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Cancer Chemoprevention: Hormones, Nonclassic Antioxidant Natural Agents, NSAIDs, and Other Agents

Cancer Chemoprevention: Hormones, Nonclassic Antioxidant Natural Agents, NSAIDs, and Other Agents

ABSTRACT: This two-part series provides an up-to-date summary of the various chemopreventive agents currently in development and testing. Part 1, published in last month’s issue, focused on the retinoids, such as all-trans-retinoic acid (ATRA [Vesanoid]), 9-cisretinoic acid (9cRA), and isotretinoin (Accutane), and the carotenoids, such as beta-carotene and lycopene, and other “classic” antioxidants, such as vitamins E and C and selenium. This second part centers on hormonally mediated chemopreventives, such as tamoxifen (Nolvadex), finasteride (Proscar), oral contraceptives, and dehydroepiandrosterone (DHEA). A number of these agents have site-specific mechanisms of action and will be discussed as such. Also discussed in part 2 are various nonclassic antioxidant natural agents, including calcium, the polyphenols, the isothiocyanates, and genistein; nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin and sulindac; difluoromethylornithine (DFMO [Eflornithine]); oltipraz; and N-acetylcysteine. [ONCOLOGY 12(12):1787-1800, 1998]

Introduction

Chemoprevention aims to directly modulate
specific steps in the carcinogenic process, block mutagenic
carcinogens, prevent DNA damage by free radicals, suppress epithelial
cell hyperproliferation, and/or modulate epithelial cell
differentiation and apoptosis (programmed cell death). Numerous
chemopreventive agents are in various stages of development and testing.

Part 1 of this two-part series, published in last month’s issue,
focused on the retinoids and carotenoids and other “classic”
antioxidants. This second part will explore hormonally mediated
chemopreventive agents, such as tamoxifen (Nolvadex), finasteride
(Proscar), oral contraceptives, and dehydroepiandrosterone (DHEA). A
number of these agents have site-specific mechanisms of action and
will be discussed as such. Part 2 will also discuss various
nonclassic antioxidant natural agents, including calcium, the
polyphenols, the isothiocyanates, and genistein, as well as the
nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin and
sulindac; difluromethylornithine (DFMO [Eflornithine]); oltipraz; and
N-acetylcysteine. The proposed mechanisms of action of the various
chemopreventive agents currently being investigated clinically and
the specific disease sites in which they are being studied are listed
in Table 1 and Table
2
, respectively.

Hormones

A substantial body of epidemiologic, experimental, and clinical
evidence indicates that hormones play an important role in the
etiology of several human cancers.[112] Neoplasia of tissues that are
responsive to hormones currently account for more than 40% of all
newly diagnosed female cancers and 25% of all newly diagnosed male
cancers in the United States.[112]

Since Bittner’s initial experimental work with estrogens and
mammary cancer in mice, the hormone responsiveness of carcinomas has
been studied in numerous disease sites, including the breast,
endometrium, prostate, ovary, thyroid, bone, and testis.[112,113] Of
note, the activity of retinoids is governed by their interactions
with receptors (retinoic acid receptors [RARs] and retinoid X
receptors [RXRs]) that belong to the steroid receptor family.[31-35]

A key element of this hypothesis is that neoplasia results from
hormonal stimulation of the target organ, accelerates cell division,
and increases the likelihood that random genetic errors accumulate
and lead to a neoplastic phenotype.[114,115] Epidemiologic findings
are consistent with this multistep genetic damage model of
carcinogenesis. Whereas the incidence of most
non–hormone-dependent adult cancers rises continuously with age,
investigators have noted that the age-incidence curves of
endometrial, ovarian, and breast cancers rise with age at a rate
similar to other cancers until menopause, at which time, there is a
distinct slowing of the rate of rise.

