The Respectfully Republican Conversation

Hillary has to be happy about the appointee to fill her seat. If I had been her I would have been fuming that CK got the seat!!  CK and her family didn't support her and now they benefit from her being the SOS??? 

I thought it was audacious for CK to even think that she deserved the seat.  That if the Kennedy's didn't sit in the Senate then what would happen? The earth would swallow itself up?? I am sure CK didn't want everyone to know how much money she had or how many servants! This woman has never held a political office and all of a sudden she wants to be a Senator??? Not the mayor, not the community organizer, hmm head of PTA?  Nope ....... go get the brass ring because of that silver spoon in her mouth she was born with .....

Do you think they will make her Ambassador over in England??

Laura---Nothing about Carter could make me laugh----but would rather make me cringe........

Vivre----Caught the bio-identical hormone show on Oprah but was really surprised that breast cancer was not addressed.

LOL OMG - too funny! Forget about picketing...let's throw tomatoes! I love French food! lol

You're right... ROCK hasn't been bragging lately...she hasn't even posted photos of her pool lately....hey Kell - are you all bundled up trying to keep warm? (love ya, Kell!)

Ha ..... it was hot here last Sunday and yes, the pool was on and I took pics but now it's chilly, we had rain, I had to wear long sleeves today and thankfully, I have another pair of sunglasses for days when it's a bit cloudy ... whew!

Rock,  I had to wear my sunglasses today too, so there! It was so windy when I took my walk that I did not want my contacts to freeze! Nothing like an invigorating walk in the cold crisp air! It was actually pretty warm today. I think it was at least 20.

I don't remember if I posted these articles on I3C, but here they are in case. You have to buy this stuff in vitamin stores. I have never seen it in health food stores. I get mine from my doc who buys it from a company out in CA called Metagenics. They only market through doctors. She went out to visit their plant because she is very picky about what she uses and she feels they make a very pure product.

http://www.sciencedaily.com/releases/2008/12/081203092435.htm

http://www.iconmag.co.uk/page.php?n=1417

Susie, I asked both my doctors(chiros) who believe in I3C and they said this study is not relevant because fish and mammals are totally different animals. They point to the evidence in the blood tests they do on their patients like me as proof.

Here is an article about a case study done by one of my doctors. This doctor does my thermographs and believes that I3C is better than hormone therapy. I am not sure how anyone can worry about this stuff since it is basically ground veggies. They both steered me away from DIM because it usually has other things in it such as soy. 

We have the dueling Trout and Mice but the answers aren't as straight forward. 

It's not just the Trout..........

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Rogan EG
The natural chemopreventive compound indole-3-carbinol: state of the science. [Journal Article, Review]
In Vivo 2006 Mar-Apr; 20(2):221-8.


The hydrolysis product of glucobrassicin, indole-3-carbinol (I3C), is metabolized to a variety of products, including the dimeric 3,3'-diindolylmethane (DIM). Both I3C and DIM exert a variety of biological and biochemical effects. Most of these effects appear to occur because I3C modulates several nuclear transcription factors. I3C induces phase I and phase II enzymes that metabolize carcinogens, including estrogens. Administration of either I3C or DIM results in increased 2-hydroxylation of estrogens. I3C also enhances DNA repair by affecting several of the proteins involved in this process. I3C induces both G1 cell cycle arrest and apoptosis. All of these activities lead to anticancer effects. Although I3C has been shown to protect against tumor induction by some carcinogens, it has also been observed to promote tumor development in animal models. In humans, I3C and DIM affect the metabolism of estrogens. Concerns have been raised that I3C might increase the formation of estrogen metabolites that induce or promote cancer, but this has not been demonstrated. I3C has been found to be effective in treating some cases of recurrent respiratory papillomatosis, and it may have other clinical uses.
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This is from the Oxford Journals --A little long but reason for some pause.

http://carcin.oxfordjournals.org/cgi/content/full/23/2/265?ijkey=1e101a2f663723fed6d4c3865bcd02a85f7ba9a6

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Carcinogenesis

    Carcinogenesis, Vol. 23, No. 2, 265-272, February 2002
© 2002 Oxford University Press
MOLECULAR EPIDEMIOLOGY
Development of a multi-organ rat model for evaluating chemopreventive agents: efficacy of indole-3-carbinol

Gary Stoner1,5, Bruce Casto1, Sherry Ralston1, Bill Roebuck2, Clifford Pereira3 and George Bailey4

1 Division of Environmental Health Sciences, School of Public Health, College of Medicine and Public Health, The Ohio State University, Columbus, OH,
2 Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH,
3 Statistics Department, Oregon State University, Corvallis, OR and
4 Medical Biochemistry Department, MFBS Center, Oregon State University, Corvallis, OR, USA

