Oltipraz looks kind of interesting. The first article below was
recently published (Fox Chase), but the interest in this apparently
goes back a number of years. It is thought to work in both primary
liver and colon cancers, which is kind of odd as these two cancers
are quite different. This stuff is apparently available as a
prescription drug, so your oncologist could prescribe it if he/she
wanted to. The article says:

"A series of experiments in laboratory rodents then demonstrated that
Oltipraz is an anti-angiogenic agent comparable in potency to two
drugs currently being tested in clinical trials. One is SU 5416, now
being tested at Fox Chase for patients with melanoma or sarcoma."

This is really an amazing statement - SU5416 is currently in clinical
trials for colon cancer!!!

*********************************************************************
http://www.sciencedaily.com/releases/2002/01/020107075155.htm
Source: Fox Chase Cancer Center (http://www.fccc.edu/)


Date: Posted 1/7/2002

Cancer-Fighting Drug May Work In Prevention And Treatment

PHILADELPHIA — The ABCs of fighting cancer these days include two big
words that describe exciting basic concepts. One is anti-
angiogenesis, a strategy to stop or prevent the growth of blood
vessels needed to nourish a tumor and allow it to spread. Another
approach is chemoprevention—using medication to halt, delay or
reverse the development of cancer.
According to new prevention research by Fox Chase Cancer Center cell
biologist Margie Clapper, Ph.D., of Harleysville, Pa., and colleagues
at Cephalon Inc. in West Chester, Pa., the drug Oltipraz holds the
potential to achieve both goals. A report on the ongoing studies
appears in the January 2002 issue of Clinical Cancer Research. Co-
authors include Dr. Clapper and Bruce Ruggeri, Ph.D., of Cephalon's
Division of Oncology.

Clapper has been studying Oltipraz for more than a decade,
concentrating on its ability to raise blood levels of protective
"detoxification" enzymes that help ward off cancer. These enzymes
resemble antioxidant compounds in broccoli, cabbage and similar
vegetables.

In early clinical studies, Clapper worked with Fox Chase medical
oncologist Christine Szarka, M.D., to see how well Oltipraz increased
protective enzymes among people at high risk of colon cancer. For
comparison, some trial participants took dried broccoli tablets
instead of the drug. Oltipraz surpassed the dietary approach by a
significant measure with few or no side effects. A later study used
Oltipraz for people at risk of lung cancer.

Most recently, with support from the Cancer Research Foundation of
America, Clapper has focused on individuals with ulcerative colitis,
which increases the risk of colon or rectal cancer by 10 times. In
studies with laboratory mice, Oltipraz has proved to inhibit colitis-
associated colon cancer. This research will form a basis for
designing the first trial of a preventive treatment for people with
this disease.

The drug's ability to boost protective enzymes and decrease DNA
damage from cancer-causing agents was thought to explain its success
in halting the development and spread of a variety of tumors in mice
and rats. But in evaluating this laboratory work, Clapper says,
"we've seen tumor growth halted without an elevation of
detoxification enzymes."

That observation led the researchers to look at Oltipraz' anti-
angiogenesis ability. They started with studies using microarray
technology, which can simultaneously analyze the activity of
thousands of genes. This revealed that Oltipraz may have the ability
to affect blood vessel growth.

A series of experiments in laboratory rodents then demonstrated that
Oltipraz is an anti-angiogenic agent comparable in potency to two
drugs currently being tested in clinical trials. One is SU 5416, now
being tested at Fox Chase for patients with melanoma or sarcoma.

"Based on our work with animal tumor models, Oltipraz may not only be
a cancer prevention agent but may also be effective in treating
patients with advanced stage cancers and metastases," Clapper
explains. "We're still doing pre-clinical testing," she emphasized.

Cephalon is screening the drug in mice with several kinds of tumors
to gain additional data about the most appropriate cancer sites for a
future treatment trial of Oltipraz in humans. In addition to support
from Cephalon and the Cancer Research Foundation of America, a
National Institutes of Health grant and Commonwealth of Pennsylvania
appropriation are helping fund research on Oltipraz' anti-angiogenic
activity.

