This paper reviews progress in the laboratory and clinical evaluation of Modified Citrus Pectin (MCP), a low molecular weight pectin that has shown promising results in the prevention of metastasis of prostate adenocarcinoma. Following the initial published in-vitro1 and animal(2) studies, we designed two trials to investigate the benefits of MCP further:

(1) a human prostate cancer pilot study, (2) an in vitro study that evaluated its cytotoxic effects on a prostate cancer cell line. Encouraging results in these two studies has led to a larger phase II clinical trial that is underway at the present time. This substance may play an important role in the prevention of cancer metastasis.

Background

Citrus pectin is a complex polysaccharide (long-chain carbohydrate) obtained from the peel and pulp of citrus fruits such as lemons, grapefruits, oranges and tangerines. This long chain of sugars has numerous branches with important binding capabilities that are related to pectin ís unique anti-metastatic attributes. Both the molecular weight and the structure of the chain influence the binding properties of the pectin. First, low molecular weight is required in order for pectin to be absorbed into the bloodstream during digestion; secondly, a reduced number of side chains facilitate the ability of the pectin molecule to bind to its target sites.

MCP is composed of citrus pectin that has been broken down into shorter chain molecules. In the laboratory, this is done by heat and pH modification. Industry progress in the production of low methoxy, low molecular weight pectins has resulted in the availability of material for both research work and public consumption.

Proprietary processing of citrus pectin results in a substance with a shorter molecular chain and low degree of methoxy content, thus allowing the lower molecular weight compound to be absorbed into the bloodstream. This processing also enhances the absorption and utilization of the polysaccharide compounds. One of these compounds is galactose, a natural sugar found on the branches of the pectin molecule. Because galactose has an affinity for galectin-3 proteins on the cancer cell surface, this naturally occurring sugar is felt to play a role in the ability of MCP to inhibit cancer metastasis.

Cancer Metastasis - The Role of Galectins

Certain cancer cell types, such as prostate cancer, breast cancer, colon cancer, lymphoma, melanoma, glioblastoma, and laryngeal epidermoid carcinoma, all have specific protein molecules on their cell surface, called galectins. It has also been observed that metastatic cells express significantly more galectin-3 than the original primary tumor cells from which they were derived. Galectins are known for their carbohydrate-binding abilities. These proteins on the cancer cell surface are involved in binding between cells. They play an important role in cellular interactions during the metastatic process, binding to galactose on neighboring cancer cells and oligosaccharides on the surface of normal cells.(3)

Human studies of colon, stomach and thyroid cancers showed that the amounts of galectin produced increased proportionally as the cancers progressed from their early to advanced stages.(4) Higher galectin levels permit greater adhesion of cancer cells and increases the ability of these cells to bind to non-cancerous cells at a distant site, where metastasis occurs. Thus, these lectin binding sites and their proclivity for binding to cancer cell surface carbohydrates appear to be the basis by which cancer cells aggregate together and bind to metastatic target sites.

A Proposed Role for Modified Citrus Pectin

It is felt that MCP works by blocking tumor cell surface galectins, so that tumor cells cannot adhere to other cells. The galactose branch chains on the modified pectin molecule appear to be the part, which has an affinity for galectins on the tumor cell surface. The impact of this galectin blockage is twofold: (1) to inhibit aggregation of cancer cells, whereby they bind to each other to form colonies, and (2) to inhibit adhesion of cancer cells to host cell surfaces. Due to these affects, MCP may also prevent the formation of organized tumor emboli.

Animal Studies

The first evaluation of the feasibility of oral use of MCP in living systems was conducted by the research team of Dr. Kenneth Pienta.(2) In an animal study, it was introduced in drinking water to rats implanted with prostate cancer cells. Only 50% of the rats given MCP developed lung metastases, significantly lower than a control population of rats where lung metastases occurred in 93.75% of the control group. In addition, the group that received 1% MCP had only one colony in the lungs (+/-1) compared to nine colonies (+/-4) in the control group. Reductions in (1) the percentage of rats that developed metastatic disease, and (2) the number of metastatic colonies per diseased animal were both statistically significant. MCP did not affect their primary tumor growth at any concentration tested.

A recent study evaluated the effect of daily oral administration of MCP on colon-25 tumors implanted in balb- c mice.(5) In comparison to the control group the investigators observed a significant reduction in tumor size. There was a 38% reduction in size in the group fed 0.8mg/ml, and 70% reduction in the group fed 1.6mg/ml of MCP. There was no statistically significant difference in mean tumor weight between the group receiving MCP and the control group. The investigators suggest that this may be due to differences in the overall tissue constituents of the excised tumors The discrepancy between the decrease in tumor size observed and the lack of change in tumor mass puts into question the results of the study, especially in lieu of the fact that Peinta(2) in his landmark animal study did not observe a change in the growth of the primary tumor. Based on the proposed mechanism of MCP in preventing tumor emboli formation(2,3) we can anticipate that MCP may effect the formation of the primary tumor and thus potentially serve as a preventative agent, but not effect the growth of the primary tumor once it is implanted. Additional studies are required to determine the exact role of MCP in treatment of the primary tumor.