Abstract

Indole-3-carbinol (I-3-C) is among the most widely and popularly known antiestrogens. Due to its putative chemopreventive action, I-3-C is being marketed to the general public in health food establishments. Although it has been demonstrated to prevent cancer in animal bioassays, I-3-C also acts as a promoter in the liver and colon. Because of this potential dual biological activity, it is important to investigate both the inhibitory and promotional activities of I-3-C in multi-organ tumorigenesis animal models. 7,12-Dimethylbenz[a]anthracene, aflatoxin B1 and azoxymethane were used to initiate mammary, liver and colon carcinogenesis, respectively in female Sprague–Dawley rats. The rats were fed continuously on a diet containing I-3-C for 25 weeks after initiation. I-3-C treatment was begun one week after the last carcinogen treatment had been administered. I-3-C treatment resulted in a delay in latency of mammary tumor formation, but did not alter tumor incidence or multiplicity among survivors. In the colon, the protocol produced a 40% decrease in aberrant colon crypt foci. However, in the liver, it strongly-induced GST-P foci in carcinogen-treated (a four-fold increase in volume percent foci) and in the vehicle controls (a 69-fold increase). These data support previous findings in other rodent and fish tumor models that I-3-C both inhibits and promotes carcinogenesis. The results of this study clearly demonstrate that I-3-C is not an appropriate chemoprotective agent for human use, in spite of its effects in the breast and colon in this rat animal model.

Abbreviations: I-3-C, indole-3-carbinol; AFB1, aflatoxin B1; AOM, azoxymethane; ACF, aberrant crypt foci; DMBA, 7,12-dimethylbenz[a]anthracene; DEN, N-nitrosodiethylamine

Introduction

The pioneering work of Wattenberg showed that indole-3-carbinol (I-3-C) inhibited mammary tumor formation induced by 7,12-dimethylbenz[a]anthracene (DMBA) in female Sprague– Dawley (SD) rats and neoplasia of the forestomach of female ICR/Ha mice induced by benzo[a]pyrene (BaP) (1). Interest in I-3-C has remained high because it has several characteristics that are desirable in a candidate chemopreventive agent. I-3-C, in vitro, is neither cytotoxic (2) nor mutagenic (3). When given orally, it has a relatively low acute toxicity (4–6) and does not appear to be teratogenic (4). It has anti-initiating activity against several classes of environmental chemical carcinogens, including nitrosamines (7), polycyclic aromatic hydrocarbons (1,8), the mycotoxin, aflatoxin B1 (AFB1) (9), and the nitroazaarene, 4-nitroquinoline-1-oxide (10). Due to the diverse etiology of human cancer, the ability to protect against many classes of carcinogens is a valuable property of a chemopreventive agent. The chemopreventive activity of I-3-C has been reported in liver, forestomach, stomach and mammary gland (1), lung (7), swim bladder (8), tongue and nasal mucosa (10), larnyx (11) and endometrium (12). Its protective effects are not limited to a particular species, since I-3-C has chemopreventive activity in mice (7), trout (8) and rats (10). Few anticarcinogens offer this degree of chemoprotection. Perhaps of greatest interest are the reports that I-3-C protects against estrogen related tumors (11,12), as well as the short-term studies in humans that show a protective effect of I-3-C against estrogen-responsive breast cancer development (13,14).

Although it has been touted as a chemopreventive agent for breast cancer, enthusiasm for its use must be tempered by the evidence indicating that I-3-C poses a considerable risk, because it can act both as an inhibitor and promoter of carcinogenesis. I-3-C or its acid condensation products can be converted to mutagenic nitrosamines by treatment with acid and nitrite under stomach conditions (15,16), suggesting possible genotoxic or promotional mechanisms in vivo. In mouse epidermis, I-3-C acts as a promoter by enhancing 12-O-tetradecanoyl-phorbol-13-acetate (TPA) induction of ornithine decarboxylase (17). Conversely, when it was given with TPA after a subcarcinogenic dose of DMBA in the two-stage mouse skin model, I-3-C significantly inhibited tumor development (18).

When dietary I-3-C was given to trout before and during administration of DMBA (8) or AFB1 (9), the number of liver tumors was reduced. In contrast, when dietary I-3-C was administered after carcinogen exposure, there was a significant dose-dependent increase in the number of tumors (8). In the case of AFB1, both inhibitory and enhancing activities were nearly equal over a wide range of I-3-C and AFB1 concentrations (6).

Administration of I-3-C (combined with wheat bran and cholesterol) to rats before, during, and after treatment with the colon-specific carcinogen dimethylhydrazine (DMH), enhanced tumor incidence in the colon (19). The main effect was attributed to I-3-C, possibly due to induction of AHH activity and enhancement of DNA alkylation by DMH. When male F344 rats were given I-3-C before and during treatment with 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) the number of aberrant crypt foci (ACF) was significantly reduced (20). I-3-C also inhibited the formation of ACF induced by the heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), in fried ground beef when it was given before and during PhIP treatment or in the post-initiation phase (21).