The rise in incidence of endometrial, ovarian, and breast cancers
prior to menopause is thought to result from sex steroid–driven
cellular proliferation. Because genetic damage that accumulated
during the premenopausal period is not lost after menopause, a
continued increase in overall incidence is seen; however, the rate of
rise decreases, presumably because cellular proliferation
substantially decreases.[115,116]

The effects of the steroid hormones differ by organ site. The mitotic
rate of the endometrial cells lining the uterus is stimulated by
estrogen and inhibited by progestins. Breast tissue undergoes cell
proliferation and loss in concert with the ovaries’ cyclic
production of estrogen and progesterone.[115] The role of estrogen as
a primary stimulant of breast cell proliferation, which contributes
to the development of breast cancer, is supported by epidemiologic
studies, animal studies, and clinical trials.[112,114] In addition,
the simultaneous presence of progesterone probably further increases
the rate of breast cell proliferation.[112]

Numerous epidemiologic findings support a role for gonadotropin
exposure and ovulation in the pathogenesis of ovarian cancer. For
example, the decreased risk of ovarian cancer seen with multiple
pregnancies and prolonged lactation is proposed to be related to
their direct suppressive effects on central gonadotropin release or
the consequent inhibition of ovulation.[117]

Because of the evidence that endogenous hormones directly affect the
risk of several cancers, chemoprevention through the manipulation of
steroid hormones are an important focus of cancer prevention. The
occurrence of key etiologic events during the premenopausal period
supports the use of prevention strategies at this time. Under this
model, prevention of cancer can be achieved by reducing the rate of
cell division during proliferative periods in the relevant epithelial tissue.[115,118]

For example, oral contraceptives and progesterone in hormone
replacement therapy have an antiproliferative, protective effect on
the endometrium. The antiestrogenic effect of tamoxifen (Nolvadex)
and related compounds in breast tissue and the antiandrogenic effects
of finasteride (Proscar) on prostate tissue are classic examples of
“antihormone” mechanisms. In addition, new agents, eg,
dehydroepiandrosterone (DHEA) and its nonandrogenic structural
analogs, are being evaluated for potential chemo- preventive activity.

Oral Contraceptives

Combination oral contraceptives include both estrogen and progestin
components and, through gonadotropin suppression, inhibit ovulation
to achieve many of their benefits.[119] The decrease in ovarian
cancer that has been observed with oral contraceptive use is
postulated to stem from either inhibition of ovulation or suppression
of gonadotropins.

Hankinson et al reviewed 20 studies, including case-control as well
as prospective cohort studies, and concluded that the summary
relative risk of ovarian cancer associated with any use of
combination oral contraceptives is 0.64 (95% confidence interval
[CI], 0.57 to 0.73). They estimated that the risk of ovarian cancer
decreases 11% with each year of oral contraceptive use.[119] This
monotonic dose-response effect appears to be independent of
parity.[118] In addition, the protective effect afforded by oral
contraceptive use appears to persist for 10 or more years after their discontinuation.

Whereas the protective effects of oral contraceptives against ovarian
cancer risk among the general population are well accepted, the
possible benefits among high-risk groups are now being explored. A
recent case-control study (involving 207 women with hereditary
ovarian cancer and 161 of their sisters as controls) has suggested
that oral contraceptives may reduce the risk of ovarian cancer in
women carrying BRCA1 or BRCA2 mutations, resulting in an odds ratio
of 0.5 (95% CI, 0.3 to 0.9) for BRCA1 mutation carriers and an odds
ratio of 0.4 (95% CI, 0.2 to 1.1) for BRCA2 mutation carriers, as
compared with the control group.[120] Questions have been raised,
however, regarding: (1) potential biases in the study and (2) a
possible increase in the risk of breast cancer with oral
contraceptive use in women with a hereditary predisposition to this malignancy.[121,122]

Oral contraceptives minimize endometrial mitotic activity by limiting
periods of exposure to estrogen unopposed by progestins. This leads
to a decreased lifetime risk of endometrial cancer. Overall,
case-control as well as prospective cohort studies show that
endometrial cancer risk among oral contraceptive users is decreased
by 40% to 50% relative to nonusers. The preventive effect lasts at
least 15 years after the individual stops using oral
contraceptives.[118,120-125] The protective effects of oral
contraceptives may be modified by nulliparity or subsequent unopposed
estrogen use.[118] Oral contraceptive use has also been suggested to
protect against the development of malignant mixed müllerian
tumors of the uterus.[126]

