JPH07502752A - Medicines that exhibit antitumor activity - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Medicines that exhibit antitumor activity The present invention relates to medicine, particularly experimental and clinical shoulder oncology, and relates to hormone 7 sensitivity in girls. Not only sexual malignant tumors, but also when these tumors lose sensitivity to hormones. can be used in the treatment of abandoned lIl oncological processes.

In in vitro experiments, as a suspension of individual cells in culture medium or in cell culture Cytotoxic effects on animal and human malignant cells present as a cell monolayer [N, D by l5lyakov and co-authors] A6 dated March 28, 1980 entitled "Drugs exhibiting antitumor activity in vitro" 1, 31/195, inventor's certificate regarding invention No. 7507117].

These are chemicals that have a simple composition and method of production, i.e. certain human and synthetic L-amino acids with a broad spectrum against malignant cells in animals. ATET-DL-Alanino, DL-Roituno, DL-Phenylalanine, DL-G Ri/no, DL-methionine, D1. -) Ributofano and DL-valine are That's it.

In contrast to the others, the synthetic amino acid DL-valine has been shown to be harmful in in vitro experiments. Most powerful against malignant cancer cells without any damage to non-sexual cells Exerts toxic effects.

However, the very important main drawback of the above drugs, especially DL-valine, is that the individual malignant cells, and in mammals, these cells form dense cancerous tumors. In experiments in vivo where tumors are formed, those that do not exhibit any such effect. It's in the ability. These drugs are used by cells suspended in the medium containing them. Culms are not easily taken up by tumor cells. Therefore, the above drugs Some types of cancerous cells, such as those that can help the dense main cancerous cells absorb them. conductor.

The inventors chose as a prototype a hormone-sensitive malignant tumor in girls, viz. There is also a well-known drug that exhibits the effect of inhibiting bacterial growth against breast cancer and ovarian cancer. , Mashkovsky: ``Medicine'', Medlzina Publishing House, 1985 , Part 1, pp. 593-603 Beno and Part 2, pp. 470-471]. child These are steroid hormones obtained by synthesis and are male hormones. It is a derivative of a powerful androgen called testosterone. Among these medicines However, the following include treatments for non-susceptible breast and ovarian cancer in girls. has found the widest clinical use for. Testostero/propionoic acid salt, metrotestro/propionate (or 2α-methyldihydrotestosterone) 2α-methyldihydrotestosteronoether mixture thing) is that. Oil solutions of 18 of these drugs are placed in the muscle. in long-term treatment , another derivative of testosterone, namely methyltestosterone, was administered. Although it has a weaker cytostatic effect, it is used lightly (sublingually). ) It is convenient and easy to administer. All of these hormones are normally , administered in very large doses of 50 to 1 oose, mainly used for breast cancer and egg cancer. Used in very advanced stages of focal cancer with metastasis. All of the above drugs Since it is a steroid derivative, it is a more or less pronounced androgen for female genital organs. After long-term treatment with effective and high doses, general toxicity leading to the following complications: The expression of f! It can cause serious side effects. Disorders of water transmetabolism, liver, kidneys and I Accompanied by severe visceral dysfunction, hypercalcemia/hypercalcemia syndrome, and strong libido. Another sign of masculinization! This is a serious complication.

In order to confirm the antitumor effect, these drugs were first administered to breasts induced with DMB^. The oil solution of the drug was given to experimental rats to treat cancer. At a dose of 2-3++ g per animal daily, i.e. approximately 15 g stomach g per kg body weight. Tested by subcutaneous or intracutaneous FT [A11. Be5kro nvL: "Anti-ulcer efficacy of 100% in breast cancer", Voprosy Oncologii, Vol. 17, No. 9 (1971), pp. 95-98. Akira]. Orally administered methyltestosterone belongs to the same group of antitumor drugs, but , its cell growth inhibitory effect is 2-3 times that of oil-soluble testosterone/derivatives. weakly, so its experimental therapeutic dosage is approximately 25-40 g, kg per day. It is.

Their antitumor effects on hormone-sensitive induced mammary cancer in rats struggle However, all of these synthetic testosterones/derivatives show a number of important experimental results. Disadvantage '5: exposed.

