DE4442257A1 - Use of sparsomycin in 5- fluoro-uracil therapy of carcinoma - Google Patents

Abstract

The use of sparsomycin, or its derivs. of formula (I), combined with 5- fluorouracil (II) is claimed for the therapy of carcinoma. R1, R2 = H or Me; X = pref. (sic) NH-CHR3-CH2-SOR4; R3 = Me or CH2OH; R4 = CH2S(CH2)nMe, CH2SCH2R, CH2CH=CH2, CH2CH=CHMe or CH2Ar; R = H or phenyl; Ar = 2-furyl or phenyl; n <= 7. Also claimed is a pharmaceutical for the therapy of carcinoma contg. sparsomycin and (II), in the form of tablets, sugared pills, capsules, solns., infusion solns. or suppositories.

Description

The invention relates to the use of sparsomycin and of these derivatives in combination with 5-fluorouracil for The therapy of carcinomas.

5-Fluorouracil is used in various oncological indi cations used, for example in metastatic Breast cancer, tumors of the gastrointestinal tract, liver, of the genitourinary tract and pancreas as well as actinic Keratoses and other precancerous skin.

5-Fluorouracil is one of the anti-cytostatics metabolites. Its effect is largely cell cycle unspe zifisch. For the cytotoxic effect the formation of Fluorodeoxyuridine monophosphate (F-dUMP) is crucial. F-DUMP  is an inhibitor of thymidylate synthase. This enzyme kata lyses the rate-limiting step of DNA Synthesis. F-dUMP irreversibly inhibits thymidylate synthase bel. As a result, there is considerable inhibition of DNA synthesis, which is usually a cell death has the consequence. Because the inhibitory effect of F-dUMP on the formation of a ternary complex from thymidylate synthase, 5-fluorouracil and methylene tetrahydrofolate, 5- Fluorouracil often in combination with folic acid derivatives used therapeutically. Such a combination therapy pie influences the therapeutic effectiveness of 5-fluoro Although uracils are cheap, they cannot decisively change them improve. The reason for this is the fact that 5-fluorouracil preferably in the liver, but also in other organs ganes such as the gastrointestinal tract, broken down very effectively and is therefore no longer available.

The degradation produces 5,6-dihydro-5-fluorouracil, α-fluoro-β-ureidopropionate and α-fluoro-β-alanine. In total, 60% to 90% of an iv dose of 5-fluorouracil is broken down and excreted renally. Less than 15% appear unchanged in the urine. The half-life (t _1/2 ) is given as 12 minutes to 37 minutes. This is extremely short.

Due to the short half-life, inope stable tumors daily for 3 to 4 days 12 mg / kg (maximum 1 g) 5-fluorouracil as IV injection and - if possible - then three to four further doses of 6 mg / kg each given second day. Correspondingly high concentrations then occur toxic decomposition products. Alternatively, you can 15 mg / kg (maximum 1 g) can be infused daily until one Total dose of 12 g to 15 g is reached or intolerable Side effects occur. With precancerous skin a 5% cream or ointment is used.  

5-Fluorouracil does not normally become oral in humans applied. The reason for this are the strong fluctuations in the Plasma concentration of 5-fluorouracil, which after the p.o. Application occur. So after p.o. administration varies from 10 to 15 mg / kg the plasma concentration of 5-fluorouracil between 0 and 10.5 µg / ml (0 to 0.8 µM). This corresponds to an organic availability between 0% and 74%.

On the other hand, the IV application, through which something more constant plasma concentrations can be achieved for pose a significant burden to patients because they are his Restricted freedom of movement, inevitably with a clinic stay connected and cause severe pain can.

5-Fluorouracil is particularly toxic to the bone marrow and the gastrointestinal tract. To its considerable side besides bone marrow suppression, effects include suppuration the mucosa and diarrhea as well as somnolence, influence on the higher motor nerves, reversible cerebral ataxia and other reversible symptoms, such as the "organic brain syndrome "(see Red List 1994, side effects 5-flu orouracil).

