Enzymes and Cancer

[Guest guest]

Enzymes and Cancer: A Look Toward

the Past as We Move Forward

Keith I. Block, MD

Several years ago, I was having lunch with a prominent

German medical oncologist at a conference on cancer

and CAM at the National Institutes of Health (NIH)

in Washington, DC. I asked him what the most exciting

thing in cancer CAM in Europe was at that time. “Enzymes,â€

he said. A bit surprised by his instantaneous response, I

asked him what the second most exciting thing was. Again

with no hesitation he blurted out, “More enzymes!â€

We did not pursue the conversation much further, but

the incident has stuck in my mind for many years now,

and I have both used and kept an eye on enzyme therapy

ever since. I have observed some of my cancer patients

who were using enzyme-based supplements, and I have

explored how active enzyme supplements might be successfully

formulated. I was thus quite intrigued when

Integrative Cancer Therapies Corresponding Editor Ralph

Moss proposed this special issue on enzyme therapy for

cancer in honor of the birth anniversary of John Beard,

the scientific founder of enzyme therapies. Ralph, in his

guest editorial, summarizes the articles in this issue, to

which he has contributed an impressive set of scholarly

biographical and historical studies of Beard and the

course of his studies on enzymes and cancer.

Oral systemic enzyme therapy for cancer is widely

used in Europe, and a therapy based on pancreatic

enzyme extracts has been the subject of an NIH-sponsored

trial in the United States. As a clinician, I find myself

most interested in the results of clinical trials. A group of

especially interesting recent studies conducted in Europe

are reviewed in this issue in the article by Beuth, but I

would like to summarize, in this editorial, some other

studies for our readers as well.

The enzyme preparations studied in Europe have

typically been formulations of trypsin, chymotrypsin, and

papain; there have also been studies of bromelain, an

enzyme derived from pineapple. Wobe-Mugos is the most commonly studied product

in cancer. It was formulated by

MUCOS Emulsions GmBH, Munich, Germany, which

also produced other enzyme products, such as Wobenzym,

widely used for inflammation and sports injuries in Europe.

The MUCOS group has since been purchased by Atrium

Innovations, Inc, Canada. A number of early studies sponsored

by MUCOS, not all of them published, are summarized

in a 1996 publication.1 Leipner and Saller reviewed

clinical studies of oral systemic enzymes in oncology in

2000,2 and they were allowed access to the MUCOS corporate

files to obtain details of some of these trials. A number

of the trials sponsored by MUCOS are in non-English

journals, and this review has made useful details of these

studies more accessible.

One of the characteristics of European evaluations

of enzyme therapy is a predominance of retrospective

designs. Enzyme therapy had become well established in

European cancer centers before systematic attempts to

evaluate its use were initiated. There is thus an effort

among interested researchers to examine existing clinical

data as a source for information regarding efficacy of the

enzyme preparations. This has led to the use of retrospective

study designs or, more specifically, retrolective

designs. In retrolective studies, data are extracted from

medical records of centers in which some patients used

enzymes (or other therapies of interest) and others did

not. Retrolective studies are essentially epidemiological,

retrospective parallel group designs. As discussed by

Beuth in this issue, these studies constitute level IIb evidence-

based medicine and, as such, are acceptable to

European Union nations as demonstrations of efficacy.

The major outcomes of most of these trials have concerned

side effects of chemotherapy and radiation treatment,

although some have also examined response and

survival outcomes. Among the older studies summarized

by Leipner and Saller, several concerned patients receiving

chemotherapy. A randomized study in lung cancer

patients, which was not statistically evaluated, employed

oral or rectal administration of enzymes and suggested

improved quality of life and reduced chemotherapy side

effects. An open study of gastric cancer patients observed

an increase in the ratio of T-lymphocytes to total lymphocytes

in patients receiving enzyme therapy when compared with those receiving

chemotherapy only. A post–marketing

surveillance study (another retrospective design, of course)

examined patients who had received hydrolytic enzymes

along with bleomycin. A major side effect of bleomycin is

pulmonary fibrosis. Because fibrosis is an inflammatory

reaction, it would not be surprising to see it suppressed by

enzymes that have anti-inflammatory properties. None of

the 58 patients reviewed in this study experienced pulmonary

toxicity. Data on response to chemotherapy are

not available in this study. A randomized, single-blind

study of ovarian cancer patients receiving chemotherapy

observed a more rapid normalization of liver enzymes in

the experimental group, but no differences in other common

laboratory analyses were evident. An unpublished

randomized, double-blind study in 60 colon cancer

patients, obtained from the MUCOS files, observed lower

levels of chemotherapy side effects and also suggested

fewer metastases and a trend toward longer survival. In

addition to this study, a later study by the same research

group is available. This retrolective cohort study of 1242

colorectal cancer patients receiving chemotherapy, with or

without enzyme therapy, showed a reduction in side

effects of medications and disease symptoms.3 More

recent trials are reviewed in this issue by Beuth.

The most interesting chemotherapy study reviewed by

Leipner and Saller, as well as by Beuth, is one conducted by

Sakalova and colleagues in multiple myeloma (plasmacytoma).

4 In this retrolective study, data were gathered on

patients with multiple myeloma. Some patients had received

enzyme treatment (Wobe-Mugos) along with chemotherapy

and others had not. The decision to use enzymes was made

in what can be characterized as a quasirandomized fashion,

according to the availability of enzyme medications at different

times but without reference to prognostic factors.

Kaplan–Meier and Cox regression analyses were performed.

