Combination of selenium-containing compounds with cytostatics

Details Combination of selenium-containing compounds with cytostatics Combination of selenium-containing compounds with cytostatics

2001-02-02

2003-12-02

Goldberg, Jerome D. (Department: 1614)

Drug, bio-affecting and body treating compositions

Inorganic active ingredient containing

Heavy metal or compound thereof

C424S649000, C514S283000, C514S449000, C514S492000

Reexamination Certificate

active

06656509

ABSTRACT:

This application is a 371 of PCT/EP99/03771 filed May 31, 1999.
The present invention relates to the use of selenium and/or a derivative thereof in combination with a cytostatic or a mixture of cytostatics.
The chemical element selenium is a trace element which is essential for humans and animals and influences above all oxidative processes as well as thyroxine metabolism. In humans it could be detected that the enzyme glutathione peroxidase and the selenoprotein P found in plasma contain selenium in the form of the amino acid selenocysteine. The selenium-containing glutathione peroxidase forms part of the antioxidative protective system of the mammalian cell. In the presence of sufficient amounts of substrate, i.e. reduced glutathione, glutathione peroxidase converts a multitude of different hydroperoxides into corresponding alcohols. It could be demonstrated that the integrity of cellular and subcellular membranes decisively depends on the intactness of the glutathione peroxidase system. Selenium as part of glutathione peroxidase can reduce the lipid peroxidation rate and the resulting membrane damage.
In animals the type-I iodothyronine-5′-deiodase was recently characterized as a selenium-containing enzyme. In the thyroid, liver and lung of humans, iodothyronine deiodase also converts thyroxine (T
4
) into triiodothyronine (T
3
), the active thyroid hormone. In the case of selenium deficiencies, e.g. phenylketonuria and cystic fibrosis, increased T
4
values could be detected at a simultaneously reduced T
3
level. By the administration of sodium selenite (Na
2
SeO
3
) the thyroid metabolism is normalized again.
As a further selenium-dependent enzyme, a human thioredoxin reductase from lung cells was recently described to contain selenium as a cofactor (Tamura and Stadtman, 1996, Biochemistry, Proc. Natl. Acad. Sci., 93: 1006-101 1). The enzyme could so far be isolated from T cells, lung tissue and placenta (Gladyshev et al., 1996, Biochemistry, Proc. Natl. Acad. Sci., 93: 6146-6151). The selenium-dependent enzyme thioredoxin reductase reduces thioredoxin. Thioredoxin is overexpressed in a number of tumors, and some experimental studies have shown that thioredoxin contributes to the growth and malign transformation of some human cancer cells. The enzyme thioredoxin reductase therefore plays a role in the regulation of the growth of normal and cancer cells.
Proof of the pathophysiological relevance of the selenium-dependent reactions has been furnished by observation of selenium deficiency symptoms in humans and in animals. Deficiency of this trace element intensifies oxidatively or chemically induced liver damage and the toxicity of heavy metals such as mercury and cadmium.
In humans the Keshan disease, an endemically occurring cariomyopathy, and the so-called Kaschin-Beck disease, also an endemically occurring osteoathropathy with strong deformations of the joints, are described as selenium deficiency symptoms. Clinically manifested selenium deficiency was also observed as a consequence of long-term parenteral feeding and of balanced diets. Cardiomyopathies and myopathies of the skeletal muscles as well as a shift in the T
3
/T
4
ratio were above all observed.
Epidemiological studies hint at an inverse correlation between blood-selenium level and the incidence of cardiovascular diseases (cardiomyopathies, arteriosclerosis, myocardial infraction) and tumor diseases, in particular of the digestive system, breast and liver. Reduced selenium levels in plasma may be present in patients with renal insufficiency and in the case of gastrointestinal diseases. Selenium deficiency can be detected through a reduced selenium level in whole blood or plasma and a reduced glutathione peroxidase activity in whole blood, plasma or thrombocytes.
Selenium substitution in the case of deficiency symptoms activates reactions of the immune defense, in particular unspecific, cell-bound and humoral reactions. The selenium-containing glutathione peroxidase influences leukotriene, thromboxane and prostacyclin metabolism. The immunomodulatory effects of selenium-containing compounds are listed in the following:
Stimulation of lymphocyte proliferation
Activation of cytotoxic T cells and NK cells
Increase in interleukin-2 receptor expression
Selective reduction of the number of T suppressor cells
Increase in interferon-&ggr; synthesis
general decrease in infection frequency
Selenium in the form of selenite (SeO
3
2−
) is not directly incorporated into proteins. In blood, selenite is first mainly taken up by erythrocytes and enzymatically reduced to selenium hydrogen. Selenium hydrogen serves as a central selenium pool for excretion and for the targeted incorporation into selenoproteins. In this reduced form selenium is bound to plasma proteins which migrate into the liver and other organs. The plasmatic secondary transportation starting from the liver into the glutathione peroxidase-synthetized target tissue probably takes place in the form of a selenocysteine-containing P selenoprotein. The further metabolic course of selenoprotein biosynthesis has so far only been known from prokaryotic model organisms. In these organisms selenocysteine is specifically incorporated-into the peptide chain of the glutathione peroxidase in the course of the translation.
Excessive selenium hydrogen in humans is metabolized through methylselenol and dimethylselenide to trimethylselenonium ion, the main excretion product. After oral application selenite is predominantly absorbed from the small intestine. The intestinal absorption of sodium selenite is not regulated homeostatically. Depending on the concentration and on additives, it is between 44% and 89%, sometimes over 90%. The amino acid cysteine promotes the sodium selenite absorption.
Organic selenium compounds must first be converted into selenium hydrogen before they are available for the synthesis of selenoproteins. Instead of methionine, selenomethionine, which is mainly contained in food, can also be unspecifically incorporated statistically in the case of protein biosynthesis into proteins that do not contain selenium.
The total amount of selenium in the human body is between 4 mg and 20 mg in a well-balanced selenium metabolism. Selenium is excreted in humans via urine, faeces and lung, depending on the dose applied. Selenium is primarily excreted renally in the form of the above-mentioned trimethylselenonium ions.
In humans acute selenium intoxications have hardly been described up to now. Garlic-like breadth, tiredness, queasiness, diarrhea and abdominal pain are regarded as signs of an acute overdosage. In humans, a safe maximum daily intake of selenium of 820 &mgr;g was inferred from observations regarding the chronic toxicity of selenium, while a dosage of up to 500 &mgr;g per day is also considered to be harmless in sensitive persons. As clinical signs of endemically occurring selenosis, alopecia, brittleness of the finger nails, skin alterations and disorders in the nerve system were observed in a study carried out in China after a daily supply of 3200-6700 &mgr;g selenium. In various species a decreased reproductive capacity because of a reduced motility of spermatozoons was described as a symptom of selenosis.
In a dose/escalation study, between 10 and 50 mg selenium were infused in the form of sodium-selenite pentahydrate in tumor patients. Within 30 minutes the selenium level in plasma rose from 200 &mgr;g/l to 1200 &mgr;g/l after administration of 10 mg selenium as sodium selenite. After 8 and 16 hours the plasma selenium decreased to 770 &mgr;g/I and 430 &mgr;g/I, respectively. After 24 hours the selenium level in plasma had again reached its initial value. Gastrointestinal toxicity was observed starting from about 20 mg selenium as sodium selenite and was reversible after the administration of the preparation had been stopped (Röhrer H., 1989, Erfahrungsheilkunde 38: 10a, 761).
As counter-measures in the case of intoxication, gastric lavage, forced diuresis, or highly dosed vitamin C administrations are possible. In the case of an ext

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