Although progesterone has inhibitory effects on the endometrium,
evidence is accumulating that it increases the rate of cell division
in breast tissue beyond that of estrogen alone.[118] Because the
combined presence of estrogen and progesterone in oral contraceptives
has stimulatory effects on breast cell proliferation, a protective
effect against breast cancer is not anticipated, nor has such an
effect been seen.[116,118]

Indeed, some studies have demonstrated a slight increase in the risk
of breast cancer after oral contraceptive use; however, the risk does
not appear to persist for more than 10 years after use.[118,127]
Other studies have shown no increased risk of breast cancer with use
of combination oral contraceptive formulations.[128,129]

Results from the Nurses’ Health Study suggest that oral
contraceptive use protects against the development of colorectal
cancer. In this prospectively followed cohort, women who used oral
contraceptives for 96 months had a 40% lower risk of developing
colorectal cancer (relative risk [RR], 0.60; 95% CI, 0.40 to 0.89
than those who never used oral contraceptives.[130] An Italian
case-control study found that ever-use of oral contraceptive was
inversely associated with colon cancer (odds ratio, 0.63; 95% CI,
0.45 to 0.87) and rectal cancer (odds ratio, 0.66; 95% CI, 0.43 to 1.01).[131]

Hormone Replacement Therapy

Hormone replacement therapy is advocated for both symptomatic and
preventive health benefits unrelated to the development of
malignancy. Since use of this therapy has become widespread,
potential benefits, including the prevention of colonic malignancies,
have been studied. Researchers for the Nurses’ Health Study have
observed a decreased risk of colorectal cancer among current users of
hormone replacement therapy (relative risk, 0.65; 95% CI, 0.50 to
0.83). However the apparent reduction in risk substantially
diminished upon cessation of therapy.[132] Hormone use was also
inversely associated with large (³ 1
cm) colorectal adenomas but not small ones.

A case-control study conducted by Italian researchers supported these
findings. This study suggested an inverse relationship between
ever-use of hormone replacement therapy and cancer of the colon (odds
ratio, 0.64; 95% CI, 0.46 to 0.88) and cancer of the rectum (odds
ratio, 0.46; 95% CI, 0.296 to 0.72). Increasing duration of use was
related to decreasing risk of colon and rectal cancers (P value for
the trend = .01).[133] In addition, researchers at the University of
California, Los Angeles, have suggested a decreased risk of
colorectal adenomatous polyps among recent users of hormone
replacement therapy (odds ratio, 0.57; 95% CI, 0.35 to 0.94) with
increasing duration of use.[134]

Consistent with the stimulatory effect of estrogen on the endometrial
lining, the use of estrogen alone as postmenopausal hormone
replacement therapy has shown a strong association with an increased
incidence of endometrial cancer.[135,136] Recent work con-firms these
findings, suggesting that even unopposed conjugated estrogen doses as
low as 0.3 mg may be associated with an increased risk of endometrial
cancer (risk relative to that of no replacement therapy, 5.4; 95% CI,
2.3 to 13), with risk increasing with increasing duration of
use.[137] How-ever, the addition of progestin to estrogen-replacement
regimens inhibits endometrial hyperplasia and may reduce the
estrogen-enhanced risk of endometrial cancer.[138]

The effect of hormone replacement therapy on breast cancer risk
remains unclear; variation in regimens and dosages, as well as in
study design, are thought to contribute to the inconsistent results
reported in the literature. A meta-analysis has shown no increased
risk of breast cancer among women who had ever used hormone
replacement therapy; in contrast, current users did demonstrate an
increase in risk (RR, 1.40; 95% CI, 1.20 to 1.63).[139]