In addition to the trout studies (8), two other attempts have been made to weigh the chemoprotective benefits of I-3-C against its promotional risk. In a multi-organ rat model, the chemopreventive potential of allyl sulfide (AS), I-3-C, and germanium (GE) were evaluated for their anti-tumor activity in tumors induced by sequential administration of N-diethylnitrosamine (DEN), N-methylnitrosourea (MNU), and N,N-dibutylnitrosamine (DBN) in the liver, lung, thyroid, and urinary bladder (22). When AS and GE were given after initiation, all three agents inhibited the formation of GST-P foci in liver. In addition, AS and GE also inhibited lung and thyroid adenomas, whereas only AS inhibited urinary bladder carcinogenesis (22). In another multi-organ rat model, Kim et al. (23) found that I-3-C enhanced liver and thyroid neoplasia when given 1 week after a 3-week initiation period with DEN, NMU, and dihydroxy-di-N-propyl-nitrosamine (DHPN).

It was hoped that I-3-C might offer a non-genotoxic alternative to tamoxifen or synergin for adjuvant therapy of breast cancer. Unfortunately, the possibility of cancer promotion by I-3-C in other organs, especially if taken as a `health food' by the disease-free general public is unknown. The protocol reported here was designed to measure inhibition and promotion by I-3-C in a multi-organ system in which mammary, liver and colon carcinogenesis were initiated sequentially in each target organ. This model was used to quantify opposing I-3-C post-initiation effects on mammary adenocarcinomas, GST-P foci in the liver, and aberrant crypt foci and carcinomas in the colon.

Materials and methods

Chemicals and diet
DMBA, AFB1, and I-3-C were purchased from Aldrich Chemical Company (Milwaukee, WI). AOM was purchased from Ash Stevens (Detroit, MI). The vehicle, tricaprylin, was obtained from Sigma Chemical (St Louis, MO). Powdered AIN-93G diet was purchased from Dyets (Bethlehem, PA).

Animals
Female 40-day-old Sprague–Dawley rats were obtained from Harlan Sprague–Dawley (Indianapolis, IN) and quarantined for 2 weeks before use in an experiment. Rats were randomly assigned to nine treatment groups (n = 20, Table IGo) and housed two per cage in animal rooms maintained at 20 ± 2°C with a 50 ± 10% relative humidity and a 12 h light/dark cycle. All animals were fed newly formulated AIN-93G rodent base diet (24) without antioxidants throughout the study. Food and water were available ad libitum with food consumption recorded at each scheduled diet renewal. Fresh diet was prepared bi-weekly and stored at 4°C. Animals were weighed weekly and the size and location of new (or regressing) palpable mammary tumors (>=3 mm3) recorded for each animal. All animal protocols were in accordance with National Institutes of Health guidelines and the Institutional Animal Care and Use Committee of The Ohio State University.

      Table I. Initiation and chemopreventive treatment protocol in a multi-organ rat model
 
Dosing and schedule
DMBA was administered in a single gastric intubation in tricaprylin vehicle at a dose of 50 mg/kg body weight. AOM was administered in two individual s.c. injections (15 mg/kg/injection) in 0.9% normal saline as vehicle. AFB1 was given by gavage in tricaprylin as vehicle at a low dose (62.5 µg/kg body weight) or a high dose (125 µg/kg body weight). I-3-C (2000 p.p.m.) was prepared in the AIN-93G diet and fed to rats for 25 weeks post-carcinogen initiation. An outline of the dosing schedule is presented in Figure 1Go.



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      Fig. 1. Dosing regimen for I-3-C chemoprevention protocol. Animals were dosed 2x with 15 mg/kg b.w. of AOM on days 1 and 8 of weeks 1 and 2 by s.c. injection of AOM contained in 0.9% saline. AFB1 was given daily on days 15–19 and days 22–26 (weeks 3 and 4) by gavage in tricaprylin at 125 and 250 µg/kg b.w. DMBA in tricaprylin was administered on day 20 (week 5) as a single gastric intubation at a dose of 50 mg/kg b.w. I-3-C at 2000 p.p.m. was incorporated into the basal diet (AIN-93) beginning at day 35 (week 7) and thereafter to time of killing at week 30.

 
Harvest of tissues and analysis
Animals were killed by CO2 anesthesia. Mammary glands were displayed for detection of non-palpable tumors. Tumors were measured by caliper for volume calculation, excised, and processed for histological examination. Livers were removed, fixed in ice-cold acetone, paraffin-embedded, and processed by the peroxidase–antiperoxidase complex method for GST-P positive foci as described (25). Liver volume percent occupied by foci, was estimated by morphometric analysis (26). Additional parameters (foci/mm3, mean foci diameter) were also assessed. Stomach and small and large intestine were removed, flushed with Krebs' Ringer solution, longitudinally slit, and pinned flat between filter paper for fixation in 10% buffered formalin for 4 h. Macroscopically evident tumors were counted and their sizes estimated. Specimens were embedded and processed for routine histology using hematoxylin and eosin staining. Colonic tumors were classified by established histological criteria (27). ACF were examined in the remaining colonic tissue after methylene blue staining by established procedures (28). Total foci and aberrant crypts per focus (classes 1–4) were recorded following counting by light microscopy.