1. Predominantly small "additional" cancers in the presence of several carcinomas in one animal The tumor underwent decomposition, whereas approximately 4. Reached a controllable size of 0cm' The "main" tumors that were present were relatively quite resistant to treatment.

2. In many cases, tumor decline does not reach its end, and drug inoculation inhibits growth, i.e. In other words, it only brought about remission, after which new irreversible growth of the same tumor occurred. It was.

3 Even if a synthetic androgen causes complete tumor regression, the same Recurrence of tumor growth was observed at the site.

4. Synthetic androgens, which initially caused a decline, may be affected by new growth or tumors after remission. Its use for the treatment of recurrent or recurrent tumors did not produce any antitumor effects. sand In other words, sensitivity to this drug was completely lost.

5. Three types of oil-soluble testosterone derivatives that are more active than methyltestosterone , i.e., testosteronobrobionate, 2α-methyldihydrotestostero /b-pionate and 2α-methyldihydrotestosterone, the administration of For each drug after 30 days, the percentage of overall decline of all tumors was 4 0%, 70% and 80%, and the percentage of complete decline (disappearance of the tumor) is 10%, 50% and 20%, respectively, and the percentage of partial tumor regression is that They were 30%, 20% and 60%, respectively. For effective antitumor activity, These values are low, with 60%, 30% and 20%, respectively, of each formulation. There were tumors that did not decline at all.

Considering the above-mentioned shortcomings of the prototype, we propose a new drug that yields high clinical efficacy. do.

This drug, which shows antitumor activity, is used in cases of hormone 7-sensitive carcinoma in girls. 2-4 g of DL-valine and non-therapeutic low doses (0.020-0.025 Mechanical mixture with g) methyltestosterone, as well as hormone-insensitive 2-4 g of D L-valine, 005-O,OIQ for use in case of tumor. g of methanodrostenolono and 03-05 g of phthyvazide (phthyva zid).

Therefore, the present invention is novel and unknown at the current level of medical development. be. The level of inventiveness of proposed medicines with anti-tumor activity is clearly increasing among girls. From the water 111 (original model) of the current development of chemotherapy for susceptible malignant tumors Not followed. The present invention is used in the outpatient treatment room for hormone-sensitive malignant W tumors in girls. For the purpose of successful treatment, this hormone sensitivity may be completely lost. Yes, in advanced cases when all conventional methods of chemical and hormonal therapy are ineffective. can be used on a large scale clinically.

The successful application of this novel drug is due to its strong cytostatic properties, complete Alongside its effective activity, which is harmless, it increases the addict's defenses and has a powerful analgesic effect. This is due to the characteristics it exhibits.

The essence of the invention is that it is complete in all its essential features which are sufficient to achieve the required results. presented by something.

Theoretical embodiment of the properties of the claimed medicine and the novelty and origin of the proposed invention. This novel anti-tumor drug was experimentally tested to confirm the level of clarity.

When used in the treatment of DMB^-induced monoclonal breast cancer in female rats, The proposed drug contains 500 to 550 mg of synthetic amino acids per 111 kg of animal weight. DI, -valine and a nontherapeutic dose of 5 to 20 g of methyltestosterone. It consists of a mechanical mixture with Ron and is administered daily by the oral route. U, )ni In the case of long-growing breast cancer tumors that have lost their hormone sensitivity, this novel antitumor The medicine is f! 500-550mg DI per kg) 7.20-25mg+71 protein anabolic methanotrostenolone, and a mechanical mixture of 40-50-g of futibazide.

In all adaptations of the application of new anti-inflammatory drugs, protein-rich and fat-poor wounds It is necessary to stick to food.

D1. - the anino acid called vari/ and a non-therapeutic dose of androgen, i.e. Methyltestosterone or methanotrostenolo/(very weak androgenic property) Novel anti-tumor drugs for cancer tumors in the form of mechanical mixtures with anabolic agents From experimental data obtained through deep research on the bacterial growth inhibitory effect on DL-barriers required for their uptake by cancer cells that form dense tumors in mammals. The mediating role of these phosphorus molecules was demonstrated.

