Carcinogenesis--a new point of view.

Presented article suggests the novel hypothesis of carcinogenesis, where the key moment for all types (biological, physical, chemical) of carcinogenesis has been discussed. For confirmation of the hypothesis thorough theoretical analysis of the mechanisms of malignant transformation of cells after influence of any type of carcinogens and results of experiments have been presented. Hypothesis highlights are formulated as follows: 1) Covalent bond disorders between S+-methionine and Fe3+ atoms in cytochrome; 2) Electron transport chain blockade with certain ligand after its penetration in cytochrome pocket with further formation of 6th coordination bond between ligand and Fe atom (in one case increase in mitochondrial pH precede-, and in other, it follows electron transport chain blockade in cytochromes); 3) Fe3+ reduction up to Fe2+ leading to blockade of aerobic glycolysis; 4) Decrease in enzyme (Е1-TDP, oxidases etc.) activity due to mitochondrial pH alterations; 5) Production of S-adenosylmethionine owing to lipoic acid amide leading to accumulation of homocysteine in cytoplasm with further penetration in cell nucleus producing DNA mutations; 6) Fe2+ wash-out from cytochrome and its deposition in ferritin.

Anticancer efficacy of hydroxyethylthiamine diphosphate in vivo.

AIM: The aim of the presented article was investigation of anticancer efficacy of hydroxyethylthiamine diphosphate (HTD) in vivo. MATERIALS AND METHODS: The study was carried out on 30 C57BL/6J mice subcutaneously transplanted with Ehrlich carcinoma. Animals were treated with intraperitoneal injections of the solution composed from pyruvic acid and thiamine bromide every other day during 10 days and thereafter, every day during 2 weeks. Treatment efficacy was evaluated by tumor growth inhibition. RESULTS: In experimental animals treated with HTD, significant tumor growth inhibition has been registered: 73% at day 45(th) compared to the control group (p < 0.001). CONCLUSION: Treatment with HTD demonstrated high anticancer efficacy in vivo.

The novel hypothesis of carcinogenesis and anti-cancer treatment perspectives - Hydroxyethylthiamine diphosphate.

In presented article, the novel hypothesis of carcinogenesis, and thorough discussion of some essential biochemical mechanisms which might be responsible for the malignant transformation of cells (bond disorders between Fe(3+) and S(+)-methionine in cytochrome; blockage of the last 3-d orbital of Fe by the certain ligand and formation of 6th coordinated bond leading to Fe(3+) reduction up to Fe(2+) and cessation of tissue respiration; increase in mitochondrial pH and further in cell, leading to decreased activity of most of enzymes (thiamine diphosphate, oxidases); formation of S-adenosyl-methionine with its further dissociation and production of adenosine and homocysteine; effects of homocysteine on DNA structures, homocysteine-induced dimethylation of certain nitrogen basis and their extrusion from strands of DNA leading to mutations and cellular atypism) has been suggested. Along with theoretical discussions, article provides results of preliminary investigations carried out on C57Bl/6J mice with Ehrlich carcinoma aimed to capture lipoic acid amide with Hydroxyethylthiamine diphosphate, and study effects of Hydroxyethylthiamine diphosphate against malignant transformation of cells. Experiments have shown inhibition of cancer growth in treated animals. Morphological investigations of cancer tissue revealed necrotic zones, inflammatory infiltrations, central necrosis with adjacent inflammatory mono- and polymorph infiltrations, must cells, segmento-nuclear leukocytes, lymphadenoid follicular hyperplasia. According to the novel hypothesis of carcinogenesis and results of experiments the new approaches and perspectives of anti-cancer treatment with the use of Hydroxiethyl-thiamine diphosphate has been suggested.

C2-alpha-lactylthiamin diphosphate is an intermediate on the pathway of thiamin diphosphate-dependent pyruvate decarboxylation. Evidence on enzymes and models.

Thiamin diphosphate (ThDP)-dependent decarboxylations are usually assumed to proceed by a series of covalent intermediates, the first one being the C2-trimethylthiazolium adduct with pyruvate, C2-alpha-lactylthiamin diphosphate (LThDP). Herein is addressed whether such an intermediate is kinetically competent with the enzymatic turnover numbers. In model studies it is shown that the first-order rate constant for decarboxylation can indeed exceed 50 s(-1) in tetrahydrofuran as solvent, approximately 10(3) times faster than achieved in previous model systems. When racemic LThDP was exposed to the E91D yeast pyruvate decarboxylase variant, or to the E1 subunit of the pyruvate dehydrogenase complex (PDHc-E1) from Escherichia coli, it was partitioned between reversion to pyruvate and decarboxylation. Under steady-state conditions, the rate of these reactions is severely limited by the release of ThDP from the enzyme. Under pre-steady-state conditions, the rate constant for decarboxylation on exposure of LThDP to the E1 subunit of the pyruvate dehydrogenase complex was 0.4 s(-1), still more than a 100-fold slower than the turnover number. Because these experiments include binding, decarboxylation, and oxidation (for detection purposes), this is a lower limit on the rate constant for decarboxylation. The reasons for this slow reaction most likely include a slow conformational change of the free LThDP to the V conformation enforced by the enzyme. Between the results from model studies and those from the two enzymes, it is proposed that LThDP is indeed on the decarboxylation pathway of the two enzymes studied, and once LThDP is bound the protein needs to provide little assistance other than a low polarity environment.