Published studies(1,6) demonstrated a time-and dose-dependent inhibition of tumor cell adhesion. This suggested that saturation of galectin cell surface sites on tumor cells by the galactose of MCP was a viable model on which to base further research. The animal research suggested that (1) the lower molecular weight of MCP allowed absorption into the bloodstream, and that (2) higher levels had a greater impact. Converting this information to a human model in a useful way led us to the design of the first human clinical trial.

Human studies and additional in vitro studies

A human clinical trial designed by our group and conducted by Dr. Steven Strum and Dr. Mark Schultz of the Prostate Cancer Research Institute, Los Angeles, CA(7) evaluated the changes in PSA level in patients with prostate cancer. The patients studied consumed 15 grams per day of MCP (PectaSolÆ EcoNugenics Inc., Santa Rosa, CA 95407). Seven patients were enrolled into the study. Cancer progression was evaluated based on the time that it takes for the PSA to double, a standard measurement of prostate cancer progression.(8-11) Lengthening of this doubling time represents a slowing in the progression of the cancer. Full response was measured as a 30% lengthening in PSA doubling time and was seen in 4/7 patients. In all, 6/7 patients showed increased doubling times in PSA levels and were classified as full or partial responders. This pilot clinical trial showed that MCP significantly slowed the PSA doubling time in prostate cancer patients with low levels of PSA. It is especially significant in patients where the PSA increase is due to secondary tumors as it signifies inhibition or retardation of the progress of cancer metastasis.

An in vitro study(12) that assessed the cytotoxic effect of MCP on PC-3 prostate cancer cell lines demonstrated a very high cytotoxic effect as compared with control. Cytotoxicity was found to be 80.7% at 1.0% concentration of MCP, and 76.9% at 0.1% concentration, compared with 3.8% with the control group. The authors concluded that MCP may interfere with the adherence of PC-3 cells to an endothelial monolayer.

Additional Benefits of Modified Citrus Pectin:

MCP may have a beneficial effect on primary tumors in addition to the main effect of slowing metastasis. A possible mechanism that can explain such an effect is that it may inhibit the formation of organized tumor emboli.(4, 13-14)

Because pectin can bind to cholesterol, a reduction of serum cholesterol has been observed. Regular pectin reduces cholesterol by binding to it in the intestines. MCP can bind to cholesterol in the bloodstream. Due to its binding effects it may have a more direct effect on preventing and reducing arteriosclerosis.(15-21)

Pectin can bind to various heavy metals and function as a chelating agent. MCP may specifically bind to heavy metals in the blood stream. At the present time we are studying the potential effects of modified citrus pectin as a single agent and in combination with modified alginate (low molecular weight alginate) as systemic chelating agents. These potential uses of pectin warrant additional research.(22-25)

Tolerance and recommended dosage

MCP is well tolerated. While, based on the human clinical trial and our clinical experience, the optimal dosage for slowing of metastasis may be 15 grams per day; the dosage that should be used for prevention is lower. Dosages as low as 3-5 grams per day can be beneficial as a preventative measure.

Conclusion

MCP may be a promising nutritional supplement. Its benefits can include the lowering of cholesterol, possible immune enhancement, (25-28) but more significantly, the inhibition of cancer metastasis. . This safe-to-use preparation is showing promising results, and will require more research in order to determine more accurately its role in the treatment and prevention of cancer.

1. Naik H, Kalemkerian G. Inhibition of in vitro tumor cell-endothelial adhesion by modified citrus pectin: a pH modified natural complex carbohydrate (Meeting abstract). Proc Annul Meet Am Assoc Cancer Res. 1995;36: 377.

2. Pienta KJ, Naik H, Akhtar A, et al. Inhibition of spontaneous metastasis in a rat prostate cancer model by oral administration of modified citrus pectin. J Natl Cancer Inst. 1995;87(5):348-353.

3. Raz A, Lotan R. Endogenous galactoside-binding lectins: a new class of functional tumor cell surface molecules related to metastasis. Cancer Metastasis Rev. 1987; 6:433-452.

4. Robert S, Bresalier RS, Yan PS, et al. Expression of the endogenous galactose-binding protein galectin-3 correlates with the malignant potential of tumors in the central nervous system. Cancer. 1997; 80:776-787

5. Hayashi A, Gillen AC, Lott JR. Effects of daily oral administration of quercetin chalcone and modified citrus pectin. Altern Med Rev. 2000;5(6): 546-552.

6. Platt D. Modulation of the lung colonization of B16-F1 melanoma cells by [modified] citrus pectin. J Natl Cancer Inst. 1992;84(6):438-442.

