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Platinum and cancer: biochemistry, physiology, medicine.

INTRODUCTION

In 1747 spanish mathematician Don Antonio de Uolya has brought samples of the serious white metal retrieved in gold deposits of Peru to Europe. Silvery grains did not fuse in the forge furnace, were not cracked at impacts on an anvil, not dissolved in the most strong acids and did not dim under operation of chemicals. De Uolya has brought them as an amusing phenomenon for probe to the European chemists. Around of "persistent" metal spores - whether simple this substance, or an alloy of known metals have immediately inflamed. In that pore the unique known unit possessing similar chemical stability, was gold. However how much searched, gold in samples of metal it was not found out. More, that, the density of metal grains appeared above density of the gold! Refractory and chemical stability were really surprising. For external similarity to silver new metal has been ironically called as platinum.

The first practical application to new metal in midpoint of XVIII century was found by counterfeiters - platinum has high density and is well alloyed with gold and silver, the price of it in those days was much lower. Not knowing a mode to determine a fake, the Spanish government has declared struggle platinum "decay", but by 1778 and itself began to mix cheaper platinum to gold of coins. Then, about 1800, from platinum have started to produce bulbs, all over again for distillation and a concentration of acids, then and for laboratory probes. Main now - the catalysis, a unit #78 has found a usage is relative recently, the first experiences on hydrogenation on the platinum catalyst concern to the end of XIX century.

Biological activity of bonds of platinum has been open "serendipitously" in 1967 Rosenberg and employees. At learning body height E.coli in an electric field of two "inert" platinum electrodes in solution NH4Cl it was revealed, that bacteria hardly expand at length and cease to share. The reason of this phenomenon (understood, by the way, not at once) consist in transition of a quantity of platinum from electrodes in a solution as Pt2+ and Pt4+ with derivation of complex bonds with ammonia and ions of chlorine. The subsequent microbiological probes have shown, that for effect observed by Rosenberg cis-complex [Pt (NH3) 2Cl2], formed by divalent platinum in conditions of experiment responds.

The further probes of Cisplatinum - so will name this complex later - have shown extremely high ability to stop body height of cells as pro-, and an eucariot. Especially strong it was affected cells of tumours (initially - sarcomas for mice), in some cases durable therapy by Cisplatinum completely cured a mouse cancer (under reservations, about it is further). Cisplatinum has sequentially passed all stages of clinical trials and now is one of the most effective and widely used preparations in therapy of a cancer for the person. Against some tumours percent of treatment (the complete lisis of a tumour and a metastasis) achieves 80 %.

Up to 70th years of the last century were not practically any data on the gear of effect of Cisplatinum (and similar bonds on the structure, synthesized later) on living cells. The gear generally accepted now including disturbance of replication by a cellular DNA, has been recreated by forces of several hundreds laboratories within the last thirty years. Some tens hypotheses concerning the nature of canceroliticed effect - from a blockage of a cellular bellow before modification of immunity were fulfilled. The fine browse of proofs of the accepted gear and deadlock variants on path to it is made by Roberts and Thomson. Operation on finding-out of details of interaction of bonds of platinum with biomolecules in general and from the DNA in particular, proceeds now, an example to that - recent Lippert browse.

The present abstract is called to mirror in general a modern view on the gear of operation of platinumconsisting antitumoral preparations and to specify some features of concrete types of bonds.

TOXICITY

Let's start with the most unpleasant - from toxicity of bonds of platinum. Being the bioxened unit, Pt at introduction in an organism or in any way itself does not show, or causes the hardest lesions, first of all kidneys, a liver, nervous and immune systems.

In itself metal platinum of toxic operation does not render, however, the impurities contained in a platinum black (first of all, a tellurium), are toxicant, and at hit of powder Pt in a gastrointestinal tract there are necrosises of sites mucous, a granular dystrophia of hepatocytes, a swelling of an epithelium of weaved canaliculuses of a kidney, and also " a general intoxication ". Lethal poisonings with metal platinum are not marked.

