1998.

  22. Table 23. Possible mechanism of anticarcinogenic effect of ginseng Authors Components Effects Year 1. Yun et al ` Red ginseng ex NK cell enhancement 1987 2. Fan et al Rg1 & Rb1NO from IFN-gamma 1995 activated macrophages 3. Surh et al Rg3 Suppression of COX-2 2001 inhibition of NF-kB & ERK 4. Bereck et al Rc & Rd T cell proliferation 2001 5. Hasegawa et al 20(S)-Protopanaxatriol NK cell mediated 2002 6. Park et al Rh2 Inhibition NO & PGE2 2003, 2004 7. Lee et al Rg1 CD4(+) T cell 2004 8. Oh et al 20(S)-Protopanaxatriol Breakage of 2004 INOS & COX-2 9. Joo et al Rg3Microglial phagocytosis 2005 10. Rivera et al Rb1 Elicit Th1 & Th2 2005 11. Liou et al Ginseng ex Potentiate humoral 2005 immune response 12 Liou et al Extract Th1-type cytokine 2006 enhancement 13. Bae et al Rg3,Rf & Rh2COX-2 inhibition 2006 expression of cytokines 14. Quan et al Ginseng ex Immunomodulation 2006 Against virus specific IgA

  23. Conclusion Panax ginseng C.A. Meyer has been established as non-organ specific cancer preventive, having dose response relationship. These results warrant that ginseng extracts and its ginsenosides should be examined for preventive effects on various types of human cancers by randomized double blind placebo controlled clinical trials.

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