Enzymes and Cancer

[Guest guest]

Enzymes and Cancer: A Look Toward the Past as We Move Forward

I. Block, MD - Dec. 2008 - Editorial Opinion

Integr Cancer Ther. 2008 Dec;7(4):223-5. No abstract available.

PMID: 19116218 [PubMed - indexed for MEDLINE]

[Excerpts from the article]

....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

2002 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 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.

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 well-designed

research that encompass a phase I to phase III model of study.

....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.