Salts of platinum give a common intoxication of an organism with destruction of experimental animals in period from three o'clock about three day after introduction of a preparation. Are most toxicant (at enteral introduction) PtCl6 (for rats LD50=0.8 mAt/kg), (NH4) 2PtCl6 (LD50=0.4 mAt/kg) and cis-Pt (NH3) 2Cl2 (that about which it was spoken in Introduction). At an inhalation poisoning with a hexachlorplatinat of an ammonium lethal concentration have not been achieved. The intoxication is accompanied by disturbance of a carbohydrate, albuminous and cholesteric exchange. For the person - a nausea, a diarrhea, dropping of a level of a hemoglobin in bloods, corrupting of kidneys. The hexachlorplatinat of an ammonium is capable to be absorbed in a skin, thus platinum is found out in all internal organs, a blood and urine, accumulation occurs in a lien, adrenals, kidneys and genitals where Pt it is found out even in thirty days after introduction. The hexachlorplatinat of a potassium entered to pregnant rats after a while penetrates into all tissues of a fetus.

Complex bonds Pt at inhalation as a dust or a fog (5-70 mg / m3) cause a cyanosis, difficulty of respiration, tussis, at durable effect a bronchial asthma. In some cases allergic responses (reddening and an ecdysis of a skin, a rash on open sites of a body) are marked. Similar operation is rendered with a platinumchlorhydrogened acid and a hexachlorplatinat of an ammonium. For chemists at operation (NH4) 2PtCl6 the photophobia, a rhinitis develops, at durable effect - an asthma. It is curious to mark, that on individual sensitivity to bonds of platinum for different people the essential differences bonded to some genetically stipulated tags are observed. For example, blondes, as a rule are more sensitive (response concentration 10^-8M causes) to solutions of salts, at the same time insensitive people to platinum do not react even to direct plotting on a skin of a solution with concentration 10^-2M.

The so-called platinose concerns to consequences of a chronic poisoning with complexes of platinum - the collection of the above-stated signs carrying constant character. For suffering the platinose detects the bias of an adrenoreceptored regulation. At a continuous duty with platinum the got allergy arises approximately in half of cases.

Main path of leadingout of platinum from an organism - kidneys and a gastrointestinal tract (at peroral reception). At single introduction in a stomach the general delay in an organism makes 0.4 %. Some bonds (for example, a coffeine) are capable to strengthen toxic operation of bonds of platinum.

All told completely concerns and to the preparations described below. Moreover, toxicity is the limiting factor in therapy by all platinumconsisting bonds. One of main directions in probes of antitumoral preparations today is development of nontoxical clones of Cisplatinum (which, by the way, at introduction to mice besides medicinal effect causes all described signs down to convulsions and lethal outcome). Some bonds, at joint introduction with Cisplatinum, essentially sink toxicity of the latter, for example, Mannitum in a combination to the big consumption of water causes a plentiful diuresis and sinks a toxic load on kidneys. In this direction also works are carried on.

As a whole though "noble" platinum already more than blepharon is to the chemists - non-organics researching coordination bonds, its toxicant character demands the serious and cautious ratio to itself.

CHEMISTRY OF PLATINUM PREPARATIONS

For platinum in physiological conditions the most stable are rates of oxidation 0, 2 + and 4 +. The first corresponds to metal platinum both some astable and extremely toxicant bonds. Platinum in this rate of oxidation does not find medicinal application. States 2 + and 4 + are characterized:

The resulted collection of properties is unique and characteristic only for a unit #78. Neither its neighbours, nor other units of Periodic System do not possess this or similar set of characteristics.

We convert now directly to platinum preparations. Right after detections of antitumoral effect of Cisplatinum, many laboratories worldwide have undertaken probes of its structural clones. Unfortunately, very much few from the retrieved medicines on a therapeutic index (the ratio activity / toxicity) have surpassed Cisplatinum. One of the most successful bonds synthesized to the present time - - wins a carboplatine at the expense of smaller toxicity. The bonds most important and used in clinical practice and their latin names are resulted on the scheme in Application 1.

