ANP: Not gene targeted. Almost certainly not curative.

By Lightbluesquare, edited by Josephine Jones

This post concerns the implications that ‘antineoplastons’ are ‘gene targeted drugs’. Something which is not only untrue, but I believe is specifically designed to mislead potential patients into thinking they will receive state of the art, targeted drug treatments with little or no toxicity. In reality, they are likely to be receiving a very old, not at all ‘gene-targeted’ drug by the popularly accepted definition of the term. While this may or may not be of therapeutic benefit, it does carry considerable risk.

Firstly it is important to understand what a gene targeted drug actually is, so I will use an example. A type of leukaemia, called chronic myeloid leukaemia (CML) was until the late 1990s almost entirely incurable, with a dismal five year survival rate of around 10%. This particular type of leukaemia is caused by something called a fusion gene (or chromosomal translocation), where two bits of DNA that are normally supposed to be separate, actually fuse together causing the normal functions of these two genes to be disrupted. In the case of CML, the gene is called the Philadelphia chromosome where two genes called BCR and ABL (a protein called a tyrosine kinase) join together to cause BCR/ABL.  This turns the normally inactive ABL on and results in leukaemia.

BCR/ABL was discovered by Dr Janet Rowley in the 1970s, a truly inspiring woman and scientist and for many years, CML patients were still succumbing to their illness. However, in the late 1990s, a drug company research group from Novartis in combination with Dr Brian Druker, and groups from elsewhere in the US, Italy and the UK specifically designed a drug which would target ABL and turn it off again, stopping the disease in its tracks. This single drug transformed the five year survival rate for CML from less than 10% to over 95%. The phase III trial carried out in the year 2000 randomised patients onto conventional treatment containing a range of chemotherapy agents or Imatinib, and the results were so staggering in favour of Imatinib, the trial was finished early for ethical reasons and all patients in the trial were treated with Imatinib. In 2001, the drug was approved by the FDA for treatment of CML (shortly followed by other countries), and holds the record for the quickest ever approval of a drug by the FDA, less than five years from discovery to widespread approval for CML patients.

Imatinib is not only a potent example of a truly targeted drug (although it must be mentioned that it does have some residual effect on other tyrosine kinase proteins such as KIT, but this is a different and complex story) with few associated side effects, but a lesson to the entire medical and scientific community in how to identify the root cause of a disease as Dr Rowley did in 1973, collaborate extensively to develop a targeted drug, test the drug quickly and efficiently and get it helping cancer patients as soon as possible.

So, onto Burzynski. Others have written about his ‘antineoplastons’, notably David Gorski with an excellent critical appraisal, summed up perfectly by the observation that what Burzynski calls antineoplastons are nothing more than the byproducts of the body’s metabolism of the orphan drug sodium phenylbutyrate. I would like to expand a little more on what antineoplastons ‘might’ do theoretically, and why I feel that even if they do have any action against cancers, there are better alternatives now available.  Burzynski calls his drugs ‘antineoplastons’, but essentially, we know that a lot of the time, he gives ‘antineoplastons’ to patients by using a recognised drug called sodium phenylbutyrate. Sodium phenylbutyrate (PB) is converted to phenylacetate (PA) and phenylacetylglutamate (PAG) by the liver and kidneys (along with a few other chemicals summarised on the Burzynski website), so although these chemicals may have slightly different effects, we can presume that treatment with PB will result in ‘antineoplastons’ being in the bloodstream. It is a little similar to giving someone a cup of tea or giving them the tea bag and some hot water to make their own tea. Either way, they will end up with a cup of tea, albeit the strength of the tea might be slightly different.

Burzynski is not the only one using antineoplastons, or the pro-drug PB. PB is approved for some other conditions such as urea cycle disorder (again summarised perfectly by David Gorski) and has been trialled in other cancer types. So what do other scientists and doctors say about it?

In a 2001 study by Gilbert et al, 28 patients with a range of solid tumours were treated with PB. Notably the paper states ‘no patient had a partial or complete response’. The paper also details side effects, particularly at the higher PB doses used, including extreme fatigue and in one case, severe neurological toxicity. Supporters of the Burzynski Clinic (including the Burzynski Patient Group, recommended by the clinic to patients) believe that the treatment is non-toxic.  This is despite patient experiences of severe hypokalaemia (low potassium), hypernatraemia (high sodium), seizures, fatigue and kidney failure. All of these can be life threatening and in the case of the kidney failure, would appear to be the cause of death in one paediatric Burzynski patient. I suspect that Burzynski uses doses at the higher range of those stated in this paper, meaning that severe side effects may occur far more regularly than he seems to let on. Indeed, in 1998, the FDA noted that 65% of the 404 patients participating in a study were suffering from hypernatraemia, which they said may have contributed to the deaths of at least seven patients.

