Cancer chemopreventionBMJ 2002; 324 doi: https://doi.org/10.1136/bmj.324.7339.714 (Published 23 March 2002) Cite this as: BMJ 2002;324:714
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EDITOR-In his clinical review,1 Peter Greenwald recommends primary
health care doctors to inform patients (with a view to recruitment in
clinical trials) of the promise shown by putative anticancer
chemopreventive agents. However, clinical trials have repeatedly
encountered the difficulty of translating the experimentally revealed
anticancer properties of molecular agents into a human setting.
A coherent biochemical explanation does exist to explain this impasse. The
original rationales for molecular chemoprevention strategies all had a
fundamental flaw: they failed to take account of the dual effects that all
anti-initiation or anti-promotion/progression strategies inevitably exert.
For example, anti-initiation strategies try to harness a molecule's
experimentally demonstrated abilities to inhibit carcinogen bioactivation
or enhance carcinogen detoxification. Thus, a natural chemical (e.g.
glucoraphanin/sulphoraphane from broccoli) may be administered to induce
phase-II enzymes capable of detoxifying carcinogens. Unfortunately, the
same enzymes also catalyse formation of active carcinogen metabolites.
Several phase-II enzymes (e.g. glutathione S-transferase, UDP-glucuronyl
transferase, acetyl transferase) are actually responsible for the
bioactivation of many carcinogens2. Thus, enhancement of phase-II enzymes
exerts a dual effect, enhancing detoxification of some chemicals, but
aggravating the carcinogenic potential of others (and we are all exposed
to a myriad of compounds every day).
Similar considerations apply for the specular rationales of phase-I enzyme
inhibition strategies, including those involving substances derived from
green tea or garlic (the putative protective effects of which have been
scaled down by a recent epidemiological meta-analysis3). In addition to
their dual activating/detoxifying nature,2 phase-I enzymes (cytochrome
P450 superfamily) are also involved in numerous endogenous reactions and
physiological functions (another reason for caution!).
phenethylisothiocyanate - the subject of an ongoing phase-I prevention
trial - is actually genotoxic.4 The issue is further complicated by the
existence of multiple genetic polymorphisms that give rise to high- or low
-metaboliser phenotypes (to each phase-I or -II enzyme) within the
population. The dual nature of metabolic polymorphisms can compound risks
linked to the chronic exposure inherent to chemoprevention.
Protective strategies involving antioxidants can invariably be subjected
to a similar analysis. For example, we have conclusively described the
biochemical mechanism determining the ambiguous effects of ß carotene5
(explaining the increased incidence of lung cancer found in cigarette
smokers who entered clinical trials). The unfortunate ß-carotene
experience underlines the importance of promoting a healthy diet rather
than molecularly based pills. A message that primary health care doctors
can safely give their patients is that regular consumption of fruit and
vegetables really is preventive.
Andrea Sapone Associate Professor
Donatella Canistro Assistant Professor
Ersilia D'Amico Assistant Professor
Gian Luigi Biagi Full Professor
Giorgio Cantelli-Forti Full Professor
Moreno Paolini Full Professor
Alma Mater Studiorum-University of Bologna, Department of Pharmacology,
Via Irnerio, 48-40126 Bologna, Italy.
1. Greenwald P. Cancer chemoprevention. BMJ 2002; 324: 714-18. (23
2. Nestle M. Broccoli sprouts as inducers of carcinogen-detoxifying
enzyme systems: clinical, dietary, and policy implications. Proc Natl Acad
Sci U S A 1997; 94: 11149-51.
3. Fleischauer AT, Poole C, Arab L. Garlic consumption and cancer
prevention: meta-analyses of colorectal and stomach cancer. Am J Clin Nutr
2000; 72: 1047-52.
4. Musk SR, Smith TK, Johnson IT. On the cytotoxicity and genotoxicity of
allyl and phenethyl isothiocyanates and their parent glucosinolates
sinigrin and gluconasturtiin. Mutat Res 1995; 348: 19-23.