Cisplatinum

Cisplatinum, which antitumoral activity has detected Rosenberg, in the structure contains at once all parameters which as now believe, are necessary for cytostatic operation:

For finding-out of biochemical reasons of such demands to structure of the complex various authors had been undertook probes of interactions of Cisplatinum (as most accessible and effective preparation) with various biomolecules in vitro. There was a following:

Fig.2

With the nucleotided basis of the DDP (a dichlordiamminplatin, the synonym of Cisplatinum) will derivate products of replacement of both atoms of chlorine from coordination sphere Pt. The atom of platinum is bound to purine nucleotides not through an exocycliced amino group as it would be possible to assume, and through heterocyclic atom of nitrogen N7, derivating complexes of structure cis-Pt (NH3) 2 (Guanine-N7) 2 and cis-Pt (NH3) 2 (Guanine-N7) (Adenine-N7). The sharp predominance of the first (detected in competitive responses) speaks derivation of additional hydrogen link between a proton of an amino group and exocycliced C6-oxygen of a guanine. Binding occurs to a citosine through N3, with a thymine and a uracil in a neutral solution it is weak. Series of "preferences" can be constructed as follows: Guanine-N7>> Adenine-N7> Adenine-N1> Cytidine-N3>> Thymine and Uracil. Presence of phosphatic group in 5 '-position of a furanosed cycle gear ups response because of derivation of hydrogen links between oxygen of Natrii phosphas and protons amminesed a ligands.

Fig.3

The further probes have convincingly shown, that a principal cause of cytostatic activity of Cisplatinum - disturbance of replication of the DNA as a result of derivation intrachain (intrastrand) platinum sews. From the beginning of the last blepharon other bonds, appealing appearance in the DNA of longitudinal and transversal links are known also. These are preparations of group of yperite (mustard gas in an English transcription). So-called "mustards", structure Cl-CH2-CH2-S-R (sulfur mustard) and (Cl-CH2-CH2) 2-NR (nitrogen mustard) are widely applied in biochemistry to this purpose. The comparative characteristic of effect on the DNA "mustards" and Cisplatinum is resulted in Roberts browse. In due time on the basis of these data output that Cisplatinum at interaction from the DNA works as the bifunctional agent has been made.

MOLECULARED - BIOLOGICAL "TERRORISTS"

Let's leave with in the side a question on how the DDP gets in a cell - by the present moment in this direction some suppositions of this or that degree of verisimilitude are stated only.

Being the intracomplex not charged bond, Cisplatinum and its clones are theoretically capable to diffuse through a bellow passively. For the benefit of such supposition correlation of activity of a preparation and its solubility in a weaklypolared dissolvent speaks (Chloroformium). Coefficient of an ex-traction of substance Chloroformium some time even used as the preliminary test for "perspectivity" of this or that bond. With detection of exceptions such tests have been stopped.

The supposition about that the DDP penetrates into a cell in the active way (having deceived any transport system) yet has not received deciding arguments neither for, nor against. One is precisely known - in cells gets is far from being all entered preparation. Most of its part is output from bloody river by kidneys, mainly in constant sort or as tetramined complexes. For this reason main "injured" of side effects of platinum medicines there is a system of selection. Amplified hydration of an organism, introduction of stimulators of a diuresis and selection of the schedule of reception of a preparation renal toxicity can be reduced to minimum.

Fig.4

Having penetrated anyhow in a cell, Cisplatinum and its clones start to bring deep distortions in operation of enzymatic systems. Already mentioned affinity of an ion of platinum to sulphidic sulfur leads to to the following: having met sulfurcontaining enzyme and having joined to SH-group, Cisplatinum in the best (and infrequent) a case inhibits it, and in the inferior (and as a rule) - is irreversible spoils. Having noticed the ratio of molecular masses of the DDP and enzymes, it is possible to see, that for disturbance of operation of many ferment systems enough pycogrammed amounts of platinum preparations. Some enzymes in a cell are present at amount of all of several tens molecules.