So, the big question is – does the treatment actually work? Unfortunately, Dr Burzynski has failed to publish any information on almost all of his clinical trials in order to answer this question. This is astounding in many ways, but mainly because if the treatment was as successful as he claims, publications would give him credibility, recognition (which it seems he badly craves and believes he is entitled to) and an increased customer base leading to, well… money (something which he also seems to enjoy). So, without any information of it in his hands – theoretically could it work?

Sadly the answer is as you might expect – not yes or no. PB is proposed to work as a histone deacetylase inhibitor (HDACi). Histone acetylation basically influences which genes are expressed in a cell and which are not expressed.  If a gene is expressed, protein can be made from it and then that protein can have any number of effects on the cell, such as making it divide, move to another part of the body or even die. Histone acetylation plays a role in controlling this and generally DNA which is very acetylated, expresses lots of genes, whereas DNA which is not highly acetylated expresses few. Therefore, disrupting histone acetylation with HDACi can alter the expression of some genes.

Sounds good so far, except there are a number of issues both with the drug and the way Burzynski sells it:

Burzynski claims that Antineoplastons ‘switch on’ tumour suppressor genes and ‘switch off’ oncogenes.

Histone deacetylase inhibitors will certainly ‘switch on’ certain genes and ‘switch off’ others (or more accurately, decrease the levels of some genes and increase the levels of others), but this spiel from Burzynski essentially claims that PB has conscious thought to switch on the good guys and turn off the bad ones. This is simply not possible. Genes in DNA are all a mixture of four DNA bases; A, T, G and C, regardless of whether they produce tumour suppressor genes or oncogenes. Although the roles of some of these genes are now apparent to us through years of research, it is ridiculous at best to suggest that a small molecule is capable of telling histones which genes to repress and which to activate. It frankly is just not that simple.

As for the drugs being ‘gene targeted’, this is quite simply untrue. The description of Imatinib above shows a truly gene targeted agent whereby activated ABL protein, characteristic of the root cause of the disease, is inhibited. Imatinib does have a few ‘off-target effects’ on a handful of other proteins, due to their structural similarity to ABL, and this has actually been used to therapeutic advantage in various other cancers such as a certain type of gastrointestinal tumour called GIST, which has an overexpression of a protein called KIT. Regardless, Imatinib can be considered to be gene targeted to just a handful of genes. PB however, will have effects on hundreds of genes via histone deacetylation, mostly not oncogenes or tumour suppressor genes, but ‘other’ genes, making the possibility of side effects quite large. Having an effect on ‘hundreds of genes’ is absolutely not a gene-targeted therapy, and it would appear that Burzynski is badly confused.

Of course, if he could publish his data regarding the mechanism of action of PB/antineoplastons in a reputable, reliable journal, maybe his claims would have more credence. The entire experiment could be achieved using now reasonably cheap ‘Gene expression microarrays’ at a cost of just a few thousand pounds – a drop in the ocean in research terms. Again, the fact that he hasn’t published this data, but continues to offer the treatment without any evidence of how it works, is astoundingly poor. At best, he doesn’t know what he is talking about, at worst, he is actively making all of this up.

Burzynski promotional literature has even gone so far to suggest that he is heralding in a new era of ‘gene targeted, personalised cancer therapy’. This is egotistical nonsense and frankly insulting to the scientists like Dr Brian Druker who truly are revolutionaries in the development of gene targeted therapies for cancer such as Imatinib. Burzynski has realised there is a party going on and attempted to gatecrash. Sadly it seems that he doesn’t even know where the party is, and has turned up a number of years late anyway. Its frankly a bit embarrassing from an outsider’s perspective.

If patients wish to try HDACi drugs, they should consider going on clinical trials using new, better HDACi drugs.