7. Strum S, Scholz M, McDermed J, et al. Modified citrus pectin slows PSA doubling time: a pilot clinical trial. (Abstract) International Conference on Diet and Prevention of Cancer (Finland). May 1999. WWW.Econugenics.com

8. Roberts SG, Blutte ML, Bergstralh EJ, et al. PSA doubling time as a predictor of clinical progression after biochemical failure following radical prostatectomy for prostate cancer. Mayo Clin Proc. 2001;76(6):576-581.

9. Lukes M, Urban M, Zalesky M, et al. Prostate-specific antigen: current status. Folia Biol (Praha) 2001;47(2);41-49.

10. Cassinat B, Wacquet M, Toulbert ME, Rain JD, Schlageter MH. Evaluation of total PSA assay on vitros ECi and correlation with Kryptor PSA assay. Anticancer Res. 2001;21(1B): 557-62.

11. Leventis Ak, Shariat SF, Kattan MW, et al. Prediction of response to salvage radiation therapy in patients with prostate cancer recurrence after radical prostatectomy. J. Clin Oncol. 2001; 19(4):1030-1039.

12. Weiss T, McCulloch M, Eliaz I. Modified citrus pectin induces cytotoxicity of prostate cancer cells in co-cultures with human endothelial monolayers. (Abstract) International Conference on Diet and Prevention of Cancer. (Finland); May 1999. WWW.Econugenics.COM

13. Kohn EC. Development and prevention of metastasis. Anticancer Res. 1993;13:2553-2559.

14. Liotta LA, Steeg PS, Stretier-Stevenson WG. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell. 1991;64:327-336.

15. Hexeberg S, Hexeberg E, Willumsen N, Berge RK. A study on lipid metabolism in heart and liver of cholesterol and pectin fed rats. Br J Nutr. 1994; 71(2):181-92.

16. Matheson HB, Colon IS, Story JA. Cholesterol 7 alpha-hydroxylase activity is increased by dietary modification with psyllium hydrocolloid, pectin, cholesterol and cholestyramine in rats. J Nutr.1995;125(3):454-458.

17. Fernandez ML Sun DM; Tosca MA; McNamara DJ. Citrus pectin and cholesterol interact to regulate hepatic cholesterol homeostasis and lipoprotein metabolism: a dose-response study in guinea pigs. Am J Clin Nutr. 1994;59(4):869-878.

18. Veldman FJ, Nair CH, Vorster HH, et al. Dietary pectin influences fibrin network structure in hypercholesterolaemic subjects. Thromb Res. 1997;86(3):183-196.

19. Fernandez ML. Distinct mechanisms of plasma LDL lowering by dietary fiber in the guinea pig: specific effects of pectin, guar gum, and psyllium. J Lipid Res. 1995;36(11):2394-2404.

20. Garcia-Diez F, Garcia-Mediavilla V, Bayon JE, et al. Pectin feeding influences fecal bile acid excretion, hepatic bile acid and cholesterol synthesis and serum cholesterol in rats. J Nutr. 1996;126(7):1766-1771.

21. Tinker LF, Davis PA, Schneeman BO. Prune fiber or pectin compared with cellulose lowers plasma and liver lipids in rats with diet-induced hyperlipidemia. J Nutr. 1994;124(1):31-40.

22. Bondarev GI, Anisova AA, Alekseeva TE, et al. Evaluation of a pectin with low degree of esterification as a prophylatic agent in lead poisoning. Vopr Pitan. 1979;(2):65-67.

23. Kushneva VS, Koltunova IG, Pectins of various degrees of esterification and pectin-containing preparation ìMedetopect as promoters of lead elimination. Med Tr Prom Ekol. 1997;(7):27-31.

24. Gong YF, Haung ZJ, Qiang MY, Lan FX, et al. Supression of radioactive strontium absorption by sodium alginate in animals and human subjects. Biomed Environ Sci. 1991;4(3):273-282.

25. Schoeters GE, Luz A, Vanderborght OL. 226Ra induced bone-cancers: the effects of delayed Na-alginate treatment. Int J Radiat Biol Relat Stud Phys Chem Med. 1983;43(3):231-247.

26. Zhu HG, Zoller TM, Klein-Franke A, Anderer FA. Activation of human monocyte/macrophage cytotoxicity by IL-2/IFN gamma is linked to increased expression of an antitumor receptor with specificity for acetylated mannose. Immunol Lett.1993;38(2):111-119.

27. Zhu HG, Zoller TM, Klein-Franke A, et al. Enhancement of MHC-unrestricted cytotoxic activity of human CD56+ CD3- natural killer (NK) cells and CD3+ T cells by rhamnogalacturonan: target cell specificity and activity against NK-insensitive targets. J Cancer Res Clin Oncol. 1994; 120(7):383-388.

28. Zollner TM, Zhu HG, Anderer FA. Induction of NK-like activity in T cells by IL-2/anti-CD3 is linked to expression of a new antitumour receptor with specificity for acetylated mannose. Anticancer Res. 1993;13(4):923-30.

(Copyright© 2001 The International Journal of Integrated Medicine. All rights reserved.)