What really attracted my attention about this article is not the story in itself, but how this is a variant of an ethical dilemma that seems to be becoming more and more frequent: is it ethical to prescribe an untested drug, or a drug tested for other purposes, to people who seem to be in dire need of it? Depending on how we define “dire need”, we could be looking at different populations: workers trying to stay awake at night, terminal cancer patients, or people affected by all the consequence of substance dependence – and possibly, other groups I cannot think of right now. There are two more examples that I can make about the other two groups, and they are both relatively recent: the use of cognitive-enhancing drugs in healthy people, and the use of DCA, a drug not tested as an oncological treatment, in terminal cancer patients.

The main issue here is whether there is any real advantage from taking these drugs. In some cases, one could make a “harm reduction” argument, but I feel that in most cases one cannot. For instance, is the muscle relaxant really solving the issues underlying alcoholism? No, but it could be used in the context of a harm reduction strategy, where people are allowed to get off their dependence on alcohol thanks to pharmacological treatment first, but are also being provided with assistance to overcome the root causes of their dependence – which should eventually allow them to avoid taking the drug altogether. This argument could also be made for drug users being provided with drugs and/or a safe place where to inject – think of the recent Swiss heroin prescription initiative, or Vancouver’s Insite.

However, can we make the argument that it is moral to provide an untested cancer treatment to severely ill patients, or that it is moral for healthy people to use cognitive enhancement drugs currently prescribed to people suffering of cognitive difficulties such as ADHD, Parkinson’s and other disorders? I seriously doubt it: in these cases, not only there is no harm reduction, but people are being exposed to potential damage at best, and being set up for future dependence and obligation to assume pharmaceuticals at worst. It is not hard to imagine a day when, if cognitive enhancer uses went mainstream, one could be obliged by a potential employer to consume certain drugs to enhance their ability to concentrate or work longer hours.

Other readings

• Read more on the discussion about the use of cognitive enhancers
• Read more about the story behind DCA, and the way it has been marketed to desperate cancer patients
• For more science blogging, and possibly the best selection of science blogging of the year, head over to this list of posts compiled by Bora at A Blog Around The Clock.

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In this blog post, I am going to examine and summarize the paper, and trying to draw some conclusions from it. Are the results reliable? Was the follow-up long enough, and their study sample of appropriate size? Find out just below the fold.

More than 17,000 patients of both sexes were randomly assigned to a group being treated with a daily dose of rosuvastatin, or placebo. The study found that, compared to the placebo group, patients being treated with the statin showed reduced cholesterol levels and C-reactive protein levels by a significant margin (50% and 37% respectively). These patients also showed reduced incidence of cardiovascular disease over a 2-year follow-up period. While rates of cancer and other causes of death were not affected, the study noticed an increase in “physician-reported diabetes”, which the results were unable to explain.

There are two main issues with this paper. The first is the strong involvement of the main authors with the funding agent — in this case a pharmaceutical company which is involved in the production and sale of the drug in question, rosuvastatin. The second one is the relatively short follow-up time: although all subjects were in age groups prone to cardiovascular disease — 60-year-old or more for men, 50-year-old or more for women — the study does not shed any light on possible long-term side-effects of statin use in healthy people. The increased diabetes reports might have turned into a substantial figure if a long-term study were conducted, but we are not going to know that until an independently funded study will try to shed light on this. Also, levels of C-reactive protein are not, at leats until now, widely recognized as a risk factor for cardiovascular disease.

Going back to the issue of the strong involvement of AstraZeneca in this study, the first thing I noticed about this paper, apart from the results of course, was the disclosure statement. Authors of academic and medical papers are required to disclose their affiliation with the funding agencies, as well as any personal benefit they might get from the results. This study was done for the JUPITER study group (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin); the head of the steering committee for the group, who is also the principal investigator, has tight professional relations with AstraZeneca. Moreover, he is

a coinventor on patents held by Brigham and Women’s Hospital that relate to the use of inflammatory bio-markers in cardiovascular disease, including the use of high-sensitivity C-reactive protein in the evaluation of patients’ risk of cardiovascular disease

C-reactive protein was used in this study as a possible indicator of risk of cardiovascular disease: in fact, the study concentrated on subjects that, by normal standards (LDL levels <130 mg/dL), are completely healthy, but who have more elevated levels of C-reactive protein, which has been showed to indicate a state of inflammation.

On the positive side, the study was conducted over a wide sample, representative of both genders and major racial groups. People with conditions that could make them prone to cardiovascular disease were excluded from the study, and so were those who were affected by diseases caused by, or resulting in, widespread inflammation. This was important, as the main hypothesis behind the study was that general inflammation levels, indicated by the abundance of C-reactive protein, could be a prognostic factor for the future occurrence of cardiovascular disease in otherwise completely healthy people. The paper is therefore also suggesting that levels of C-reactive proteins might be indicative of a susceptibility to cardiovascular disease in people with normal cholesterol levels.