Survival of patients with stage III multiple myeloma who

were treated with enzymes was 83 months, whereas that of

patients who did not receive enzymes was 47 months, a significant

difference. Sensitivity analysis of a variety of prognostic

covariates indicated that age, sex, and known risk

factors indicated no statistically significant differences in the

covariates between the 2 groups.

On the basis of this study, an application was submitted

to the US Food and Drug Administration, which resulted in

the designation of Wobe-Mugos as an Orphan Drug for

multiple myeloma. An initial Orphan Drug designation permits

further research on a drug for potential approval in the

US market, and a phase III trial was indeed begun for stage

II or III patients to receive Wobe-Mugos in combination

with chemotherapy.5 However, the trial was never completed,

apparently because of business disagreements

between the German and US companies involved. Thus,

Wobe-Mugos has never been submitted for actual approval

as an Orphan Drug and, consequently, does not have regulatory

status as a prescription drug in the United States.

Leipner and Saller review 3 early (1976-1992) trials of

enzyme therapy given with radiation, in addition to 2 trials

from the MUCOS files that were later published. A

post–marketing surveillance study of patients with lung

cancer receiving radiation observed that appearance of

metastases was lowered and radiographic abnormalities

were reduced in size among patients treated with enzyme

therapy. Gastrointestinal cancer patients undergoing radiotherapy

had a reduced duration of side effects with enzyme

treatment in a prospective randomized trial. A randomized

open trial in patients with oral cancers undergoing radiation

observed a lower incidence of mucosal necrosis.

Published radiotherapy trials broaden the evidence

base on enzymes and radiation. Two open randomized trials

observed reductions in side effects of radiation therapy

in head and neck cancers.6,7 An open randomized trial

in uterine cancer patients undergoing radiation indicated

a reduction in side effects.8 These trials and those in the

preceding paragraph, however, suffer from defects in trial

design, for example, lack of double-blinding. Two more

recent trials, both double-blind trials, did not find such

encouraging results. A double-blind randomized trial in

patients receiving pelvic radiation did not show any

reduction in side effects or treatment interruptions.9 A

2007 randomized, placebo-controlled trial failed to find

any effect of Wobe-Mugos in reduction of radiationinduced

mucositis in patients with head and neck cancer.

10 It is somewhat concerning that the double-blind

trials of enzyme therapy did not confirm the indications

of the previous, less well-designed trials of enzymes in

radiation therapy, although this cannot be taken as a final

judgment of the efficacy of enzyme therapies in general.

It is not clear from information available to me at this

time, for instance, whether dosing was similar in all the

trials or whether formulations of the product have

remained the same over the years.

An interesting direction for research is highlighted by

the work of Desser and colleagues on the effect of oral

enzyme therapy on transforming growth factor-β (TGF-β).11

Patients with rheumatoid arthritis, osteomyelitis, or herpes

zoster, some of whom had elevated TGF-β, were given oral

enzymes, as were a normal control group. No change in

serum TGF-β levels was observed in normal controls or

patients with normal TGF-β levels. However, TGF-β levels

declined significantly in patients with initially elevated

TGF-β levels.

TGF-β is associated with inflammatory conditions, as

in the example of bleomycin-induced fibrosis mentioned

above. Interestingly, TGF-β also plays a role in the very

recent publication on genomic analysis of pancreatic cancer.

12 This study found that large numbers of genes are

mutated or otherwise abnormal in pancreatic cancer

cells, such that each pancreatic tumor had nearly 60

abnormal genes. These genes, however, could be grouped

into 12 biochemical pathways that were considered highly

 

abnormal. One of these abnormal pathways was the TGF-

β signaling pathway. This study obviously has major implications

for multitargeted natural therapies, a topic that I

have discussed before.13 If enzyme therapies are able to

help normalize the TGF-β pathway, as this study hints,

they might play a role in such multitargeted therapy regimens.

The possibility certainly deserves investigation.

There remains the more immediate question of the usefulness

of enzyme therapies as adjuncts to conventional

treatment or as anticancer or chemopreventive agents.

Having observed cancer patients taking enzyme supplements

for several years, I am convinced that they do effect

a positive change in the internal biochemical environment.

Suppression of inflammation is particularly noticeable.

Under what circumstances they might be used most profitably

in the clinic remains an open question. Certainly the

contrasting results of the recent negative double-blind studies

on radiation therapy and the prior, positive less welldesigned

studies is instructive. However, the intriguing data

on TGF-β, and the equally interesting data discussed in the

quantitative studies of Wald, Elzer, and Beuth in this special

issue, as well as the interesting link Burleigh proposes to

cancer stem cell theory suggest a need for further welldesigned

research that encompass a phase I to phase III

model of study. Selection of what clinical outcomes would

be best studied should be linked to the mechanistic information

available on the various enzyme therapies rather

than solely on existing nonrandomized studies. It may also

be profitable to use enzymes in combination with other

therapies for a truly multitargeted approach to cancer.

Enzyme therapies are, as Beuth points out in this

issue, beginning to enter the realm of evidence-based

medicine with the recent studies he reports, and those

discussed in this editorial. But restricting our judgment

about the usefulness of enzyme therapy to the existing trials

may result in a limited and deceptive assessment of

their ultimate contribution to clinical medicine. There is

certainly a history of mechanistic theories about enzyme

activity that are not in keeping with current understandings

of cancer treatment. However, as recent work has

shown, including the articles in this special issue, there is

much more to be learned about oral enzyme therapy.

Enzyme therapies in the future may indeed have many

biologic and therapeutic roles for the cancer patient.