Gammill/ S. Debate

[Guest guest]

On November 16, 1999, this letter was first posted to the e-mail resource 'cures for canceregroups.

www.jsr1936.com The Cure for Cancer? jsr1936@...

,

Thank you for posting your scientific and medical references to cures for canceregroups on November 15,1999.

To facilitate our debate I am posting again my November 7, 1999 letter titled, 'To Dr. Varmus, Director, National Institutes of Health (NIH)'.

, two of your entries detail the toxicity of Thiazolidine-4-carboxylic acid (Thioproline):

" Thiazolidine-4-carboxylic acid (A.T.C.) has been marketed in France since 1964 for the treatment of hepatic and biliary disorders. {Hepalidine (Riker Lab.): Packs of 20 tablets, each containing 100 mg. Thiobiline (Riker Lab.): Packs of 20 vials, each containing 100 mg.] As early as 1970, both the Paris and Marseilles Poison Control Centres had emphasized the toxicity of this drug which induces convulsions in children subject of overdosage [1]. Brugarolas and Gosalvez have recently suggested the use of A.T.C. in the treatment of epidermoid carcinoma. They believe that the drug causes reverse transformation of tumor cells to normal ones [2]. If its efficiency is confirmed, A.T.C. should soon be very widely used and therefore its therapeutic risk needs to be clarified. "

" Among the calls for information recently received by the French Poison Control Centers, 78 concerned a liver protecting agent, thiazolidine carboxylic acid. In almost every case, doses well above the therapeutic range have provided a status epilepticus. Thus confirming the neurotoxicity of the drug which had been known to the Poison control Centers for the past 10 years. Several patients had also metabolic acidosis, severe hypoglycaemia, or, more scarcely, hyperglycaemia. Seizures convulsions occurred specially in young children whose immature blood-brain barrier allowed penetration into the CSF of thiazolidine carboxylic acid, later metabolized locally into the strongly irritant compound formaldehyde. In view of its toxicity, the drug should never be administrated to young children. The usual measures to prevent intoxication should be applied and in case of overdosage the patients should be admitted to hospital for observation. Long-lasting anti-epileptic treatments should be avoided. "

, please note that I also detail this acid's toxicity in the 'To Dr. Varmus' letter:

" Thiazolidine-4-carboxylic acid is rapidly absorbed from the gastrointestinal tract (75% in 30 min) and rapidly concentrated in the liver where it is metabolised to cysteine and formaldehyde. The pathway for the detoxification of formaldehyde is oxidation to formic acid then to carbon dioxide and water. In overdosage the degradation capacity of the liver is exceeded; the drug is distributed throughout the body tissues, especially in the cerebrospinal fluid where it is metabolised. Acute intoxication leads to intrameningeal liberation of formaldehyde, the irritating action of which is responsible for the symptoms observed.

Overdosage induces status epilepticus and coma shortly after ingestion (15 min to an hour). The dangerous dose varies from one person to another. It is especially small in young children whose blood-brain barrier is less effective and allows a large passage of the drug. Seizures may occur with doses of 30 mg/kg; they are always reported with more than 50 mg/kg. In adults seizures were recorded with 60 mg/kg. These neurological symptoms are associated with blood glucose disturbances (initial and brief hypoglycaemia followed by a more long-lasting hyperglycaemia) and sometimes with hyperthermia. "

, in one of your references only the title and author's name printed out - 'Thioproline (Norgamem): a useless drug in the treatment of squamous cell carcinoma.' by Alberto P.

My 'To Dr. Varmus' letter refers to this study and states this:

" .....This study is in the form of a 'Letter to the Editor' to the 'Eur J Cancer Clin Oncol, Vol. 17, No. 9, pp. 1061-1062, September, 1981. The study is one page long and includes a bibliography with two entries. The author is Pierre Alberto. The study involved 37 patients and concluded:

' Thus, the previously reported anti-tumor activity of thioproline in squamous cell carcinoma could not be reproduced with an identical dose schedule in the present multicentric trial. Although local or neurological complication were relatively infrequent, the treatment was poorly tolerated by most patients, due to the large number of intramuscular injections. "

The 'To Dr. Varmus' letter has the researcher's (Dr. Gosalvez) response:

" .....None of the head-and-neck patients in Alberto and Boccardo's trials had pulmonary metastasis..... "

Dr. Gosalvez also stated:

" .....In my opinion neither the drug nor the concept have failed. It might seem that the failure by Alberto and of Boccardo et al to reproduce our preliminary results with thioproline represents a failure of the drug to live up to expectations. However, reports of our later work given at scientific meetings or in the pipeline, confirm that thioproline does induce reverse transformation and that the whole concept, despite its complexities, is promising. (j.s.r. emphasis)

The 'To Dr. Varmus' letter also contains this letter by T.F. Slater which I think everyone has overlooked:

" Sir, - I have followed with interest Lancet contributions on the possible anti-tumour action of thioproline (Jan. 12, p.68) and on the toxicity of this agent (Feb. 16, p.365), and the usefulness of screening related adducts (Feb. 16, p.365). Thioproline is the parent compound of an extensive series of substances already studied by various laboratories and for differing purposes. The non-enzymic reversible interaction of alpha, beta-unsaturated aldehydes with cysteine (and other thio-containing substances) has been reported on extensively by Schauenstein and Esterbauer's group in Graz. The thiazolidine and furan derivative produced by interaction of 4-hydroxy-alk-2-en1-als with cysteine have been studied over many years for anti-tumour action in animal tumours, and some of the parent hydroxy-unsaturated aldehydes have also been tested on human cancer. The initial stimulus for these animal studies was generated by the knowledge that such unsaturated aldehydes are formed as products of lipid peroxidation and that the cysteine adducts are less toxic than the parent aldehyde. These unsaturated aldehydes have similarities to the ketoaldehyde, methylglyoxal, which has been proposed by Szent-Gyorgyi to have a key role in helping to reverse the behaviour of tumour cell membranes back towards a normal pattern. In this respect, it is worth noting that methylglyoxal has been shown to inhibit membrane adenyl cyclase at micromolar concentrations (M.U. Dianzani, L. Paradisi, and C. Panagini, unpublished)