The question on, whether gets the DDP in a nucleus by passive diffusion or deceiving intracellular system of transport, remains obscure. In experiments on a natural two-chain DNA in vitro it is shown, that in presence at a solution simultaneously the DNA and fibers, preparations of platinum are bound mainly to the DNA. It is the strange fact since it is grey (sulphidic, or a thiourea) supersedes monomeric nucleotides from coordination sphere of platinum. Engaging of " stericaled factors " and chelated effect does not give a faultless explanation.

In experiences in vitro it is shown, that replication "platinized" by the DNA occurs to the gross errors, similar that arise at replication of the DNA with timidined dimmers and auprined sites in cells with genetically disconnected systems of repair (experiences on E.coli). On an intestinal rod the big functional similarity platinized by the DNA from a DNA, received is shown also at a x-ray or radioactive irradiation of a cell. This radiomimetic the effect allows to use the DDP as a sensitinogen of tumours at a radiotherapy.

In norm timidined dimmers and other damages originating at an irradiation or chemical effect ** on the DNA, cellular systems of a specific, excisioned and postreplycatived reparation manage. The second is most effective, the essence of its(her) operation briefly consists in "cut" of the injured site by nucleases and the subsequent subsynthesis normal chains on saved complymentaried. The postreplycatived reparation switches on at detection of defects of a recombination again synthesized chains. In experiences on E.coli it is shown, that a cell, deficient on genes of key components of those or other reparation systems, is much more sensitive to effect of the DDP, than healthy. It gives some explanation to selective operation of platinum preparations on series (quite concrete) sorts of tumours. In a cancer cell the part of reparation systems can not function. However, the return variant - the artificial selection called(caused) by introduced toxin is probable also, leads to to selection from a population and to reproduction of mutants in which systems of a reparation are extremely active. It is shown, that durable cultivation of cells on platinumconsisting medium causes appearance in them fastnesses to the increased doses of Cisplatinum. For some cells (most "problem" now tumours) this fastness is present initially. The given fact makes difficulty in a chemotherapy as there are patients congenital fastness to preparations of platinum (platinum-resistant patients). For the some people fastness appears during therapy. In such cases the medicinal effect disappears, toxicity remains at a former level.

Normal concentration of recoverable defects in a cellular DNA - one - two some tens thousand nucleotides. At platinization of the DNA in vitro some platinum sews on 20-30 bp without effort have been received. Even on the order lower concentration of defects to cellular systems of a reparation appears not under force. Replication of the DNA occurs to not remedied errors, there and then and derived molecules "are loaded" with platinum, and, at last, after one or several divisions, the cell perishes.

The condition " after one or several divisions " has critical importance. It is known, that cells of a cancer tumour share much more often, than cells of the majority of tissues of an organism. It allows a platinum preparation to render selective effect on a tumour, not injuring a tissue of an organism.

The gear of destruction of cells described above operation of preparations of platinum is very effective. But, unfortunately very much often the victim of the platinum complex to a cancer tumour has no any ratio. As a rule, together with a tumour at therapy by Cisplatinum and clones all rapidly growing or updated tissues of an organism - mucosas of a gastrointestinal tract, respiratory system, eyes, an epithelium of a skin and a cornea, a blood, tissues adjoining to wounds, etc. are injured. Their cells, receiving the same amount of platinum (its penetration into cells not selectively) and so fast sharing, suffer from therapy the same as also a tumour. The result, besides "cosmetic" damages of a skin and abaissement of hair, can be the got immunodeficiency(immunity-scarced), ulcerations of a gastrointestinal tract and a mouth, difficulty with an adhesion of wounds. On all this the acute toxic effects described above are superimposed.

In the total, despite of high performance of suppression of body height of tumours preparations of platinum, such therapy manages to an organism very much and very dearly. The question at treatment of the advanced tumours before the patient is usually put so: to die in some months of a cancer or in five - six years from consequences of its therapy. The third, unfortunately, it is not given yet, but intensive searches of more effective and less toxiferous medicines are now carried on in hundreds laboratories worldwide.