The quantitative limits of the mixture components depend on the overall activity of the antitumor preparation. experimental research As shown, the optimal dose of DL-valine is 550 mg/kg, and 500 mg/kg. Reducing the dose to Even doubling the amount has no effect. DL-valine dosage below 500 mg/kg The decrease in ), the attenuation effect disappears completely. DL-valine Methyltestos at a non-therapeutic dose of 5 g/kg body weight in combination with Teron still has very high hormone sensitivity 4, 0-6.　0cm ’, which provides an optimal bacterial growth inhibition effect against induced shocks of the size of 6. Polmono susceptibility decreases as the tumor grows. 0c ■ 8 to IOe over 1 For tumor sizes up to m', methyl test 10 mg/kg body weight It turned out that it is better to use DL-valine in combination with steroids.

These optimal doses of methyltestosterone are only those without DL-valine. In this study, there was no attenuation or even inhibition of the growth of parasitic breast cancer shoulder tumors in rats. Since it does not occur, it is considered non-therapeutic. Methyltestosterone/only Now, body! l Such experiments begin only with a dose of 25 mg per kg In this case, the decline is caused by the treatment of oil-soluble testosterone derivatives (original). type) exhibits all of the above-mentioned disadvantages of the cell growth inhibitory effect. According to our data, Mechanical mixture of DL-valine with 255g/kg methyltestosterone It has the same drawback of anti-vesicle growth effect, but is less noticeable than the original. DL-ba Doses of methyltestosterone below "g/kg in combination with phosphorus This results in a relatively marked and mild decline of hormone-sensitive carcinomas in patients.

IOc 1 or more with partial or complete loss of androgen sensitivity In experiments with long-term growing tumors of similar size, 20 to 2 Methanthroste, another very weak androgen, at a dose of 5-g/ A mechanical mixture of DL-valine with Ron was found to be optimal. DL-Bali A two-fold reduction in the dose (12,5 mg/kg) in a mixture with instead of a decline in growth, a slight inhibition occurred, and increasing the dose had no effect on this result. Ta.

However, a mixture of DL-valine with methanthroste/ron only was administered. The decline of experimental carcinomas in rats is so slow that by the 30th day of the experiment, all All tumors declined by only 30-71% of their initial size, with an average of 5% It declined by only 2% (Table 1).

Futibazide is a known drug with strong anti-olfactory effects against tuberculosis; Methanthrosterone/Lone injects into the cells of dense tumors that are proliferating for a long time in the mammary glands of women. It has been found that the conductivity of DL-valine can be significantly increased. border, <site Based on experience, the optimal dose is 45-50 mg/kg per 111 kg of body. It is clear that Significant or decreased dose may result in tumor growth. It may not affect or even promote reproduction.

(550 g/kg) and methanthroste/ron (25 g/kg) Data 1 week 2 weeks 3 weeks 4 weeks Control group (no administration) 1 4 78 20.2 37.3 Death 23.95fufu, 013.320.2 3a)” 6.0 10.2 16.0 25.1 Death S, Q 5.0 5.3 8.26g, 0 9.6 20, 0 36.0 Death 7 3J 4. 5 9.5 14.2 23.0 Arithmetic mean 5.3 8, 7 11.6 20, 2 20.7 Fluctuation range 3.8-8.0 4.5-12.5 5.3-20 7. 8-37.3 8.0-42.0P" <Q, O5 <0.01 <0.01 < 0.01 judgment progress Number Data Week 1 Week 2 Week 3 Week 4 (%) Experiment IJ (DL-valine and Methanthroste/ron) 2 10.5 11.2 6.9””6. +5.0 527 L6 6.3 5.6 4.6 4.2 36 arithmetic mean L5 5J 4J 3.7 3.1 52 fluctuation range 4.5-10.6 3.0-11.2 2.6-6.9 2.1-6.1 2.0-5.5 3O-71P">0.0 5 <0.05 <0.01 <0.01 Judgment Decline 00.P - Comparison with initial data for each week.