Although still in clinical development for its broad-based
chemoprevention activity, Oltipraz could turn out to be a doubly
potent weapon against cancer—either helping prevent it in high-risk
people or shrinking cancerous tumors by depriving them of their blood
supply.

This wouldn't be the first time Oltipraz showed promise beyond its
established use, however. It was first approved as an anti-
schistosomal treatment, to eliminate parasites known as blood flukes.
In the same way, research aimed specifically at preventing cancer may
serendipitously yield new approaches to cancer treatment as well.



Fox Chase Cancer Center, one of the nation's first comprehensive
cancer centers designated by the National Cancer Institute in 1974,
conducts basic and clinical research; programs of prevention,
detection and treatment of cancer; and community outreach. For more
information about Fox Chase activities, visit the Center's web site
at http://www.fccc.edu or call 1-888-FOX CHASE
********************************************************************


http://www.statepi.jhsph.edu/olti/oltipraz.html Chemoprevention
Trials

http://www.acetylcysteine.org/oltipraz.htm Background material

http://www.niehs.nih.gov/dert/profiles/hilites/2001/ethiones.htm
University of Kentucky



**********************************************************************


http://www.globaltechnoscan.com/11thApr-17thApr01/cancer.htm
Stop cancer before it starts

HALF of all cancers may soon be prevented simply by taking a pill
once a week, say researchers working on drugs that activate our
body's natural defence mechanisms.

One such drug, called oltipraz, is already being tested. Developed
and approved for treating schistosomiasis, oltipraz was found to
stimulate the body to make an enzyme called glutathione S-
transferase. GST neutralises carcinogens such as benzene, preventing
them damaging DNA and allowing the body to get rid of the by-
products. Tests in animals have shown it can prevent cancer.

Toxicologist Thomas Kensler of Johns Hopkins University in Maryland
is carrying out trials of oltipraz in China, where as many as 1 in 10
adults die from liver cancer caused mainly by a chemical called
aflatoxin, which is found in moulds growing on rice and cereal
grains. Kensler gave oltipraz once a week for two months to
volunteers in
Qidong.

They excreted over twice as much neutralised aflatoxin in their urine
as volunteers given a placebo, he told a meeting in San Diego last
month. "GST was boosted in these people," says Kensler. "The
carcinogen interacts with GST rather than with their DNA." Kensler is
now analysing the results of a longer study. If the results are good,
trials will take place over many years to see if oltipraz really
reduces cases of liver cancer.

GST and related enzymes detoxify a broad range of carcinogens, so the
approach should protect against other types of cancer too. Raymond
Bergan at Northwestern University in Illinois is now enlisting
volunteers for a trial to investigate whether oltipraz can protect
smokers against lung cancer. People smoking more than one pack per day
will take either a placebo or an oltipraz pill weekly for 3 months,
to see if the drug can alter the level of carcinogens in their lungs.

Clive Bates of the British anti-smoking group ASH fears the drug will
give smokers an excuse not to quit. But Bergan argues the drug would
help those who can't kick the habit. "What we're looking to do is
decrease the side effects for people who can't quit," he says.

High-risk groups will be the first to benefit from such
"chemoprotective" drugs, but the ultimate aim of researchers is to
find ways to lower cancer risk for everyone. "The cancer problem
can't be solved by simply devising treatments [for people who've
already got it]," says pharmacologist Paul Talalay of Johns Hopkins
University,
who studies how enzymes such as GST work.

In the immediate future, the best general approach is likely to be a
dietary one. Chemicals that boost the production of enzymes such as
GST are present in vegetables such as broccoli and Brussels sprouts,
so Talalay and others are developing vegetables that contain larger
quantities. "Fruit and vegetables aren't just good for you because of
vitamin C. It's much more profound than that," says Raymond Wolf, a
researcher for the Imperial Cancer Research Fund at Dundee
University. "A key difference between drugs like oltipraz and
antioxidants such as vitamin C is that with agents that induce gene
expression, the effects are long-lasting."

Yongping Bao of the Institute of Food Research in Norwich predicts
that in three years' time we will be able to use chemicals isolated
from vegetables in pills or to fortify food. Changing our diet, he
says, may prevent up to half of all cancers. "If we can isolate these
chemicals, there is the potential for a huge impact on cancer,"
agrees Wolf.