PB was discovered decades ago, and although it has been successful in treating a few disorders such as urea cycle diseases, there is little to suggest it is particularly useful in cancer. New generation HDACi drugs are in clinical trials across the US and other countries, which will likely have a higher efficacy (less drug needed for same effect), fewer side effects and may target histones in a different way. Regardless, there is a reason why PB has been largely forgotten about by mainstream medicine (and it’s not because Burzynski owns it, he doesn’t… it is owned by a mainstream pharmaceutical company he has no connection with). It is not as good as other available alternatives and is largely obsolete. Clinicaltrials.gov currently offers 145 open trials for HDACi drugs, almost all in a variety of cancers . In contrast, there is not a single trial listed for PB in any cancer. Uninformed critics may claim this is due to money and drugs companies not profiting from old drugs. This belief can be easily quashed by the observation that there are 28 open clinical trials for another HDACi drug; valproic acid, which has been around for in excess of 30 years (albeit in treatment for epilepsy – its HDACi properties were discovered comparatively recently), hence it is off-patent, exceptionally cheap and drug companies will likely only be able to make minimal profit from it. PB has not passed even phase II clinical trials for most applications, let alone phase III (a milestone which all drugs must normally pass, before being offered widely to the general public – another black mark on the dealings of Burzynski). However there are some phase I clinical trials (such as Gilbert et al, mentioned earlier), which appear not to have been followed up, indicating that the researchers were not pleased enough with the outcome to pursue the drug any further. In contrast newer HDACi Vorinostat is approved for treatment for a type of lymphoma (passed phase III)  and 95 open clinical trials are investigating its use in a range of other cancers.

There is very little evidence that HDACi are useful in cancer when used alone.

There is some preliminary evidence that HDACi in combination with other agents may be useful. For example, HDACi Vorinostat has been proposed to increase sensitivity of tumour cells to radiotherapy. Evidence suggesting that HDACi is useful alone in treatment of cancers, as various patient blogs and Twitter accounts have implied, is severely lacking.

Essentially, flogging a dead horse does not even begin to describe the way that Burzynski is using ‘antineoplastons’. I suspect he knows they don’t work very well either and is just attempting to engorge the Burzynski pension fund as much as possible. Potential Burzynski patients should know that yes, HDACi may have some effects in some tumours, but putting their trust in Burzynski who:

• Is not an oncologist, but is arrogant enough to presume he can dabble in one of the most complicated medical disciplines with no formal training;
• Is not a paediatrician, but experiments on children with a drug which has not even passed (or begun) phase III trials;
• Seems to be happy for patients to believe his treatment is non-toxic when this is simply not the case;
• Continues to sell antineoplastons as novel agents, when in fact PB is metabolised into the same chemicals;
• Implies that antineoplastons are gene targeted, when this is clearly not the case at all;

…may be a big mistake.

I understand that a lot of these patients are in truly impossible situations where their cancer is terminal. I would urge them to speak to their oncologists regarding current trials, and even search the Clinicaltrials.gov website themselves, to find properly controlled clinical trials of new drugs, or new combinations of drugs that they may be eligible for. Most of the CML patients who opted in for the first phase III trial with Imatinib are probably still alive to this day, over ten years later. It would be unfair to claim that ‘Imatinib style successes’ happen frequently in clinical trials, as this is not the case, but improvement in outcome, whether it be months more than conventional treatment regimes, years or sometimes as in the case of Imatinib, a ‘cure’, do happen in clinical trials. Even a small chance of achieving a cure, or more time might be an improvement on Burzynski. His absolute reluctance to produce any kind of data and subject it to scrutiny from his peers indicates that Burzynski has no confidence in his outcomes either and this should set alarm bells ringing for any patients considering his treatment.

If patients are particularly interested in pursuing HDACi drug treatment, then I would suggest researching alternatives to Burzynski and be aware that very few bona fide, well respected centres will offer them on their own, due to absolutely no proof that they are ‘curative’ as single agents. The Burzynski treatment is out of date, will probably have worse side effects and as described by many others, the level of care received at the clinic seems simply inadequate for cancer patients trying an experimental treatment. After starting a new treatment in trials, patients should be closely monitored, not sent to nearby hotels and then rushed to other, mainstream hospitals if treatment complications arise – as recommended in Burzynski patient literature and as described in a recent patient blog.

Cancer treatment is complex, can be dangerous for the patient and should be studiously monitored by professionals. Burzynski appears to underestimate many of these critical factors and his patients may be suffering as a result.