Statistical analysis
All analyses comparing groups with and without 1-3-C were performed using the SAS System for Windows release 8.1 (SAS Institute, Cary, NC). Two-sample t-tests (SAS Test procedure) or Exact Wilcoxon tests (SAS Npar1way procedure) were used to detect shift alternatives. t-tests were used when approximate normality was a reasonable assumption on either the original (aberrant crypts/foci counts for groups 6 and 8) or log scale (all liver foci measurements for groups 6 and 8 and per foci bearing animal measurements for groups 7 and 9). Exact Wilcoxon tests were used whenever a normality assumption was not reasonable (other liver foci measurements for groups 7 and 9, all aberrant crypt foci counts for groups 7 and 9, mammary tumor multiplicity, time until first mammary tumor, and colon tumors per animal). To detect more general alternatives, the Kuiper two-sample test (SAS Npar1way procedure) was used for time until first mammary tumor data. Fisher's Exact test (SAS Freq procedure) for r by c tables was used to detect general differences in mammary tumor multiplicity and colon tumors per animal. Fisher's Exact test was also used for comparing colon tumor incidence, liver foci incidence, and proportion killed.

Results

Establishment of treatment schedule
Two preliminary experiments were carried out to determine a satisfactory carcinogen treatment schedule. In the first trial, two groups of rats (n = 8 for both high and low dose experiments) were given a single subcutaneous (s.c.) dose of AOM at either 15 or 30 mg/kg body weight on day 1, followed by administration of a single gavage of DMBA at 25 or 50 mg/kg body weight on day 8, and multiple gavages of AFB1 (62.5 and 125 µg/kg body weight) beginning at day 15 for five days per week over a 2-week period. The rats were killed 21 weeks after initiation and analyzed for mammary tumors, GST-P foci in the liver, and colonic ACF. Although there was some variation in body weight and food consumption between the high and low dose groups over a period of 2–3 weeks, there were no significant differences in either parameter for most of the experimental period. Mammary tumor incidence reached 100% by week 16 in both high and low dose groups. The frequency of induced liver foci was sufficient for future chemopreventive studies (data not shown). However, the rapid development of mammary tumors did not allow sufficient time for development of either ACF or colon tumors. This treatment schedule was therefore deemed inappropriate for additional studies.

In the second trial, the treatment schedule shown in Figure 1Go and in Table IGo was evaluated (four rats per group). In this modified dosing schedule animals received two rather than one AOM treatment, and the post-initiation period was lengthened from 26 weeks to 30 weeks. In addition, DMBA was applied as the final carcinogen in order to avoid undue delay between mammary initiation and onset of I-3-C treatment (C.Ip and H.Thompson, personal communication). This protocol allowed adequate time for development of mammary adenocarcinoma, liver GST-P foci and colon ACF as quantifiable endpoints. Though the AFB1 protocol used is sufficient to produce hepatic tumors after 12 months, mammary tumor development limits the total post-initiation period to ~6 months. In the liver, the volume % GST-P foci ranged from 3.3% to 16%, the number of foci per cm3 from 2465 to 5040 and the mean diameter/focus from 137 to 362 µm. For colon ACF, total numbers per rat ranged from 100 to 225 with 50 to 140 ACF showing >=4 aberrant crypts per focus.

Based upon the data from these studies, a final study was performed using the scheme outlined in Figure 1Go. The study design used 20 animals per variable to establish and validate the multi-organ initiation protocol (Table IGo, groups 1–7), and to examine the effects of I-3-C on initiated and control animals (group 6 versus group 8 and group 7 versus group 9, respectively).

Effect of I-3-C on mammary tumor response
In the final protocol, mammary tumors were induced by the administration of DMBA alone (group 1), in combination with AOM (group 4), or with AOM and AFB1 (groups 5 and 6) (Table IIGo). Neither AOM nor AFB1 alone induced formation of mammary tumors (Table IIGo, groups 2 and 3) when compared with the vehicle-treated controls (group 7). At terminal sacrifice (week 30, Figure 1Go), tumor incidence in the DMBA alone, DMBA + AOM, and DMBA + AOM + high AFB1 groups (groups 1, 4 and 6, respectively) was ~100%, with no significant differences in mean yield as tumors/rat, or multiplicity (mean tumors/tumor bearing rat) between carcinogen treatments. The effects of post-initiation I-3-C treatment on mammary tumor response are revealed by comparing groups 6 and 8. As seen in Table IIGo, 2000 p.p.m. dietary I-3-C treatment of initiated animals for 25 weeks post-initiation did not result in a reduction of cumulative mammary tumor incidence during the study. Moreover, I-3-C did not reduce tumor multiplicity among rats surviving at week 30, nor did it produce any evident reduction in mean tumor size. We note that animals in any treatment group were killed if and when mammary tumor burden exceeded six tumors per animal or individual tumor size exceeded 1.5 cm in diameter. Thus, information from these animals was included in cumulative mammary tumor incidence and in time-to-first-tumor data, but not in final tumor multiplicity at week 30. We note, however, that the distribution of survivors was very similar between groups 6 and 8, and statistical tests did not detect any evidence for differences for surviving tumor bearing animals (t-test, Wilcoxon test, Fisher's Exact test, all P > 0.5). Although the percent killed prematurely due to excessive tumor burden is higher in group 6 and in group 8, the difference is not statistically significant (Fisher's Exact test, P = 0.30).



