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Modified Citrus Pectin

MODIFIED CITRUS PECTIN SLOWS PSA DOUBLING TIME: A Pilot Clinical Trial
Stephen Strum MD, Mark Scholz MD, Jon McDermed Pharm D, Michael McCulloch BA, Isaac Eliaz MD
Presented at the International Conference on Diet and Prevention of Cancer
May 28 ­ June 2, 1999
Tampere, Finland

ABSTRACT
The purpose of this pilot clinical trial was to evaluate the ability of Modified Citrus Pectin to influence the PSA slope in men with prostate cancer. Patients who had either relapsed after or failed prior treatment for prostate cancer (PSA range 0.63 to 7.50) were given Modified Citrus Pectin (PectaSol ^®, EcoNugenics, Inc., San Rafael, CA 94901) at a dosage of 15 grams per day in three divided oral doses. PSA doubling time was calculated. A response (more than 30% lengthening of PSA doubling time) was seen in 4/7 patients (57%). One patient (1/7) had a partial response, one patient (1/7) had stable disease, and one patient (1/7) did not respond. Modified Citrus Pectin appears to lengthen the PSA doubling time in prostate cancer patients with low levels of PSA. Study responses are additionally compelling, as all study participants are still alive and evaluable for long­term follow­up almost three years after completion of this study. More research involving larger numbers of patients is needed to full), define the role of MCP in prostate cancer treatment.

PURPOSE
The purpose of this pilot clinical trial was to evaluate the ability of Modified Citrus Pectin to influence the PSA slope in men with prostate cancer.

INTRODUCTION
For prostate cancer to spread, research indicates that a clump of cells may be required rather than a single cell or a few individual cells together. The ability for cancer cells to "clump" appears to be mediated, at least in part, by carbohydrate­binding, proteins (CBP's) located on the cell surface. One such CBP is a galactoside­binding lectin or "galectin" called galectin­3.

In human studies involving colon, stomach and thyroid cancers, the amounts of galectin produced increased proportionally as the cancers grew from their earliest to their most advanced stages. It is reasonable to hypothesize that the higher galectin levels permit greater adhesion and clumping of cancer cells at a "target site," i.e. the site of metastasis. Thus, these lectin binding "receptors" and their ability to bind cell surface carbohydrates and glycoproteins may serve as the cement that allows cancer cells to clump and possibly bind to metastatic target sites.

Plant fiber derived from citrus fruit contains "citrus pectin", a highly non­branched complex polysaccharide that is rich in galactosyl (sugar carbohydrate) residues. MCP is citrus pectin that has been pH­modified into smaller, less complex molecules that dissolve much better in water and are absorbed more completely by the body when taken by mouth. MCP appears to compete with the galectin­3 receptor sites thereby interfering with cancer cell­cancer cell and cancer cell-metastatic target site interactions.

In a study by Pienta et al, two groups of rats serving as an animal model for human prostate cancer were injected with MAT­LyLu Dunning, R3327 rat prostate adenocarcinorna cells. (MAT­LyLu cancer cells grow more rapidly and have a greater tendency to metastasize throughout the body). Half of the rats were "controls" and were given plain drinking water, while the others were given MCP in their water at a 0.1% concentration.

Results from this study showed 7/14 (50%) of 0.1% MCP-treated rats developed lung, metastases, which was significantly lower in 15/16 of control animals (93.75%). When 1% MCP was studied in the same manner, lung metastases occurred in 9/16 (56.3%) of MCP­treated animals. The number of metastatic colonies in the lungs of the 1.0% MCP group (1 +/- 1) was significantly lower than in the control group (9 +/- 4).

The same authors later showed that MCP also reduced the ability of rat prostate adenocareinoma cells to bind to rat endothelial cells (the type of cells that form the inside lining of blood vessels) in a dose­dependent manner. In other words, with higher doses of MCP, proportionately greater reductions in cancer cell binding to endothelial cells were observed. When human prostate cancer cells metastasize, they appear to bind to the same target receptor site, i.e. galectin­3, that MCP binds with (Pienta KJ et al, J Natl Cancer Inst. 87:348-353,1995).

MATERIALS & DOSAGE
Modified Citrus Pectin (PectaSol ^®, EcoNugenics, Inc., San Rafael, CA 94901) was orally administered at a dosage of 15 grams per clay in three divided doses. The study material specifications had a molecular weight (MW) of 10,000-15,000 daltons and methylation (DM) less than 10%.