As part of today's chemotherapy with 5-fluorouracil the organism is negatively affected in two ways. One on the one hand, the high bolus dose of the cytostatic has toxic Effect not only in the desired way on the malignant cell len but also undesirably on healthy tissue. On the other hand, the effective catabolization of the Cytostatic toxic breakdown products in correspondingly high Cans formed. The side effects described are based for example on the known inhibition of G proteins by fluoride ions released from α-fluoro-β-alanine  can, or on the function of β-alanine as a structure analogue of the important inhibitory neurotransmitter γ-aminobutyric acid.

The side effects of chemotherapy could only be overcome slowing down or inhibiting enzymatic degradation decrease from 5-fluorouracil. A preferred point of attack would be the enzyme dihydropyrimidine dehydrogenase, which the first and also speed-determining step of the Degradation path catalyzed. Reducing the breakdown would allow lower amounts of 5-fluorouracil overall use and so of course also on the toxic Ab building side effects to improve building products. This confirm studies on patients from genetic or other reasons decreased activity of the dihydro pyrimidine dehydrogenase (see Fleming, R. A., Milano, G.A., Gaspard, M.H., Bargnoux, P.J., Thyss, A., Plagne, R., Renee, N., Schneider, M., and Demard, F. (1993) Dihydropyrimidine dehydrogenase activity in cancer patients. Eur. J. Cancer, 29A: 740-744,). 5-fluorouracil acts in such patients in much less than that normally applied amounts.

In addition, the activity of the dihydropyrimidine Dehydrogenase depending on a day / night rhythm. These fluctuations also have an impact on 5-fluoroura cil therapy (Zhang, R., Lu, Z., Liu, T., Soong, S. J., and Diasio, R. B. (1993) Relationship between circadian-dependent toxicity of 5-fluorodeoxyuridine and circadian rhythms of pyrimidine enzymes: possible relevance to fluoropyrimidine chemotherapy. Cancer Res., 53: 2816-2822).

A large number of compounds have so far been found in the literature gene as inhibitors of dihydropyrimidine dehydrogenase in  described in vitro (Naguib et al. (1989), Biochem. Pharmacol., 38 (9), 1471-1480; Structure-activity relationship of ligands of dihydrouacil dehydrogenase from Mouse Liver, Tatsumi et al. (1987), Inhibitory Effects of Pyrimidine, Barbituric Acid and Pyridine Derivatives on 5-Fluorouracil Degradation in Rat Liver Extracts, Japan Cancer Res. (Gann.), 78, 748-755; Baccanari et al. (1993), 5-Ethynyluracil: A Potent Modulator of Pharmacokinetics and Antitumor Efficacy of 5-Fluorouacil, P.N.A.S., USA, 90, 11064-11068; Porter et al. (1992), Mecha nism-based inactivation of dihydropyrimidine dehydrogenase by 5-ethynyluracil, J. Biol. Chem., 267, 5236-5242 and therefore et al. (1991), Inhibition of fluoropyrimidine catabolism by benzyloxybenzyluracil, Biochem. Pharmacol., 41, 1887-1893). Almost all of these connections come for various reasons chemotherapy is out of the question. For example, wise barbituric acid derivatives that have been studied as inhibitors have been the known undesirable side effects.

The acetylene analogues 5-ethynyluracil and 5-propynyluracil were created by a working group at the Welcome Research Labo ratories with regard to their effect on the dihydropyrimidine Dehydrogenase examined (see Porter, D.J., Chestnut, W.G., Merrill, B.M., and Spector, T. (1992) Mechanism-based inacti vation of dihydropyrimidine dehydrogenase by 5-ethynyluracil, J. Biol. Chem., 267, 5236-5242). The effectiveness of the Inakti 5-Ethynyluracil is 500 times larger than that of 5-propynyl uracil. It is concluded that the Substituents at position 5 of the uracil ring a certain size must not exceed or have a certain polarity must. These substances react as acetylene analogues however relatively unspecific and can result in a number of Cause side effects.  