      Table II. Effect of multiple carcinogen exposures and I-3-C post-treatment on rat mammary tumors
 
Figure 2Go suggests, however, a major difference in tumor latency between groups 6 and 8 during weeks 12 to 17. Statistics based on the empirical distribution function (EDF) were used to detect more general differences between distributions (other than just shift in location). For this two-sample case, the Kuiper test provides evidence of a difference (P = 0.052) in the distributions of time-to-first-tumor for the two groups. Tumor incidence was similar beyond week 18 and there did not appear to be a simple overall shift toward a longer time-until-tumor for one group. Consistent with this observation, analysis methods designed to detect an overall shift in location do not indicate an overall significant difference between the groups (Wilcoxon test, P = 0.145).



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      Fig. 2. Effect of I-3-C on mammary tumor incidence. Rats were treated with carcinogens only (n = 20) or carcinogens plus I-3-C (n = 17) according to the schedule in Figure 1Go. Animals were examined weekly for tumors beginning at the 10th week. Data for weeks 24–30 are not included, since the two groups have a similar incidence of mammary tumors after week 23. There was a significant difference (P = 0.052) in time-to-tumor between group 6 (carcinogens only, white bars) and group 8 (carcinogens + I-3-C, black bars).

 
In conclusion, 2000 p.p.m. dietary I-3-C treatment of carcinogen exposed animals for 25 weeks did not significantly decrease cumulative mammary tumor incidence or multiplicity among surviving rats. It did, however, result in a 3–4 week delay in time-to-first-tumor detection and a significant difference in cumulative incidence kinetics over the earlier time periods (through week 17) in this study.

Effect of I-3-C on GST-P foci in liver
Treatment of rats with DMBA plus AOM plus low or high doses of AFB1 produced strong induction of GST-P foci in the liver (e.g. focal volume percent = 3.05 and 6.96 for groups 5 and 6, respectively) (Table IIIGo). Responses in groups receiving one or two carcinogens (groups 1–4) were much lower, but still 35–400 fold greater than that seen in the group 7 vehicle control. Protocol treatment for group 6 (or 5) provided adequate dynamic range for detection of promotional or suppressive effects of I-3-C treatment in this model. Comparison of groups 8 and 6 shows that 2000 p.p.m. I-3-C had a significant promotional effect (P < 0.0001, t-test) in the development of hepatic GST-P foci when evaluated as mean focal area (55.1 versus 14.7), mean volume (43.9 versus 5.7), or by the focal volume percent (26.8 versus 6.9). The focal volume percent is considered to be the most robust measure of foci formation and is analogous to tumor burden (26). Analysis of the focal volume percent response revealed that I-3-C induced ~4.1-fold increase over that observed in the carcinogen combination treatment (group 6 versus group 8; 95% CI, 2.5- to 6.8-fold).


      Table III. Effect of I-3-C on formation of GST-P foci in a multi-organ rat model
 
Chronic I-3-C treatment also influenced foci development in non-initiated animals. In groups 6 and 8, all of the animals presented with foci. In the vehicle control (group 7), only one of eight animals had foci whereas in the vehicle + I-3-C (group 9), eight of nine demonstrated liver foci. When analyzed by the Wilcoxon test, statistical differences were evident between groups 7 and 9 by foci per cm2 (P < 0.0001), mean focal area per mm2 (P < 0.004), mean number of foci per cm3 (P < 0.0001), mean volume per mm3 (P < 0.004), and volume per cent of foci (P < 0.0001). These volume percent data indicate that I-3-C also strongly promoted an increase in spontaneous GST-P foci in the liver with 0.002% in group 7 (vehicle alone) to 0.14% in group 9 (vehicle + I-3-C), a 69-fold increase. This reflects the observed data, where I-3-C treatment resulted in a 100-fold increase in GST-P foci per cm2.

Effect of I-3-C on colon tumors and aberrant crypt foci (ACF)
The relatively short duration carcinogenesis protocol was aimed at colonic ACF rather than tumors as the endpoint. Nonetheless, treatment of rats with 30 mg/kg body weight of AOM alone and in combination with DMBA was able to elicit colon tumors (tubular adenoma and adenocarcinomas) in 26% (group 2) and 22% (group 4) of the animals, respectively (Table IVGo). When AOM treatment was combined with AFB1 and DMBA, tumor incidence was similar, at 45% (AFB1 low dose) and 27% (AFB1 high dose) (groups 5 and 6). Post-treatment of animals for 25 weeks with I-3-C (Table IVGo, groups 6 versus 8) did not appear to reduce tumor incidence or tumor multiplicity, but the tumor response in this protocol was minimal (only three and two animals had tumors in groups 6 and 8, respectively).