The Nurses’ Health Study showed an increased risk of breast
cancer among women currently using unopposed estrogen (RR, 1.32; 95%
CI, 1.14 to 1.54) or a combined estrogen- and progesterone-containing
regimen (RR, 1.41; 95% CI, 1.15 to 1.74), as compared with those who
had never received hormone replacement. This increased risk was
limited largely to women who had used hormone therapy for ³ 5
years. For women who last used hormone replacement 5 or more years in
the past, the relative risk was 0.95 (95% CI, 0.74 to 1.25).[118,140,141]

A population-based case-control study conducted in Washington state
found that the use of an estrogen-progestin combination for hormone
replacement was not associated with an increased risk of breast
cancer in middle-aged women.[142] Also, a recent meta-analysis of 31
studies showed no increased risk of breast cancer among women who had
ever used hormone replacement therapy.[129] Until more definitive
studies have been completed, the potential risks and benefits for an
individual patient must be weighed when deciding whether or not to
use hormone replacement therapy.

A recent meta-analysis raises the possibility that hormone
replacement therapy may be associated with an increased risk of
developing epithelial ovarian cancer. In this analysis, ever-use of
hormone replacement therapy was associated with an odds ratio of 1.15
(95% confidence interval, 1.05 to 1.27).[143] In contrast, a number
of studies failed to demonstrate a significant association between
the use of hormone replacement and the risk of developing epithelial
ovarian cancer.[144]

Luteinizing Hormone–Releasing Hormone Agonists

The development of approaches that decrease exposure of the breast to
the cyclic ovarian sex steroids of the premenopausal period should
reduce breast cancer incidence. Among premenopausal women, a proposed
strategy for retaining the benefits of combination oral
contraceptives on endometrial and ovarian cancer while decreasing the
risk of breast cancer is the use of luteinizing hormone–releasing
hormone (LHRH) agonists.[115,118] Clinically, these drugs suppress
gonadotropin secretion, leading to an inhibition of ovulation and
ovarian steroidogenesis.[145]

Spicer, Pike, and colleagues have reported on a pilot study of a
contraceptive regimen that utilizes monthly injections of leuprolide
acetate depot (Lupron), an LHRH agonist, among patients with a
fivefold or greater risk of breast cancer.[115] The adverse side
effects of elimination of ovarian steroid production include hot
flashes, bone loss, and an increased risk for cardiovascular disease
associated with an alteration in cholesterol levels. To compensate
for these effects, patients in this study received low-dose estrogen
(ie, 0.625 mg of oral conjugated estrogens) for 6 out of every 7
days. Patients also were given intermittent progestin, in the form of
medroxyprogesterone acetate (10 mg PO for 13 days of every fourth
28-day cycle) to avoid any increased risk of endometrial stimulation
and resulting neoplasia.

Use of this contraceptive regimen for 10 years has been estimated to
reduce lifetime breast cancer risk by 50%. In addition, the
protection against ovarian cancer is projected to be identical to or
greater than that afforded by combination oral contraceptives.
Protection against endometrial cancer may also be seen, although not
with the same magnitude as is seen with use of combination oral contraceptives.[115,116]

In the pilot study, 21 patients at fivefold or greater risk of breast
cancer were randomized to the contraceptive regimen (14 patients) or
a placebo (7 patients). At the end of the first year, symptom
questionnaires revealed fewer complaints in the treated group,
because of the elimination of premenstrual syndrome–related
symptoms. Persistent hypoestrogenic effects of hot flashes and
vaginal dryness were eliminated with an increase in the estrogen dose
to 0.9 mg. A beneficial increase in high-density lipoprotein (HDL)
cholesterol was also noted in treated patients.

Loss of bone mineral density in the subjects receiving the
contraceptive regimen was addressed by the addition of a low dose of
an androgen, similar to that produced by normally functioning
ovaries. Preliminary results of this study suggest that no bone
mineral density loss occurs with this modified regimen.

Finally, at the end of the first year, a substantial reduction in
mammographic parenchymal density was seen in the contraceptive group,
as measured by both expert examination and a computer-based method.
This finding suggests reduced breast cell proliferation, which is
hypothesized to lead to a reduction in long-term breast cancer
risk.[115] Long-term follow-up of this study cohort is still pending.[115,146]

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