5-Benzyloxybenzyluracil is another very effective ingredient bitor of dihydropyrimidine dehydrogenase, which in animal models (isolated, perfused rat liver) the 5-fluorouracil effect improved. The exact mechanism of action is still not cleared up. So far, however, 5-benzyloxybenzyluracil is have not yet been used as a therapeutic and its Characteristics related to pharmacogenetics and side effects not yet examined.

So far, there is no possibility that in the course of Therapy applied to reduce 5-fluorouracil doses in which in combination with a dihydropyrimidine dehydro genase inhibitor is used. On the other hand, there is an increase need to lower doses of the cytostatic add and thus the side effects of chemotherapy far going to reduce. Under these conditions, could on the one hand, avoid chemotherapy due to the strong side effects must be stopped, which in a not inconsiderable percentage of patients is. On the other hand, the cytostatic could last longer Applied period and thus its effect can be increased.

It is therefore an object of the invention to use chemotherapy 5-Fluorouracil available to those named Needs met and the disadvantages of previous chemotherapy based on 5-fluorouracil.

According to the invention, the object is achieved by using Sparsomycin and its derivatives in combination with 5-fluoro uracil for the treatment of carcinomas solved.

In combination with sparsomycin, the breakdown of 5-fluoro Uracil surprisingly significantly reduced. Out of it there are numerous in its parallel application Advantages over previous chemotherapy based of 5-fluorouracil alone.  

Sparsomycin unexpectedly prolongs the half-life time, increases the AUC value and increases bioavailability of 5-fluorouracil. In addition, it unexpectedly enables the ge targeted setting of 5-fluorouracil plasma concentrations after both i.v. and p.o.application. Overall, therefore the amount of 5-fluorouracil used is reduced, which also causes the massive side effects of the cytostatic be pushed back. It also gets completely unexpected possible to administer 5-fluorouracil orally.

Sparsomycin is one in Streptomyces fermentation media sparsogenic and Streptomyces cuspidosporus found sw antibiotic with the following structure:

Sparsomycin inhibits the growth of many different organisms such as bacteria or fungi. It prevents protein biosynthesis, while RNA synthesis proceeds unimpeded. Protein biosynthesis is inhibited by inhibiting the peptidyl transferase that is responsible for the growth of the polypeptide chain. However, its antibiotic properties are no more favorable than those of other antibiotics, which is why it is not used as an antibiotic. The total synthesis of sparsomycin has been described (Helm quist and Shekhani, (1979), Total Synthesis of (R _C ) -Spar somycin, J. Am. Chem. Soc., 1057-1059 and Ottenheÿm et al. (1979), Total Synthesis of Enantiomeric Sparsomycin, Tetrahe dron Letters, 4, 387-390) and was manufactured by Upjohn Co.

Instead of the sparsomycin, its derivatives can also general forms are used:  

in the
R₁ and R₂ are H or methyl and
X preferred

represents
where R₃ is methyl or hydroxymethyl,
R₄ one of the radicals CH₂SCH₃, CH₂S (CH₂) _n CH₃,
CH₂SCH₂-phenyl, CH₂-CH = CH₂, CH₂-CH = CH-CH₃,
CH₂-2-furyl and CH₂-phenyl, and n is an integer 7.

Although the following description is essentially based on Sparsomycin may have comparable results to that of Derivatives as mentioned above can be obtained.

Using the model of the dihydropyrimidine dehydrogenase from pigs It was now possible to show that sparsomycin was responsible for this Enzyme inhibits. On this preliminary as well as the following The combination was based on the experiments therapy of carcinomas with sparsomycin and 5-fluorouracil developed. As part of the developments, the next ones existing studies on the modulation of pharmacokinetics such as the bioavailability and antitumor activity of 5-fluo rouracils performed by sparsomycin. Based on this Experiments were galenical formulations for therapy on People developed.  