[Effect of ethanol and ethylene glycol on the circadian rhythm of adenylic nucleotide levels in muscles]. / Vliianie étanola i etilenglikola na sutochnyi ritm soderzhaniia adenilovykh nukleotidov v myshtsakh.

The 24-hour's changes in ATP content in the gastrocnemiuses of intact rast are not significant. Both the ADP and AMP content is subjected to 24-hour's variations. It reaches its maximum within the time period from 12 to 15 o'clock p.m. for ADP and at 18 o'clock p.m. for AMP. Intragastric administration of ethanol and ethylene glycol to rats in a dose of 1/3 LD50 once per 24-hour period at 9 a. m. during a 7-days-long period dramatically changes the 24-hour's rhythm of adenylic nucleotide content in the rat gastrocnemius. It has been found that ethanol increases the average 24-hour's content of ATP, but decreases that of ADP. It increases the range of their 24-hour period variations and changes the acrophase. Ethylene glycol decreases the average 24-hour content of the both ATP and ADP, but it increases that of AMP. It changes their acrophases and increases the ranges of 24-hour-period variations of ATP.

[Antivitamin activity of oxythiamine disulfide nicotinate]. / Antivitaminnaia aktivnost' oksitiamindisul'fidnikotinata.

The B1-antivitamin activity of oxythiamine disulphide nicotinate has been determined in experiments on albino mice and it is shown that in the liver this derivative exerts the equal action while in the blood and heart--a more profound and prolonged inhibitory action on the transketolase activity in comparison with oxythiamine disulphide. Like the initial compound oxythiamine disulphide nicotinate does not penetrate through hemato-encephalic barrier and does not inhibit the brain transketolase.

[Comparative antivitamin activity of oxythiamine disulfide and its monosulfoxide]. / Sravnitel'naia antivitaminnaia aktivnost' oksitiamindisul'fida i ego monosul'foksida.

The B1-antivitamin activity of oxythiamine disulphide monosulphoxide has been determined in experiments on albino mice. It is shown that this derivative is less toxic and exerts a more profound and prolonged inhibitory action on the pyruvate dehydrogenase and transketolase activity in the animal body in comparison with initial oxythiamine disulphide.

[Effect of oxythiamine disulfides on the pancreas and thyroid of rats]. / Vliianie disul'fidov oksitiamina na podzheludochnuiu i shchitovidnuiu zhelezy krys.

Single administration of oxythiamine (200 mg/kg) or an isomolar amount of oxythiamineamyldisulfide to rats does not change the content of insulin in 72 h, whereas oxythiaminehexyldisulfide slightly increases the blood level of the hormone. Oxythiamine and its disulfides cause changes of the thyroid indicating considerable suppression of its function. It is assumed that hormonal mediation of oxythiamine nonspecific metabolic effects results predominantly from the involvement of the thyroid hormones rather than insulin.

[Antivitamin activity of O-acyloxythiamine disulfides]. / Antivitaminnaia aktivnost' O-atsiloksitiamindisul'fidov.

B1-antivitamin activity of symmetrical oxythiamine disulphide esters with succinic and o-phthalic acids has been studied in experiments on albino mice. It is shown that O-acyloxythiamine disulphides exert more profound and prolonged inhibitory effect on the transketolase activity in the animal body in comparison with the known antagonist of vitamin B1, oxythiamine, and the initial oxythiamine disulphide.

[Comparative evaluation of the action of oxythiamine and its derivatives on animals with Erhlich's ascitic cancer]. / Sravnitel'naia otsenka deistviia oksitiamina i nekotorykh ego proizvodnykh na zhivotnykh s astsitnym rakom Erlikha.

It is found that hydroxythiamine ester with sebacic acid surpassed hydroxythiamine in its antitumour effect on Ehrlich ascites tumour in albino mice. A linear correlation is observed between the values of activity coefficients of hydroxythiamine and its esters with dicarboxylic acids and some morphometric data.

[Changes in the permeability of the blood-brain barrier to oxythiamine]. / Ob izmenenii pronitsaemosti gematoéntsefalicheskogo bar'era dlia oksitiamina.

Activity of transketolase was distinctly inhibited in mice brain after simultaneous administration of hydroxythiamine and 3,3-dimethyl-l-phenyl-l-phthalyl acetic acid. The rate of the enzyme inhibition correlated with an increase of the acid concentration in the mixture studied. The data obtained suggest that permeability of blood-brain barrier for hydroxythiamine was altered in simultaneous administration of the vitamin with some biologically active preparations.

[Transketolase inhibitors based on disulfide derivatives of oxythiamine with branched hydrocarbon chains]. / Ingibitory transketolazy na osnove disul'fidnykh proizvodnykh oksitiamina s razvetvlennymi uglevodorodnymi tsepiami.

The experiments on mice have shown that oxythiamine disulphide derivatives with the branched hydrocarbon chains are less toxic in the organism as compared to oxythiamine and corresponding disulphides with the unbranched hydrocarbon chains and also induce a more pronounced inhibition of transketolase in the liver and other tissues. It is found that under the effect of the above substances the recovery of enzymic activity is slower than in the case with the oxythiamine application.