MEDICINES

In summary the report of the most perspective now preparations of platinum - the so-called preparations of the second generation possessing improved metrics of antitumoral activity and toxicity in comparison with Cisplatinum will be given. Structural formulas are resulted in Application 1.

Carboplatin (synonyms CBDCA, JM-8).
Place of synthesis: the Great Britain
Range of optimal doses: 20-25 mg / kg
Spectrum of operation: fine and notfine- cellular cancer mild, ovaries, a kidney, thick and a rectum, a dairy gland, a seminoma, a melanoma, a sarcoma of soft tissues, tumours of a head and a neck, a cancer an endometria, a cancer of a thyroid gland, the mesothelioma of a pleura.
Main side effects: a hematotoxicity, an aplasia of an adenoid tissue, an atrophy of sexual glands, damage of an epithelium of an intestine.
Advantages: a small nephrototoxicity, solubility in water (in 5 times is higher than the DDP).

DACCP (a synonym: JM-82).
Place of synthesis: the USA
Range of optimal doses: 600-800 mg / m2
Spectrum of operation: a cancer mild, a stomach, a gudgeon of a uterus, nasopharyngeal area.
Main side effects: a mielodepression, thrombus-and a leukopenia, an atrophy of lymph nodes.
Advantages: toxicity at 8-10 times is lower than the DDP, we shall well dissolve in a solution of a hydrocarbonate.

Spyroplatin (a synonym: TNO-6).
Place of synthesis: the USA and Netherlands
Range of optimal doses: 30 mg / m2
Spectrum of operation: a cancer of a dairy gland, an adenocarcinoma mild.
Main side effects: a mielodepression, a nephrototoxicity, electrolytic disturbances of structure of a blood, difficulty of salivation, loss of taste.
Advantages: absence of two-dimensional fastness from the DDP, good solubility in water.
Disadvantages: it is astable in a physsolution, highly it is toxic.

PHIC.
Place of synthesis: France
Range of optimal doses: ~100 mg / kg
Spectrum of operation: it is not informed.
Main side effects: it is not informed.
Advantages: we shall perfectly dissolve in water, has no two-dimensional fastness from the DDP, does not possess nephro-, a hematotoxicity, it is fast distributed on organs and tissues.
Disadvantage: so he all the same treats?

PYP.
Place of synthesis: it is not informed.
Range of optimal doses: 10-30 mg / m2
Spectrum of operation: a leukosis, a melanoma, an adenocarcinoma of a dairy gland.
Main side effects: an aplasia of an osteal brain, a nausea, a vomiting, a diarrhea.
Advantages: we shall well dissolve in water, possesses additive operation from the DDP.
Disadvantage: it is astable in a physsolution.

Cyctoplatame.
Place of synthesis: the USSR.
Range of optimal doses: 10-25 mg / m2
Spectrum of operation: " (citation) has appreciable therapeutic breadth ".
Main side effects: it is not informed.
Advantages: we shall well dissolve in water, does not show a nephrototoxicity, has no two-dimensional fastness from the DDP.
Disadvantage: The Soviet preparations has no disadvantages! :)

Iproplatin (synonyms: CHIP, JM-9).
Place of synthesis: the USA.
Range of optimal doses: 100-200 mg / m2
Spectrum of operation: it is not informed.
Main side effects: an aplasia of an osteal brain, damage of an adenoid tissue, damage of a gastrointestinal tract, a nausea, a vomiting, a hypotension.
Advantages: does not show a nephrototoxicity, we shall well dissolve in water.

Oxoplatin.
Place of synthesis: the USSR.
Range of optimal doses: it is not informed
Spectrum of operation: "wide" (citation)
Main side effects: it is not informed
Advantages: possesses strong antimetastatic operation, does not show a nephrototoxicity.
Disadvantage: we shall badly dissolve in water.

Application 1. Clinically used anticancerogenic complexes of platinum.

Application 1. Clinically used anticancerogenic complexes of platinum.