Experiment 1 Inhibition of dihydropyrimidine dehydrogenase by sparsomycin

The ratio of the Michaelis-Menten constants (substrate con centering at which the substrate is traveling at half maximum speed is implemented) to the concentration at which a half-maximum inhibition of implementation occurs is a measure to what extent the substrate (5-fluorouracil) and the Inhi bitor (sparsomycin) around the binding site on the enzyme dihydro pyrimidine dehydrogenase compete. With saturation concents trations of the second substrate (NADPH, 60 µM) Michaelis-Menten constant for 5-fluorouracil at 5.5 µM. The The half-maximum inhibition constant is measured by meßtech niche corrections for sparsomycin 0.014 µM. The The ratio of the two constants is thus 393: 1. If saving somycin in a 400 times smaller concentration tration is present as 5-fluorouracil, both are accurate bound so well to the enzyme. Sparsomycin binds irreversibly to the enzyme. Because of the suicide inhibition mechanism stand for enzyme molecules to which sparsomycin has bound pyrimidine catabolism is no longer available. The higher the ratio of the Michaelis-Menten constant to the constant te for half-maximum inhibition, the more interesting it becomes the inhibitor for a therapeutic application. A relationship nis of 400: 1 leaves sparsomycin for therapeutic use already seem extremely interesting.  

Experiment 2 Modulation of the pharmacokinetics of 5-fluorouracil by Sparsomycin

To inhibit dihydropyrimidine dehydrogenase in vivo animal experiments were started to investigate by sparsomycin Rats or mice. The active ingredients were in phy saline solution dissolved in a volume of 10 ml / kg applied.

In extracts from the livers of such animals, 6 hours after egg treatment with sparsomycin (a single p.o. Sparsomycin of 2 mg / kg = 5.5 µmol / kg) were taken the pyrimidine degradation (i.e. that of 5-fluorouracil) to more than 95% inhibited. In addition, the time of day related rhythms of dihydropyrimidine dehydrogenase activity switched off in the presence of sparsomycin. This effect occurs at plasma concentrations as they usually do when using the sparsomycin as an antibiotic are set (<0.1 µM).

Pretreatment with sparsomycin also increases the Half-life with which 5-fluorouracil is excreted and increases the area under the plasma concentration / time curve (AUC). In the experiment, rats each became 50 mg / kg 5-fluoro uracil administered intravenously or orally. Was investigated the half-life of 5-fluorouracil in plasma and AUC Value. Table 1 shows the comparative data for administration of 5-fluorouracil with and without pretreatment with sparsomycin (2 mg / kg, oral, 1 hour before 5-fluorouracil administration) ben.  

Table I

Pharmacokinetics of 5-fluorouracil

The bioavailability of orally applied 5-fluorouracil is 100% in rats pretreated with sparsomycin, such as one can see from the AUC values in such experiments. The plasma concentration of 5-fluorouracil was determined seeks. So if you have pretreatment with sparsomycin, total applied amount of the cytostatic 5-fluorouracil desirably the anabolic route (inhibition of Thy midylate synthase).

In comparison, we are not treated with sparsomycin only 65% of the fluorouricil administered po taken. As described in the introduction, this is in line with the observed fluctuations in the bioavailability of 5-Fluorouracil after p.o. application to humans. A be the proportion of fluorouracil is already here degraded in the gastrointestinal tract. Firstly, this creates considerable quantities of the toxic degradation products of 5-fluorouracil and second who the considerable amounts of the cytostatic of the intended effect withdrawn.  

In the 24-hour urine of animals reserved with sparsomycin 80% of an IV dose of fluoroura is found cil in unchanged form. In contrast, in animals, the 5-Fluorouracil received alone, only 13% unchanged.

In addition, you get in the rat model after pretreatment with sparsomycin a linear relationship between the AUC area and the amount of 5-fluorouracil administered. This applies to a total dose of 30 mg / kg 5-fluoro uracil too. Above these doses (e.g. at 50 mg / kg) takes place a slight deviation in linearity. Analogue applies to the maximum plasma concentration of 5-fluorouracil. After a 50 mg / kg dose of 5-fluorouracil, it lies after pretreatment with sparsomycin (2 mg / kg, orally, 1 hour de before 5-fluorouracil administration) at approx. 240 µM. Without parallel Administration of sparsomycin can neither be a linear combination still between 5-fluorouracil and the AUC area 5-fluorouracil dose and the maximum plasma concentration determine.