      Table IV. Effect of I-3-C on formation of colon tumors and ACF in a multi-organ rat model
 
There was, however, a readily detectable and significant decrease (P = 0.03, t-test) in the mean number of foci with aberrant crypts (ACF) between animals receiving control diet (group 6, 285 ACF) or 2000 p.p.m. I-3-C diet (group 8, 170 ACF) for 21 weeks following initiation. The number of ACF with greater than four aberrant crypts was also reduced in the presence of I-3-C (167 versus 113), but not significantly (P = 0.20, t-test). Unlike the promotional effect observed in liver, I-3-C demonstrated a moderate chemopreventive effect with respect to the development of spontaneous ACF in the vehicle control (P = 0.13, Exact Wilcoxon, group 7 versus group 9). Additionally, the number of foci with greater than four aberrant crypts was reduced in the presence of I-3-C, but the difference was not significant by Fisher's Exact test (P = 0.21).

Effect of I-3-C on mean body weight
Figure 3Go shows the cumulative weight data in all nine groups during the 30-week bioassay. In most of the weeks 17 to 29, the mean weight of rats treated with vehicle + I-3-C (group 9) was significantly (P < 0.05) lower than that in rats treated with vehicle only (group 7). Similarly, beginning in week 18, rats treated with the three carcinogens + I-3-C (group 8) weighed less than those treated with the three carcinogens only (group 6; P < 0.05). These data indicate that the addition of the dietary I-3-C led to a potential toxic effect in both control and carcinogen-treated animals.




      Fig. 3. Mean body weight data in all groups during the 30-week bioassay. See Table IGo for an explanation of specific treatments in each group.

 
Discussion

Development of the three-organ rat model
A major feature of the multi-organ rat model developed in this study is that it permitted an assessment of the activity of I-3-C against mammary, liver and colon cancer in the same animal. These three cancer types were selected because mammary and colon cancer are two of the leading causes of cancer death in the United States, whereas liver cancer is one of the top three causes of cancer mortality world-wide. Previous studies in multi-organ models (22,23,29) either did not permit or did not report simultaneous comparison of I-3-C post-initiation effects in these three tissues. I-3-C is currently being proposed for suppression of mammary cancer in women, yet most publications indicate that post-initiation treatment with I-3-C promotes liver cancer (8,23), and one report indicates possible promotion of colon cancer (19). A limitation in the usefulness of this three-organ model became apparent as this study progressed. While tumors can be generated in the mammary gland and in the colon within the span of the 6-month bioassay, liver tumor development requires at least 12 months using this protocol. Due to this, it was necessary to use a well-established marker for liver tumor risk, GST-P foci. This marker would appear to be predictive of I-3-C effects since, in other model systems such as trout, I-3-C has been shown to promote the development of hepatocellular carcinomas (8).

Post-initiation effects of indole-3-carbinol
The results of the present study indicate that post-initiation dietary I-3-C at 2000 p.p.m. provided some degree of protection against mammary tumors and colon ACF, but greatly promoted hepatic GST-P foci in animals jointly initiated for all three endpoints. I-3-C increased the mean focal area and the volume % of GST-P foci in the liver of rats treated with all three carcinogens ~4-fold. I-3-C also increased the volume % GST-P foci in vehicle-treated control animals as well as the number of foci per cm3 >100-fold. These data are consistent with the observations of Kim et al. (30), who found that I-3-C inhibited DEN-induced hepatic GST-P foci if given prior to DEN injection, but significantly increased GST-P foci if given in the diet for 6 weeks beginning 4 weeks after initiation. Both the number (no./cm2) and area (mm2) of GST-P foci were increased as a result of I-3-C post-treatment.

Beginning at 17 weeks, animals treated with I-3-C had lower body weights than vehicle controls indicating that the compound itself elicited some toxicity in the animals. In addition, animals treated with the three carcinogens plus I-3-C had lower body weights than those treated with the three carcinogens alone. Thus, it is possible that the mild reduction in mammary tumors and colon ACF in I-3-C treated rats was a result of the reduction in body weight.

There is evidence for two basic mechanisms for I-3-C post-initiation suppression of mammary tumorigenesis – alterations in hepatic estrogen metabolism leading to reduced systemic estrogens, and receptor-mediated suppressive mechanisms within the mammary epithelial cell. The systemic anti-estrogenic effect is widely ascribed to induction of hepatic cytochrome P450 (CYP) 1A1 by dietary I-3-C (31–33). At the cellular level, treatment of mouse mammary epithelial cells (34) and human MCF-7 cells with I-3-C (35) induced CYP1A1 and produced anti-estrogenic responses including a reduced C16-{alpha} to C2 hydroxylation ratio, decreased nuclear estrogen receptor (ER) and progesterone receptor binding, and decreased estrogen-induced cellular proliferation. Bradlow et al. (36) have suggested that an increased mammary cancer risk is associated with a decrease in the C2-hydroxylation: C16-{alpha} hydroxylation ratio, a mechanism that might be overcome by I-3-C mediated induction of C2-hydroxylation.