He also raises the tantalising possibility that protecting our DNA
from damaging chemicals will not only prevent cancer but also slow
the ageing process. "In animals, you can keep switching on these
enzymes for life, and the only side effect is increased longevity,"
Wolf says.

Author: Joanna Marchant

New Scientist issue: 7th April 2001

Contact: Claire Bowles
claire.bowles@...
44 207 331 2751
New Scientist


**********************************************************************
http://www.newswise.com/articles/2001/3/BROCCO.JHM.html
Johns Hopkins Medical Institutions
13-Mar-01


Powerful, Natural Anti-Cancer System Exists
Library: MED
Keywords: CANCER BROCCOLI ENZYME PHASE II MICE
Description: Scientists at Johns Hopkins and Tsukuba University in
Japan have confirmed the existence of a long-suspected natural system
the body uses to block the cancer-causing effects of toxic chemicals
in food and the environment. (PNAS)



March 9, 2001

Johns Hopkins Medical Institutions' news releases are available on an
EMBARGOED basis on Newswise at http://www.newswise.com and from the
Office of Communications and Public Affairs' direct e-mail news
release service. To enroll, call 410-955-4288 or send e-mail to
bsimpkins@....

On a POST-EMBARGOED basis find them at http://www.hopkinsmedicine.org

*********************************
EMBARGOED FOR RELEASE UNTIL MONDAY, MARCH 12 AT 5 P.M., EST
*********************************

STUDIES SHOW POWERFUL NATURAL ANTI-CANCER SYSTEM EXISTS
GOAL NOW: FINE-TUNE IT

Scientists at Johns Hopkins and Tsukuba University in Japan have
confirmed the existence of a long-suspected natural system the body
uses to block the cancer-causing effects of toxic chemicals in food
and the environment.

The system hinges on a sharp boost in protective enzymes, called
phase II enzymes, which can dispose of toxic chemicals. The enzymes
effectively neutralize toxins' ability to damage DNA and trigger
cancer, the researchers say.

In two studies appearing in the current Proceedings of the National
Academy of Sciences, they've not only demonstrated the fundamental
workings of the system, but have also pinpointed the key "switch"
that regulates it. "We've gained long-awaited proof of a basic
mechanism that can reduce the risk of cancer," says molecular
pharmacologist and team member Paul Talalay, M.D.

Scientists already know that natural substances in plants, such as
the sulforaphane in broccoli, as well as some man-made chemicals, can
tap into this system -- that they're somehow "chemoprotective" -- but
the route hasn't been clear. The new work, a result of 20 years'
research, "confirms that raising the levels of phase II enzymes can
offer a highly effective way to achieve protection against
carcinogenesis," says Talalay. "We always had faith," he adds; "Now,
in our animal studies, we have a direct demonstration."

"Our precise understanding of this system should make it fairly easy
to design drugs that can fine-tune it," says team leader Thomas W.
Kensler, Ph.D., a Hopkins toxicologist who's now overseeing early
clinical trials of one such drug in China. "We have evidence that we
can increase the system's levels of protection in people," he says,
"and are planning long-term studies that would reveal any lowered
incidence of cancer."

In the study, the researchers focused on strategies cells use to
control activity of the phase II enzymes. "The levels of these
enzymes are tightly controlled by the cellular equivalent of a dimmer
switch," says Kensler. The scientists knocked out the switch -- a
protein called Nrf2 -- in genetically engineered mice and saw the
activity of phase II enzymes drop dramatically compared with mice
whose "switch gene" was intact.

When they exposed both the knockout mice and normal mice to
benzpyrene, a potent carcinogen in cigarette smoke, both developed
tumors, but the knockouts -- apparently disconnected from the
protective system -- had significantly more.

In a more telling demo of the system, the scientists gave both the
normal and the knockout mice a drug called oltipraz along with the
benzpyrene carcinogen. Oltipraz has been used for parasite
infections. But it was also shown in earlier Hopkins studies to raise
levels of phase II enzymes and lower cancer risk.