These experiments clearly show that it was the combined one Administration of 5-fluorouracil and sparsomycin for the first time allowed a relationship between administered dose to produce 5-fluorouracil and plasma concentration. There with, the maximum plasma concentration can also be reached for the first time lig precisely to optimal therapeutic concentrations be put.  

Experiment 3 Modulation of bioavailability and antitumor activity of 5-fluorouracil by sparsomycin

Using two mouse tumor models, subcutaneously induced Colon 38 and MOPC-315 myeloma, was examined to what extent Sparsomycin ver the antitumor activity of 5-fluorouracil strengthens. In parallel, it was examined what influence the Treatment with sparsomycin for the toxicity of the cytostati kums has.

The reduction is used as a measure of the anti-tumor activity nes defined tumor depending on the difference treatment methods. The size is egg tumor after treatment with a combination of Sparso mycin and 5-fluorouracil or with 5-fluorouracil alone measure and with corresponding tumors in untreated individuals duen compared (tumor size after treatment minus tumor size in the control experiment: T-C). About the toxicity make a statement based on the drug-related death rate (LD₅₀).

Mice bearing a Colon 38 tumor were identified before the onset of the 5-fluorouracil therapy treated with sparsomycin (1 mg / kg; intraperitoneal). After that, the animals became variable every day Amounts of 5-fluorouracil administered orally. T-C and LD₅₀ was determined over a period of 9 days. The he Results of the experiments are summarized in Table II.  

Table II

As can be seen from Table II, the effect of saving is strengthen somycins on the antitumor activity of 5-fluorouracil more pronounced than its effect on its toxicity. Additional The fact that sparsomycin itself has some anti-tumor activity since it is the protein inhibits biosynthesis. However, treatment with increases an optimal amount of sparsomycin alone - this dose ent speaks about the LD₁₀ value - the survival rate of the behan animals only by a factor of 1.17 (van den Broek, L.A.G. M .; Lazaro, E .; Zylicz, Z .; Fennis, P. J .; Missler, F.A.N .; Lelieveld, P .; Garzotto, M .; Wagener, T .; Ballesta, J.P. G .; Ottenjeÿm, H.C. J. (1989), J. Med. Chem. 32, 2002-2015: Lipophilic Analogues of Sparsomycin as strong Inhibitors of Protein Synthesis and Tumor Growth: A Structure Activity Relationship Study). The tumor growth here is less than 10% reduced.  

In mice implanted with MOPC-315 cells subcutaneously you can find comparable results.

The therapeutic index of 5-fluorouracil, i.e. H. the ver ratio of LD₅₀ to the minimum effective dose of 5-fluorouracils, is pretreated with sparsomycin improved by a factor of 5 in animal experiments.

According to the invention, the use of sparsomycin for Chemotherapy in combination with 5-fluorouracil is available posed.

With continuous administration of sparsomycin too Together with 5-fluorouracil, it can also be stable in humans 5-fluorouracil levels can be obtained in the blood. This can on the one hand by continuous IV infusion of both sub punching can be achieved. Other procedures are accurate conceivable, for example, oral administration of sparsomycin before starting treatment with 5-fluorouracil, each of which many possible modes of 5-fluorouracil therapy applied can be.

In contrast to those observed after oral administration Fluctuations in bioavailability and plasma concentration of 5-fluorouracil is the bioavailability of 5-fluorouracil in animal experiments (see above) after oral administration close to 100%. The combination therapy of 5-fluorouracil with sparsomycin thus enables oral administration of the 5-fluorouracil also in humans. However, the oral application provides in A significant comparison with continuous infusion Relief for the patient.