The inhibition of hepatocarcinogenesis by I-3-C when given before carcinogen treatment is thought to be attributed to the induction of metabolizing and detoxification enzymes (33,37,38), a decrease in covalent binding of carcinogens (39–41), or the scavenging of free radicals (42). However, the means by which I-3-C promotes liver tumors is less well defined. One report (43) attributed post-initiation I-3-C promotion of hepatocarcinogenesis in trout to both estrogenic and Ah receptor pathways. Protection was biphasic, with I-3-C levels as low as 250 p.p.m. giving evidence for induction of estrogen biomarkers, whereas induction of P450 CYP1A1 was observed at dietary levels of 1000 p.p.m. and higher. Both Ah receptor and estrogen pathways were significantly elevated at I-3-C doses above 1000 p.p.m.

As with I-3-C inhibition of liver carcinogenesis, mechanisms for blocking the initiation of colon carcinogenesis by pretreatment with I-3-C have been described by several investigators. These include induction of metabolizing and detoxification enzymes (23,44,45) and a reduction of DNA adducts (20). The present study provided evidence that post-initiation I-3-C suppresses development of AOM-initiated ACF in the colon. This finding is consistent with previous evidence (21) for I-3-C suppression of PhIP-induced ACF. However, mechanisms for I-3-C suppression of the ACF biomarker, and the relationship to final carcinoma development, have not been fully elucidated. Recent results from our laboratory suggest that post-initiation effects of I-3-C or chlorophyllin in the rat colon is dependent upon the initiator used (46,47). Post-initiation treatment was either inhibitory or enhancing, apparently depending on the particular spectrum of ß-catenin mutations elicited by the carcinogen chosen (46). Until these opposing activities are better understood, caution should be applied in the proposed use of I-3-C for the suppression of human colon cancer.

With the exception of the studies cited in this report (6,22,23), no other attempts have been made to weigh chemoprotective benefits against promotional risk for I-3-C. In spite of the hope that I-3-C might be a non-genotoxic alternative for tamoxifen or synergin for adjuvant therapy, the risk of promoting colon and liver cancer, especially if I-3-C is used as a `health food' by the presumably disease-free general public is unwise and potentially dangerous.

The results of this study and other published reports clearly show that I-3-C is not an appropriate chemopreventive agent for human use, despite the protective effects in the breast and colon in the rat multi-organ model.

Notes

5 To whom reprint requests are to be sent: Division of Environmental Health Sciences, School of Public Health, 1148 CHRI, 300 W. 10th Avenue, Email: stoner.21@osu.edu Back

Acknowledgments

The authors wish to acknowledge the technical assistance of Charlotte Morgan, Balvinder Sidhu, and Laura Kresty in conduct of animal experiments and Denise MacMillan and Karen Baumgartner for assistance in evaluating the hepatic foci. This work was supported in part by NIH/NCI Grants CA-34732 (GSB)and CA-39416 (BDR).

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Received December 27, 2000; revised October 26, 2001; accepted October 31, 2001.
------------

More rats

http://www.ncbi.nlm.nih.gov/pubmed/3459919?dopt=Abstract

Dr Nick told me that these studies are funded by drug companies who are constantly trying to refute inexpensive treatments because they stand to lose a lot of money. Anyway, I cannot see any harm in taking something that is ground up veggies. As I said, my blood work shows results that are just as good as arimidex, with no side effects, and a lot less expense. If this stuff is dangerous, then why don't they tell us not to eat broccoli or cabbage. I3C is active in these veggies. I found a lot more negative information when I began to research arimidex, such as the way it is used by body builders in their steroid concoctions and the bad long term effects it may have on the heart. I do not feel I am choosing the lesser of two evils. I feel I am choosing something that will help me without causing a new set up problems.If you look at the case study that Dr Nick has on his site of a his patient, you can see proof that I3C shrunk fibroids in the cervix. Most other doctors would say this requires surgery.

Vivre--I was not aware that DIM had soy in it.    Phosphatidylcholine (whose usual source is from soy beans)  is included in some of the brands.  I think that is what you are referring to.

 

But I did run across this amazing and potentially useful  information about the use of Taxotere with DIM ---from Medline---Fascinating results.

-----------------------------------------------------------------------------

1: Mol Cancer Ther. 2007 Oct;6(10):2757-65. Epub 2007 Oct 3.Click here to read Links
    Inactivation of NF-kappaB by 3,3'-diindolylmethane contributes to increased apoptosis induced by chemotherapeutic agent in breast cancer cells.
    Rahman KM, Ali S, Aboukameel A, Sarkar SH, Wang Z, Philip PA, Sakr WA, Raz A.

    Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 715 HWCRC, 4100 John R, Detroit, MI 48201, USA. kmrahman@med.wayne.edu

    Constitutive activation of Akt or nuclear factor-kappaB (NF-kappaB) has been reported to play a role in de novo resistance of cancer cells to chemotherapeutic agents, which is a major cause of treatment failure in cancer chemotherapy. Previous studies have shown that 3,3'-diindolylmethane (DIM), a major in vivo acid-catalyzed condensation product of indole-3-carbinol, is a potent inducer of apoptosis, inhibitor of tumor angiogenesis, and inactivator of Akt/NF-kappaB signaling in breast cancer cells. However, little is known regarding the inactivation of Akt/NF-kappaB that leads to chemosensitization of breast cancer cells to chemotherapeutic agents, such as Taxotere. Therefore, we examined whether the inactivation Akt/NF-kappaB signaling caused by B-DIM could sensitize breast cancer cells to chemotherapeutic agents both in vitro and in vivo. MDA-MB-231 cells were simultaneously treated with 15 to 45 micromol/L B-DIM and 0.5 to 1.0 nmol/L Taxotere for 24 to 72 h. Cell growth inhibition assay, apoptosis assay, electrophoretic mobility shift assay, and Western blotting were done. The combination treatment of 30 micromol/L B-DIM with 1.0 nmol/L Taxotere elicited significantly greater inhibition of cell growth compared with either agent alone. The combination treatment induced greater apoptosis in MDA-MB-231 cells compared with single agents. Moreover, we found that NF-kappaB activity was significantly decreased in cells treated with B-DIM and Taxotere. We also have tested our hypothesis using transfection studies, followed by combination treatment with B-DIM/Taxotere, and found that combination treatment significantly inhibited cell growth and induced apoptosis in MDA-MB-231 breast cancer cells mediated by the inactivation of NF-kappaB, a specific target in vitro and in vivo. These results were also supported by animal experiments, which clearly showed that B-DIM sensitized the breast tumors to Taxotere, which resulted in greater antitumor activity mediated by the inhibition of Akt and NF-kappaB. Collectively, our results clearly suggest that inhibition of Akt/NF-kappaB signaling by B-DIM leads to chemosensitization of breast cancer cells to Taxotere, which may contribute to increased growth inhibition and apoptosis in breast cancer cells. The data obtained from our studies could be a novel breakthrough in cancer therapeutics by using nontoxic agents, such as B-DIM, in combination with other conventional therapeutic agents, such as Taxotere.

    PMID: 17913854 [PubMed - indexed for MEDLINE]

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        *
          Inactivation of NF-kappaB by 3,3'-diindolylmethane contributes to increased apoptosis indu...Inactivation of NF-kappaB by 3,3'-diindolylmethane contributes to increased apoptosis induced by chemotherapeutic agent in breast cancer cells.

   

Obama pitches his plan to reverse economic slide

WASHINGTON - President Barack Obama on Saturday laid out more pieces 

of an economic plan he says would add 3,000 miles of electrical lines,

increase security at 90 ports and double the United States' renewable

energy capacity within three years.

This is a portion of an article about stimulating the economy...the rest is

SSDD stuff, but I LOVE the "increase security at 90 ports" part.

My question/comments...if all President Bush did was lie about terrorism,

why do we need to waste money on increasing security at 90 ports?

Or did the current calamity finally see enough briefings to UNDERSTAND the threats?

 Now if that is the case perhaps it could be passed on down to the rest of the lemmings.

And a big WELCOME BACK <----------------------------------------I was wondering how I was

going to get my daily laugh!

Speaking of Limbaugh

President Obama warned Republicans on Capitol Hill today that they need to quit listening to radio king Rush Limbaugh if they want to get along with Democrats and the new administration. 

 I did not vote for Obama but I felt good after the election as I thought he was a centrist man, but he is far from it. The comment above is an example of it and as the one below 

While discussing the stimulus package with top lawmakers in the White House's Roosevelt Room, President Obama shot down a critic with a simple message."I won," he said, according to aides who were briefed on the meeting. "I will trump you on that."

 His new plan does not apear to provide any quick jobs creation. My worry is that the economy will start recovering on its own as it usually and then we will be hit with all this spending that will slow us down again. I wish they just help banks to get rid of the toxic assets and get mortgages back on track and then step away and let the economy recover on its own term.

And we don't have enough Republicans in the Senate to oppose it. We need to wait 2 years for this. I do think that after 18 months of Obama , people will be ready to vote some Republicans in.

Meanwile help us G-d 

Its wide because of the long link in Saluki's post making the page wide.

Could we be seeing the first inkling of attempts to abolish freedom of the press?  Watch for the Fairness Doctrine to come up again soon. 

vivre,

Rush has been a thorn at liberal side so long, he is like a red cloth to bull for them.

I just heard a funny thing on Fox news from Steve Forbes. He said that he did not understand why people were so opposed to Geithner nomination, after all the guy demonstrated that he strongly believed that people should pay less taxes