In the study, carcinogen-exposed normal mice on oltipraz had their
tumor number cut by half. But the knockout mice were tumor-ridden,
even with the protective drug. "This shows the great importance of
the Nrf2 'switch,'" says Tsukuba University molecular biologist
Masayuki Yamamoto, M.D., Ph.D.; "Without it, the mice couldn't be
protected."

Earlier work by Yamamoto showed that protective chemicals, such as
those in plants, work by sparking cells' release of Nrf2. Then Nrf2
activates a common DNA sequence on the genes of all phase II enzymes,
switching them on.

"Scientists have tried to learn what makes some people more
susceptible to cancer," Kensler adds. "They've looked at genes for
single phase II enzymes here and there. But with NRf2, you have the
control for all of them. With slight changes in the 'switch,' you can
get a tremendous step up in a body's sensitivity to cancer agents."

Turning the system up or down might have value, says Yamamoto. "By
turning down an organism's ability to squelch carcinogens, you could
get an exquisitely sensitive model for testing, say, which pollutants
in the Chesapeake Bay cause tumors to form. Likewise, you could turn
it up and, in theory, increase any animal's resistance to cancer or,
perhaps, other diseases."

The researchers believe the system is a common, general one in many
animals. "Also," says Kensler, "we think it may be part of a broader
way animals deal with many types of toxicity -- not just carcinogens.
Toxicity plays a role in many conditions such as atherosclerosis and
neurodegenerative diseases."

The studies were funded by grants from the National Institutes of
Health and by gifts from the Lewis and Dorothy Cullman Foundation,
New York.

The Nrf2-depleted mice were developed by Masayuki Yamamoto, M.D.,
Ph.D.

Others on the research teams were Minerva Ramos-Gomez, Sc.M., Mi-
Kyoung Kwak, Ph.D., Patrick M. Dolan, B.S. and Albena Dinkova-
Kostova, Ph.D., from Hopkins; and Ken Itoh, M.D., Ph.D., from Tsukuba
University in Japan.

You can access some fairly dramatic photos from this study, showing
the difference in the stomach lining of normal mice given the
benzpyrene carcinogen--they have some natural protection--and the
knockout mice where the protective system has been destroyed. The
large mass in the knockouts, which looks like mashed potato, is
tumor. Go to: http://www.hopkinsmedicine.org/brocosystem.htm
**********************************************************************
Wednesday, 4 April, 2001, 23:03 GMT 00:03 UK
Pill to 'stop cancer'
BBC News

Scientists are developing a once-a-week pill they hope will prevent
half of all cancers.
The drug - called oltipraz - works by activating the body's natural
defence mechanisms to block tumours before they have a chance to
form.

It is already undergoing trials in China.

If we can isolate these chemicals, there is the potential for a huge
impact on cancer

Dr Roland Wolf, Imperial Cancer Research Fund
Oltipraz was originally developed to treat schistosomiasis - a
disease caused by parasitic worms.

However, New Scientist magazine reports that the drug was found to
stimulate the body to make an enzyme called glutathione S-transferase
(GST).

GST neutralises substances such as benzene which are known to cause
cancer by damaging the genetic material of cells.

Tests in animals have confirmed that GST can prevent cancer.

The China trials are being carried out by toxicologist Dr Thomas
Kensler, of Johns Hopkins University in Maryland.

Liver cancer common

In China as many as one in 10 adults die from liver cancer caused
mainly by a chemical called aflatoxin, which is found in moulds
growing on rice and cereal grains.

Dr Kensler gave oltipraz to volunteers in Qidong once a week for two
months.

They excreted over twice as much neutralised aflatoxin in their urine
as volunteers given a placebo.

Dr Kensler said: "GST was boosted in these people.

"The carcinogen interacts with GST rather than with their DNA."

Dr Kensler is now analysing the results of a longer study. If the
results are good, trials will take place over many years to see if
oltipraz really reduces cases of liver cancer.

GST and related enzymes detoxify a broad range of carcinogens, so the
approach should protect against other types of cancer too.

Raymond Bergan at Northwestern University in Illinois is now
enlisting volunteers for a trial to investigate whether oltipraz can
protect smokers against lung cancer.

People smoking more than one pack per day will take either a placebo
or an oltipraz pill weekly for three months, to see if the drug can
alter the level of carcinogens in their lungs.

