DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 67–2
Chemopreventive Agents Being Studied in Humans
CHEMOPREVENTIVE EXAMPLE NATURAL SOURCE CANCER CURRENT
CLASS COMPOUND OR TYPE OF DRUG TYPE(S) MECHANISM STATUS
Isothiocyanates Phenethyl Cruciferous Liver, lung, ↓CYP, ↑GSH, Phase 2 clinical
isothiocyanate vegetables breast, etc. ↑NQO1, trials
↑apoptosis
Synthetic drugs Oltipraz Anti-schistosomal Liver, lung ↓CYP, ↑GSH, Beneficial effects on
that modify drug ↑NQO1 biomarkers in phase
metabolism
2 clinical trials
Flavonoids and Catechin Green tea, red wine, Lung, ↓ROS, ↓CYP, Phase 2 clinical
other polyphenols berries, etc. cervical, etc. ↑GSH, ↑NQO1 trials
Other plant Curcumin Turmeric (curry) Colorectal, ↓ROS, ↓CYP, Phase 2 clinical
compounds pancreatic, ↑GSH, ↑NQO1 trials
etc.
Other plant Chlorophyllin All plants Liver Reaction with Beneficial effects on
compounds active biomarkers in phase
intermediates, 2 clinical trials
↓ROS, ↓CYP
Other antioxidants α-Tocopherol Food Prostate Antioxidant, anti- Phase 3 clinical
(vitamin E) inflammatory trials
Anti-hormonal Tamoxifen Adjuvant for breast Breast Inhibit ER in FDA-approved for
therapies cancer breast chemoprevention
NSAIDs (see Aspirin Anti-inflammatory Colorectal, Inhibit PG Phase 3 trials
chapter 34) drugs etc. formation
COX-2 selective Celecoxib Anti-inflammatory Colorectal, Inhibit PG Phase 3 trial found ↓cancer
inhibitors (see drugs etc. formation but unacceptable side
Chapter 34)
effects for prevention
CYP, cytochrome P450; GSH, glutathione; NQO1, quinone reductase; ROS, reactive oxygen species; ERα, estrogen receptor-; FDA, U.S. Food and
Drug Administration; NSAIDs, nonsteroidal anti-inflammatory drugs; COX-2, cyclooxygenase-2; PG, prostaglandin.
are approved drugs to prevent carcinogenesis due to
endogenous estrogen (tamoxifen and raloxifene)
and viruses (hepatitis B and human papillomavirus
vaccines).
Chemopreventive agents interfere with the
processes of initiation and promotion (Figure 67–2).
One mechanism of anti-initiation is prevention of carcinogen
activation. Isothiocyanates and similar compounds
inhibit CYPs involved in activating many
carcinogens and also upregulate genes controlled by the
antioxidant response element (ARE); the ARE-responsive
group includes -glutamylcysteine synthase light chain
(the gene responsible for the rate-determining step in
GSH synthesis) and quinone reductase (NQO1).
Increased expression of ARE-regulated genes is predicted
to increase the detoxification of proximate carcinogens.
Isothiocyanates also stimulate apoptosis of
p53-deficient cells via the formation of cytotoxic DNA
adducts. Compounds that act as antioxidants may provide
protection because many carcinogens work through
the generation of ROS. Some compounds simultaneously
prevent carcinogen activation and act as antioxidants.
For example, flavonoids and other polyphenols
found in a wide variety of plants are potent antioxidants
that inhibit CYPs and induce expression of ARE-regulated
genes. Chlorophyll and other compounds can protect
against carcinogens by binding to or reacting with
carcinogens or their metabolites and prevent them from
reaching their molecular target.
Inflammation is a potential target for chemoprevention
through interference with promotion. The
COX-2 inhibitor celecoxib (described in Chapter 34)
has been tested in phase 3 studies that demonstrated
efficacy at reducing the risk of colorectal cancer.
However, this benefit was offset by an increased risk of
death due to cardiovascular events, forcing the early