In conclusion, although the results outlined in this paper will need further scrutiny, if confirmed, then they strongly suggest that healthy people could greatly benefit from a daily dose of rosuvastatin, in case it is shown that the statin is not directly responsible for an increase in diabetes cases in the test cohort.

Post Scriptum: Thank you to Alex Palazzo for including this post in the latest edition of the Molecular & Cell Biology Carnival.

P. M Ridker, E. Danielson, F. A.H. Fonseca, J. Genest, A. M. Gotto, J. J.P. Kastelein, W. Koenig, P. Libby, A. J. Lorenzatti, J. G. MacFadyen, B. G. Nordestgaard, J. Shepherd, J. T. Willerson, R. J. Glynn (2008). Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein New England Journal of Medicine DOI: 10.1056/NEJMoa0807646

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• Who’s afraid of Bisphenol A? (part 1) (5)

The situation for food can coating resins (also known to release biologically active amounts of BPA) is similar, with industry studies contrasting research on the amount of leaching from food cans.

Does this mean that one of the sides is lying? Well, a honest skeptical answer would be…no. There is no need for conspiracy theories to explain these disagreements. Mostly, the debate is fueled by the fact that nobody really knows how to assess the effects of xenoestrogen in humans and their significance. What amount of BPA do we need to ingest such that it will have an impact on our health? Should we consider amounts that are ingested all at once, in a short period of time, or over a lifetime? Is the concept of “lifetime xenoestrogen load” useful or not?

Answering these questions is what would unlock the current debates, as by now all sides are at least willing to accept that BPA has unquestionable biological activity as a xenoestrogen. Here is a short list of papers (there are many more) discussing the biological effects of BPA absorption in animals, effects directly related to estrogenic activity:

• Prepubertal exposure to compounds that increase prolactin secretion in the male rat: effects on the adult prostate. Biol Reprod. 1999 Dec;61(6):1636-43 (PMID: 10570013)
  
• The xenoestrogen bisphenol A induces growth, differentiation, and c-fos gene expression in the female reproductive tract. Endocrinology. 1998 Jun;139(6):2741-7 (PMID: 9607780)
• The environmental estrogen bisphenol A stimulates prolactin release in vitro and in vivo. Endocrinology. 1997 May;138(5):1780-6 (PMID: 9112368)
• The developmental toxicity of bisphenol A in rats and mice. Fundam Appl Toxicol. 1987 May;8(4):571-82 (PMID: 3609543)
• Bisphenol A in the aquatic environment and its endocrine-disruptive effects on aquatic organisms. Crit Rev Toxicol. 2007;37(7):607-25 (PMID: 17674214)

You might have noticed that these papers are about ten years old. What is the current consensus on the biological activity of BPA, and its mode of action in animals? Here are a few more recent papers addressing these questions:

• In vivo effects of bisphenol A in laboratory rodent studies. Reprod Toxicol. 2007 Aug-Sep;24(2):199-224. (PMID: 17683900)
• An evaluation of evidence for the carcinogenic activity of bisphenol A. Reprod Toxicol. 2007 Aug-Sep;24(2):240-52. (PMID: 17706921)
• In vitro molecular mechanisms of bisphenol A action. Reprod Toxicol. 2007 Aug-Sep;24(2):178-98. (PMID: 17628395)

The second paper is of special interest, as it summarizes the results of a panel discussion organized by the National Institutes of Health (NIEHS, NIDCR) and the United States Environmental Protection Agency, which “convened an expert panel of scientists with experience in the field of environmental endocrine disruptors, particularly with knowledge and research on bisphenol A (BPA)”. This review suggests that there is a wide scientific consensus regarding the possible role of BPA in carcinogenesis. The consensus arising from the panel discussions is succintly summarized in the Conclusions section of the paper:

Based on existing evidence, we are confident of the following:
1. Natural estradiol-17β is a carcinogen as classified by the International Agency for Research on Cancer [37], [106] and [107].
2. BPA acts as an endocrine disruptor with some estrogenic properties among other hormonal activities.

Based on existing evidence, we believe the following to be likely but requiring more evidence:
1. BPA may be associated with increased cancers of the hematopoietic system and significant increases in interstitial-cell tumors of the testes.
2. BPA alters microtubule function and can induce aneuploidy in some cells and tissues.
3. Early life exposure to BPA may induce or predispose to pre-neoplastic lesions of the mammary gland and prostate gland in adult life.
4. Pre-natal exposure to diverse and environmentally relevant doses of BPA alters mammary gland development in mice, increasing endpoints that are considered markers of breast cancer risk in humans.

Based on existing evidence, the following are possible:
1. BPA may induce in vitro cellular transformation.
2. In advanced prostate cancers with androgen receptor mutations, BPA may promote tumor progression and reduce time to recurrence.