Vegetables

Chemicals that boost the production of enzymes such as GST are found
naturally in vegetables such as broccoli and brussels sprouts.

Dr Yongping Bao, of the Institute of Food Research in Norwich,
predicts that in three years' time we will be able to use chemicals
isolated from vegetables in pills or to fortify food.

Dr Roland Wolf, a researcher for the Imperial Cancer Research Fund
based at Dundee University, said: "If we can isolate these chemicals,
there is the potential for a huge impact on cancer."

Dr Wolf also believes that if DNA can be protected from damaging
chemicals it might be possible not only to prevent cancer, but to
slow the ageing process.

He said: "In animals, you can keep switching on these enzymes for
life, and the only side effect is increased longevity."

However, he added: "These 'chemoprotective' drugs are at a very early
stage of their development however, and have only just begun to be
tested on patients, so a 'pill to prevent cancer' is a long way off.

"The best immediate way to help to reduce your risk of cancer is to
eat plenty of fresh fruit and vegetables and not smoke."

Professor Gordon McVie, director general of the Cancer Research
Campaign, said: "Oltipraz is in the very earliest stages of testing
in people. If it works according to predictions, it could be helpful
in preventing cancers known to be caused by certain chemicals.

"The results of this trial will not be known for several years."
**********************************************************************
Published in Cancer Detection and Prevention 2001; 25(4):352-361.

Chronic Dosing of Oltipraz in People at Increased Risk for Colorectal
Cancer
Christine E. Szarka, MD,a Kang-Shen Yao, PhD,b Gordon R. Pfeiffer,
BS,a Andrew M. Baishem, BA,a Samuel Litwin, PhD,a Harold Frucht, MD,a
Eric B. Goosenberg, MD,a Paul F Engstrom, MD,a Margie L. Clapper,
PhD,a and Peter J. O'Dwyer, MDb

aFox Chase Cancer Center, Departments of Population Science,
Medicine, and Biostatistics, and bThe University of Pennsylvania
Cancer Center, Philadelphia, PA
Address all correspondence and reprint requests to: Christine E.
Scarka. MD, Fox Chase Cancer Center, 7701 Burholnte Avenue.
Philadelphia. PA 19111.

ABSTRACT: The dithiolethione oltipraz is being developed as a
chemopreventive agent for many malignancies, including colorectal
cancer, on the basis of its in vivo protective activity against
chemically induced tumors in a variety of animal models. This
protection has been associated with an enhanced capacity to detoxify
reactive carcinogens and, more recently, with increased DNA repair.
In a previous single-dose study, elevated detoxification gene
expression was observed in the days after oltipraz dosing. Now, in
this clinical study, we evaluated the effects of oltipraz when given
over a 3-month period. Fourteen individuals with increased risk for
colorectal cancer were randomly assigned to one of two oral doses
(125 or 250 mg/in2) of oltipraz twice weekly for 12 weeks. Two of
seven subjects at the 250 mg/in2 dosage required dose reductions,
owing to significant fatigue. The 125 mg/in2 dose level was well
tolerated by all patients. Blood or colon tissue (or both) for
evaluation of glutathione, glutathione S-transferase, DT-diaphorase
activity, and DT-diaphorase mRNA expression were obtained prior to
treatment and at weeks 6, 12, and 16. No significant modulation of
phase II detoxification enzymes was seen at either dose studied
during this period. Phase 11 trials evaluating a tolerable regimen of
oltipraz (as demonstrated in this study) and other possible
mechanisms that may be responsible for the protective activity of
oltipraz should be pursued.
**********************************************************************
Clin Cancer Res 1997 May;3(5):783-91 Related Articles, Books,
LinkOut


Cellular kinetics of induction by oltipraz and its keto derivative of
detoxication enzymes in human colon adenocarcinoma cells.

O'Dwyer PJ, Clayton M, Halbherr T, Myers CB, Yao K.

Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, and Kimmel
Cancer Center, Thomas Jefferson University, Philadelphia,
Pennsylvania 19107, USA. podwyer@...

Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione] is a
synthetic dithiolethione with chemopreventive activity against
carcinogen-induced neoplasia of liver, lung, and colon in several
animal model systems. Protection from tumor formation is associated
with elevation of Phase II enzymes, including glutathione (GSH)
transferase and NAD(P)H:quinone oxidoreductase (DT-diaphorase) in
experimental carcinogenesis models in vivo. To investigate the time
and dose relationships of the pharmacological action of oltipraz and
to develop a model for its investigation, a human colon
adenocarcinoma HT29 cell line was primarily used. In this cell line,
oltipraz resulted in increased activity of both GSH transferase and
DT-diaphorase. At the maximum effective concentration (100 microM),
the elevation of GSH transferase was 3-fold and that of DT-diaphorase
was 2-fold. The optimal duration of oltipraz exposure to HT29 cells
was 24 h, following which the peak in enzyme activity was observed at
24 h after removal of the drug, and activity had almost returned to
control levels after 72 h in drug-free media. Steady-state mRNA
levels for DT-diaphorase were observed to increase during the period
of drug exposure and remained elevated, even as catalytic activities
declined to control levels, suggesting additional mechanisms for
control of the activity of this enzyme. More prolonged drug exposure
was associated with less induction of the detoxication enzymes,
prompting an investigation of the possible toxicity of oltipraz to
these cells. Although the 3-(4, 5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide assay revealed inhibition of
proliferation (IC50, 100 microM oltipraz), a clonogenic assay
demonstrated no loss of clonogenicity. Oltipraz is known to be
extensively metabolized in many species; two major metabolites
include a 3-ketone (metabolite 2, M2) and a molecular rearrangement
to a pyrrolopyrazine derivative (metabolite 3, M3), numerous
conjugates of which are formed in vivo. To investigate the potential
cause of the lag in response, we synthesized two major oltipraz
metabolites (M2 and M3) and tested their efficacy in enzyme
induction. The activity of DT-diaphorase was induced similarly by
both oltipraz and M2 (2.6- versus 2.8-fold baseline) at 100 microM,
whereas M3 was inactive at all concentrations. M2 also resulted in a
5.8-fold elevation of steady-state DT-diaphorase mRNA levels. Both
enzyme activity and steady-state mRNA peaked at 24 h as with the
parent compound. Thus, the oxidative desulfuration of oltipraz
results in the formation of an active metabolite, but this process is
not rate limiting for the induction of detoxicating enzymes. These
data support the use of intermittent schedules in oltipraz in
clinical trials of chemoprevention because of evidence of attenuation
of response. The metabolite M2, but not M3, is as active as the
parent compound and may be considered for clinical development in its
own right.

PMID: 9815750
*********************************************************************
Proc Soc Exp Biol Med 1997 Nov;216(2):192-200 Related Articles,
Books, LinkOut


Detoxication enzymes and chemoprevention.

Wilkinson J 4th, Clapper ML.

Division of Population Science, Fox Chase Cancer Center,
Philadelphia, Pennsylvania 19111, USA.

Detoxication enzymes protect cells from a wide variety of xenobiotics
and endogenous toxins. Current data suggest that the balance between
the Phase I carcinogen-activating enzymes and the Phase II
detoxifying enzymes is critical to determining an individual's risk
for cancer. Human deficiencies in Phase II enzyme activity,
specifically glutathione-S-transferase (GST), have been identified
and associated with increased risk for colon cancer. The increased
frequency of the GST M1 null genotype among individuals with
primarily smoking-related cancers has been documented. Induction of
Phase II enzymes by naturally occurring or synthetic agents
represents a promising strategy for cancer prevention. Both the
required characteristics of potential chemopreventive agents and the
role of the antioxidant response element in the monofunctional
induction of Phase II enzymes have been discussed. The synthetic
dithiolthione oltipraz induces a battery of Phase II enzymes and
inhibits chemically induced tumors in a variety of target organs. Its
ability to induce Phase II enzymes in human colon tissue and blood
lymphocytes has been reported. Other promising inducers with
chemopreventive activity include the isothiocyanates and polyphenols.
These data collectively support the future development of Phase II
enzyme inducers as clinical chemopreventive agents.

Publication Types:
Review
Review, Tutorial

PMID: 9349688
*********************************************************************