5. Paolini M, Cantelli-Forti G, Perocco P, Pedulli GF, Abdel-Rahman SZ,
Legator MS. Co-carcinogenic effect of beta-carotene. Nature. 1999, 398,
Acknowledgement. We are grateful to Robin M.T. Cooke for scientific
Competing interests: No competing interests
The Greenwald paper presents a remarkable summary of the multiple
origins of human cancer which suggests that both a preventive or a cure
for cancer may require a compound with synergistic potential. Some
interventions from a single or multiple drug or dietary supplement do
present a chemopreventative action. The structured path for the
development of diet-derived constituents as cancer chemopreventive agents
is synergistic not necessarily from isolating a single compound. After
reviewing each single or multiple chemopreventative agents currently
selected for Phase I, II, or III studies listed in table 1, one may
conclude the mechanisms for cancer are multiple by target organ in spite
of some agents having been selected for application in more than one
Multiple factors, known and unknown, contribute to human
cancer. Gescher et al., concluded, "The investigation of dietary
constituents should follow a structured design, incorporating parallel
preclinical studies of the food source and the isolated agent in terms of
efficacy, toxicity, biological mechanisms, and pharmacokinetics. Either
the food source or the isolated agent should be selected for further
development on the basis of dose-efficacy and toxicity data. Pilot
clinical trials on the pharmacokinetics and mechanism-based markers of
efficacy of the selected intervention should precede phase I-III
development in suitable populations."  Giovannucci et al.,
concluded, "Frequent consumption of tomato products is associated with a
lower risk of prostate cancer. The magnitude of the association was
moderate enough that it could be missed in a small study or one with
substantial errors in measurement or based on a single dietary
assessment."  Zhang et al., advised what previously others have
repeatedly reported in the literature on reducing cancer risk through
dietary interventions, "Ovarian cancer risk declined with increasing
consumption of vegetables and fruits but vice versa with high intakes of
animal fat and salted vegetables." 
The concept of how long what
combinate diet reduces the risk of cancer is neither new nor is the time
to test such a hypothesis lengthy. The results from the World War II
Norway study suggest that residential history may influence the risk of
breast cancer. Breast cancer incidence was observed to decline for the
post-war cohorts, which is discussed in relation to a diet. Reduction in
energy intake and specific resulted in decreased incidence in breast
cancer from the coerced influence of dietary intervention during World War
II.  This may call for consideration of a specific dietary intervention
trial examined over a 3-5 year period for determining the synergistic
influence of a multiple of constituents presented in tact from whole food
Why then is Phase Trial examination spent on one, two, or three
substances, when it may be a complex number of synergistic food substrates
that indeed reduce the risk of cancer? The literature is full of
suggestions for by which a whole foods menu may reduce the risk of cancer
and the specific dietary interventions or toxins which increase it. Why
not isolate for 3-5 years, a high-risk population in twain, one with
dietary modifications known to reduce the risk of cancer and the other
without dietary restrictions?
Bill Misner Ph.D.
The author no competing interests in this subject area.
-Gescher A J, Sharma R A, Steward W P. Cancer chemoprevention by
dietary constituents: a tale of failure and promise. Lancet Oncol. 2001
-Giovannucci E, Rimm EB, Liu Y, Stampfer MJ, Willett WC. A
prospective study of tomato products, lycopene, and prostate cancer risk.
J Natl Cancer Inst. 2002 Mar 6;94(5):391-8.
-Zhang M, Yang ZY, Binns CW, Lee AH. Diet and ovarian cancer risk:
a case--control study in China. Br J Cancer. 2002 Mar 4;86(5):712-7.
-Robsahm TE, Tretli S. Breast cancer incidence in food- vs non-
food-producing areas in Norway: possible beneficial effects of World War
II. Br J Cancer. 2002 Feb 1;86(3):362-6.
Competing interests: No competing interests