The paper also highlights areas of BPA research that require further enquiry:

1. Does BPA exposure induce or promote cancers in mammary and prostate? What is its mode of action?
2. Does BPA increase cancer susceptibility in estrogen-target organs (prostate, mammary gland, uterus, vagina, testis, ovary, etc.)?
3. Does BPA reprogram target tissues during development through epigenetic mechanisms, including epigenetic marking of genes and morphogenetic processes involving tissue interactions?
4. What are the most appropriate life stages for examining BPA-induced cancer susceptibility?
5. Under what conditions might BPA promote DNA and/or microtubule aberrations?
6. Identify biological consequence of long term, low-dose exposure on genomic integrity, cooperation with oncogenic insult and tumor management.
7. Development of carcinogenesis paradigms with relevance to humans for assessing the ability of BPA to alter cancer risk.
8. What species/strains are the most appropriate for assessing BPA-induced cancer susceptibility?
9. Developing three-dimensional culture models to assess the mechanisms involved in altered morphogenesis of the target organs that may lead to neoplastic development.
10. Epidemiology studies and development of new methodologies to evaluate BPA-cancer risks in humans.
11. Development of markers for total xenoestrogen insult in humans.

Do you remember the recent studies published in the journal Cancer Research, which received strong media attention? One showed that BPA induces changes in gene expression in breast cancer cell lines coherent with those of high-grade lesions; the other suggested that BPA is also able to alter the epigenetic profile in the progeny of BPA-treated epithelial cells. These papers are already addressing points 1 and 3 in the “further research needed” list, even if partially.

Past and present data, as well as the current consensus, seem to suggest that it might be prudent to limit BPA intake in humans until further research determines whether BPA is relatively safe – as we already know that it is not absolutely safe. Until the time when more rigorous studies are conducted, and larger data sets on humans collected, we will not know for sure whether BPA poses a significant danger to human health – it is left to the individual, but also to public health agencies around the world to make a decision on whether to forbid BPA use especially in places where it can enter the food chain…or not. But it seems that there is reasonable evidence that BPA release in the environment should be limited as much as possible, as smaller organisms are sensitive to much smaller amounts of BPA than humans seem to be.

Making decision in relation to BPA is made even more complicated by the fact that there are many estrogen-like compounds in our environment which are already in the food chain, and which we can absorb by consuming both animal and vegetable products: BPA absorption might only be the tip of the iceberg when it comes to xenoestrogen intake. It would be useful to see what the “total xenoestrogen insult” is in an average adult who consumes meat, vegetables and dairy, and to see what role BPA is playing to increase this insult. Only then we will be able to assess whether cancer risk arising from BPA ingestion is significant, or whether we would do better to worry about different sources of xenoestrogen.

KERI, R., HO, S., HUNT, P., KNUDSEN, K., SOTO, A., PRINS, G. (2007). An evaluation of evidence for the carcinogenic activity of bisphenol A. Reproductive Toxicology, 24(2), 240-252. DOI: 10.1016/j.reprotox.2007.06.008

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• Who’s afraid of Bisphenol A? (part 1) (5)
• Is cancer a cure? (0)

While I try to figure out something really interesting to talk about, I am going to pick some science news for you (from Science Daily). Read along, I am sure you’ll find something interesting…such as the news that reducing your caloric intake can help you prevent cancer. This not completely unexpected, as it is also known that a reduced-calorie diet also improves longevity. But are you, are we, going to start depriving us of food (and thinking about food 50% of the time) in exchange of a reduced chance to contract cancer? I honestly doubt it.

Stem Cell Marker Controls Two Key Cancer Pathways

Researchers at Georgetown University Medical Center have discovered that a gene associated with human breast stem cells can stimulate development of mammary cells by activating two critical cancer pathways. They say this finding, reported at the annual meeting of the American Association for Cancer Research (AACR), provides new evidence that breast cancer can arise from stem cells and that targeting this gene might provide a new way to treat cancers of the breast as well as other tumor types.

More here.

Molecule Prompts Blood Stem Cells To Help Repair Heart Damage In Animal Model

Researchers at UT Southwestern Medical Center have for the first time used drug-treated blood stem cells to repair heart damage in an animal model, results that might point to methods for healing injuries from heart attacks or disease.

More here.

Calorie Restricted Diet Prevents Pancreatic Inflammation And Cancer, Study Suggests

Prevention of weight gain with a restricted calorie diet sharply reduced the development of pancreatic lesions that lead to cancer in preclinical research reported April 15 by researchers from The University of Texas at Austin and The University of Texas M. D. Anderson Cancer Center at the American Association for Cancer Research annual meeting.

More here.

Ovarian Cancer Stem Cells Identified, Characterized

Researchers at Yale School of Medicine have identified, characterized and cloned ovarian cancer stem cells and have shown that these stem cells may be the source of ovarian cancer’s recurrence and its resistance to chemotherapy.

More here.

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