Since the level of 5-fluorouracil after switching off the dihydropyrimidine dehydrogenase  Sparsomycin can be set precisely for the first time, can do a lot targeted a certain plasma concentration therapeutically be used. In addition, to achieve the therapeutic plasma concentration much lower doses of fluorouracil needed. By in the presence of Spar somycin achieved improvement in therapeutic index and the lower one for setting a certain plasma concentration Tration necessary amount of 5-fluorouracil has the consequence that much less toxic breakdown products arise and there significantly reduced with the side effects of chemotherapy will.

The optimal treatment mode and the plasma to be set Concentrations depend on the type of tumor to be treated or the individual clinical picture of the patient. At a parallel application of sparsomycin is optimal Plasma levels between 0.5 and 10 µM 5-fluorouracil (65.2 to 1304ng / ml). These values can be used in the following applications forms can be achieved:

• 1. 24 hour continuous intravenous infusion of 0.5 up to 10 mg / (kg × day) of 5-fluorouracil together with 2.5 up to 25 µg / (kg × day) of sparsomycin over a period of time from 6 days up to a total dose of 10 to 30 mg / kg, preferably 15 mg / kg 5-fluorouracil.
• 2. 24 hour continuous intravenous infusion of 0.5 up to 10 mg / (kg × day) of 5-fluorouracil over a period of time from 6 days up to a total dose of 10 to 30 mg / kg, preferably 15 mg / kg 5-fluorouracil with simultaneous oral or intravenous administration of 2.5 to 25 µg / (kg × day) Sparsomycin.  
• 3. Parallel oral application from 2.5 to 25 µg / (kg × day) and 0.5 to 10 mg / (kg × day) of 5-fluorouracil daily a period of 6 days up to a total dose of 10 to 30 mg / kg, preferably 15 mg / kg.

5-Fluorouracil is therefore used in doses of 0.5 to 10 mg / (kg × day), preferably from 1 to 7 mg / (kg × day) and especially preferably used of 2.5 mg / (kg × day).

Dosages of sparsomycin are in the range of 2.5 to 25 µg / (kg × day), preferably from 5 to 15 µg / (kg × day) and very particularly preferably at 10 µg / (kg × day).

The absolute amount and also the total amount of 5-fluoroura cil, a patient regardless of the specific therapy must be administered in order to achieve an optimal effect gel can be achieved with parallel application of Sparso mycin in combination with 5-fluorouracil is definitely essential less than the doses of 5-fluoro applied today uracil. Dosages of 5-fluorouracil administered to date amount to z. B. 12 to 15 mg / (kg × day) - maximum 1 g daily - until a total of 12 to 15 g is reached or in tolerable side effects occur. Another one, currently Dosing schedule used suggests IV injections of 12 mg / (kg × day) over 3 to 4 days before and, if possible, then 3 to 4 further doses of 6 mg / kg every second Day. A person weighing 70 kg will therefore be at maximum 5.04 g of 5-fluorouracil fed. In contrast, in the Combination therapy according to the invention 0.5 to 10 kg / (kg × day) administered up to a total dose of 30 mg / kg, d. H. a 70 kg patient receives 6 days of treatment a maximum of 2.1 g of 5-fluorouracil. At treatment The preferred dosage regimen receives one  Patient total 1.05 g of 5-fluorouracil. This reduction is possible because the entire 5-fluorouracil applied to the effect Spiegel contributes (100% bioavailability). Because of the dra tical reduction of the applied doses will also side effects of 5-fluoroura occurring in the patient cils significantly reduced, which for the patient himself considerable relief and improved tolerance of the Chemotherapy.

According to the invention, a pharmaceutical preparation is ready which 20 to 1000 g of 5-fluorouracil and 0.125 to 2.5 g sparsomycin together with a pharmaceutically acceptable contains th carrier (ad 2 kg). Preferably, the Preparation 0.2 to 2 g sparsomycin, 75 to 525 g 5-fluoro uracil and carrier ad 2 kg and particularly preferably 0.75 g Sparsomycin, 187.5 g 5-fluorouracil and carrier ad 2 kg. Choice part of the carrier can be replaced by folic acid (30 to 60 g) can be replaced. 2 kg correspond to 1000 daily doses.