STUDY PROTOCOL
Eligibility Requirements
1) Prostate cancer patients failing first­line androgen deprivation therapy.
2) Patients in relapse after radical prostatectomy, external beam radiation therapy, brachytherapy or cryosurgery.
3) Untreated patients, or those off Intermittent Hormone Blockade (IHB), both having low levels of PSA and a defined PSA doubling time.

Baseline Studies
1) CBC, chemistry panel, PSA and other tumor markers as appropriate.
2) Radiological studies pertinent to the patient's clinical stage of disease.
3) Physical examination and complete review of systems.

RESPONSE EVALUATION
All patients were seen in office follow­ups at least once a month. Follow­up studies included a CBC, chemistry panel, PSA and/or other tumor markers, physical examination, and a review of systems. PSA doubling time was plotted using computer software. The PSA doubling time reflects the speed at which the cancer is growing. The faster the growth, the shorter the PSA doubling time. Lengthening of the PSA doubling time represents a decrease in the rate of growth of the cancer. PSA doubling time data was evaluated at 3, 6, and 12 months intervals. A minimum of 3 months on study was required for patients to be evaluable for this study.

CRITERIA FOR STUDY DISCONTINUATION
Patients were discontinued from the study when there was (1) a lack of response to MCP, (2) clinical findings of progressive disease unrelated to PSA, or (3) patient intolerance to MCP.

RESPONSE DEFINITION
Response = More than 30% lengthening of PSA doubling time
Partial response = Less than 30% lengthening of PSA doubling time
Stable disease = Less than 50% shortening of PSA doubling time
No response = More than 50% shortening in PSA doubling time
Progression = 50% PSA increase above baseline measured on two successive monitoring, intervals, or clinical evidence for disease progression unrelated to the PSA response.

RESULTS
Clinical Data: MCP Results In 7 Patients With Prostate Cancer

¹ DT = PSA Doubling Time
² Cryo = Cryosurgery

DATA ANALYSIS
Seven patients were enrolled into this study and considered evaluable. A response (more than 30% lengthening of PSA doubling time) was seen in 4/7 patients (57%). All of these were patients off IHB. In one patient there was a 5.7% lengthening in his PSA doubling time (PSADT). He was thus judged to have had a partial response. One patient had a 6.7% shortening in PSADT. He was judged to have stable disease. The remaining patient had a 69.4% shortening in PSADT, and so had no response.

CONCLUSIONS
Modified Citrus Pectin appears to slow the PSA doubling time in prostate cancer patients with low levels of PSA. More research involving larger numbers of patients is needed to fully define the role of MCP in prostate cancer treatment. Study responses are additionally compelling, as all study participants are still alive and evaluable for long­term followup almost three years after completion of this study.

REFERENCES
Inohara H, et al. Effects of natural complex carbohydrate ([modified] citrus pectin) on murine melanoma cell properties related to galectin­3 functions. Glycoconj J 1994 Dec; 11(6): 527­32

Naik H, et al. Inhibition of in vitro tumor cell­endothelial adhesion by modified citrus pectin: a pH modified natural complex carbohydrate (Meeting abstract). Proc Annu Meet Am Assoc. Cancer Res; 36:A377 1995

Pienta KJ, et al. Inhibition of spontaneous metastasis in a rat prostate cancer model by oral administration of modified citrus pectin [see comments]. JNatl. Cancer Inst 1995 Mar 1; 87(5): 348­53

Platt D. Modulation of the lung colonization of B 16­Fl melanoma cells by [modified] citrus pectin. J Natl Cancer Inst 1992 Mar 18; 84 (6): 438­42

Zhu HG, et al. Activation of human monocyte/macrophage cytotoxicity by IL­2/IFN gamma is linked to increased expression of an antitumor receptor with specificity for acetylated mannose. Immunol Lett 1993 Oct; 38 (2): 111­9

Zhu HG, et al. Enhancement of MHC­unrestricted cytotoxic activity of human CD56+ CD3­ natural killer (NK) cells and CD3+ T cells by rhamnogalacturonan: target cell specificity and activity against NK­insensitive targets. J Cancer Res Clin Oncol 1994, 120 (7): 383­8

Zollner TM, et al. Induction of NK­like activity in T cells by IL­2/anti­CD3 is linked to expression of a new antitumor receptor with specificity for acetylated mannose. Anticancer Res 1993 Jul­Aug; 13(4): 923­30