The weight ratio of 5-fluorouracil to sparsomycin is in the range of 160: 1 to 400: 1, more preferred example in the range from 190: 1 to 375: 1 and especially be the ratio is preferably 250: 1.

The following recipes are intended to explain the invention, they but do not restrict.

1. Combination preparations for oral application

The solid preparations for oral administration (a to e) can tableted and, if necessary, with coatings according to the state the technology.

2. Combination preparations for intravenous administration

For oral combination therapy, sparsomycin and 5-Fluorouracil administered in a combination preparation the. This can be in the form of tablets, coated tablets, capsules, Microcapsules, solutions and drops are administered. To the active ingredients can be treated with pharmacologically and carrier materials such as lactose, sucrose, mannitol, gela tine, polyvinylpyrrolidone, and optionally further additions Substitutes to improve the tolerance, effect (e.g. folic acid derivatives) or absorption can be combined. The formulations can with the help of the prior art corresponding known methods portioned, for example tabletted.

The active ingredients can be used for intravenous infusion Buffer and salt solutions should be formulated. The Formu lation and sterilization can be according to the state of the art corresponding, known methods.

In all forms, sparsomycin is preferred in dosages from 0.125 to 2.5 mg daily, preferably 0.2 to 2 mg daily  and most preferably from 0.75 mg daily, in combination nation with 20 to 1000 mg 5-fluorouracil daily, preferred 75 to 525 mg daily and most preferably 187.5 mg 5-fluorouracil daily, up to a total of 0.5 to 3 g, preferably 0.7 to 2 g and very particularly preferably 1.05 g administered.

Claims (8)

1. Use of sparsomycin in combination with 5-fluoro uracil for the treatment of carcinomas, it being possible to use derivatives of the general forms instead of the spar somycin: in the
R₁ and R₂ are H or methyl and
X preferred represents
where R₃ is methyl or hydroxymethyl,
R₄ one of the radicals CH₂SCH₃, CH₂S (CH₂) _n CH₃,
CH₂SCH₂-phenyl, CH₂-CH = CH₂, CH₂-CH = CH-CH₃,
Represents CH₂-2-furyl and CH₂-phenyl and n is an integer 7. 2. Use according to claim 1, characterized in that daily 2.5 to 25 µg / kg, preferably 5 to 15 µg / kg savings somycin and 0.5 to 10 mg / kg, preferably 1 to 7 mg / kg 5-fluorouracil individually or in combination up to Achieve a total of 10 to 30 mg / kg 5-fluoroura cil can be applied.   3. Use according to claim 2, characterized in that daily 10 µg / kg sparsomycin and 2.5 mg / kg 5-fluorouracil individually or in the form of a combination product up to applied to a total of 15 mg / kg 5-fluorouracil will. 4. Pharmaceutical preparation for chemotherapy from Karzi noun, which sparsomycin in combination with 5-fluorouracil contains and in the form of tablets, dragees, capsules, solutions genes, infusion solutions or suppositories. 5. Preparation according to claim 4, characterized in that the combination preparation 0.125 to 2.5 g, preferably 0.2 to 2 g and particularly preferably 0.75 g sparsomycin and 20 to 1000 g, preferably 75 to 525 g and particularly preferred 187.5 g of 5-fluorouracil together with a pharmaceutically suitable carrier and optionally 30 to 60 g of folic acid contains. 6. Preparation according to one of claims 4 or 5, characterized characterized in that the combination preparation in one for the oral application is in a suitable form. 7. Use according to one of claims 1 to 3, characterized characterized in that the sparsomycin orally or intravenously and 5-fluorouracil orally, intravenously or in the form of an ointment is applied. 8. Use according to claim 7, characterized in that the sparsomycin administered orally and the 5-fluorouracil Therapy of precancerous skin in the form of a cream worn or used intravenously to treat other carcinomas is handed over.