・Meeting・: Necrosis Experiments with the prototype, an oil-soluble synthetic testosterone derivative, given orally 19 A comparative analysis conducted based on the data shows that the claimed novel anti-tumor drug is It was shown that there was a marked increase in the number of children.

1. The alleged anti-cancer drug consists of two components of a mechanical mixture, i.e. DL- can produce an independent cytolytic effect only on individual cancer cells of the same type. The amino acid ``Bali'' and small non-therapeutic doses can treat solid malignant tumors in mammals. Close contact with androgens, which can play the role of conductor of this amino acid into the cell. It exerts a cell growth inhibitory effect through close interaction.

The alleged drug in a mechanical mixture with the amino acid 2, Dl, -valine is ! ! 2 (25-40 ■*/kg) compared to non-therapeutic doses (5-10 g/kg) of methyltestosterono, a testosterone derivative, and D Without L-bal) 7, no cell growth inhibitory effect is exhibited at all.

3. The new anti-cancer drug is also distinct from the original in that it has a highly effective cell growth inhibitory effect. significantly different: i.e. (8) Controllable size of 4°Oe in the presence of several tumors in one animal s’) [The main Jllll tumor is the first or the same as the “additional” tumor. sometimes undergoes decomposition.

(b) interruption of decline prior to irreversible tumor growth by administration of a li regulatory agent; or No appearance of remission is observed.

(C) No recurrence of tumor growth is observed after its complete resolution.

(d) No loss of sensitivity to the new preparation was observed even after repeated use. I can't do it.

(e) Suggested! Daily administration of the two drugs for 30 days will determine the degree of tumor sensitivity. and methyltestosterono produce a dose-related decay effect: i.e. 5 According to wg/kg role '4m, the percentage of general decline is 89% (10% tumor- 2 out of 17 cases did not degrade), and complete regression <m tumor disappearance) 65% (case II of 17) and partial decline (53% of the initial size of the tumor). ~85%) was observed in 24%, or 4 out of 17 tumors (Table 2). I According to the Osg/kg dose, general decline was observed in 100% of tumors and all This means that all tumors degrade by an average of 80%, with complete decline seen in 20%. , and in 80% of tumors, degradation occurs within 30 days of the experiment, reducing the tumor's original size. It reached 61-95% (Table 3).

4. The alleged anti-tumor drug is compared with the original and other known cytostatic agents. In addition to having a degrading effect on malignant tumors, as shown below, Carrying motion. It can also increase defenses, i.e. resistance to tumors: i.e. , (8) marked increase in animal body chambers with decline (Table 4).

(b) Stimulation of hematopoiesis leading to its normalization in the process of II tumor regression (Table 5).

(C) After the end of the experiment, the anti-Wa tumor effect was evident compared to that of control (untreated) animals. 2-3 times the survival time of the animals achieved in the 30 days of the experiment without significant ) 111 addition.

The size is cm').

χi control group (not administered) 16.4 7,5 11.5 18.4 21.324.66.47.17.1 7.3 3 7.2 B, 4 8.4 144 17.26 3.9 6.22 23. 4 Death -73,85,39,5+SJ21 8 3.9 5.8 5.9 6.7 9.6, number 7 tumors, 10・'11 Fluctuation range 3.8-7.2 1.8-12.5 2.7-23.4 L69-36 ．． 4 7.3-59.41',' <0.05 <0.01 <Q, Ol <0 ．． 01 experimental group (administered this preparation) + 4.4 2.0 04I 0 0 1002 4.2 2.2 0.7 0 ．． 4 0 1003 4.4 1.0 0.04 0 0 to.

4 4.0 0.8 0.04 0 0 1005a+”” 5.6 2.8 0 0 0 +00b)”’ 1.0 0.8 0 0 0 +006 4.9 4.7 3.8 2.8 1.0 807 4.8 0.4 0. + 0 0 1008a) Ll 5.3 4.8 2.9 3.0 53b+0.2 0 0 0 0 100'+ 4.7 3.5 1. + 0.1 0 1001 0 5.7 3.2 2.2 1. OQ to.

11 7.6 6.5 3.9 3.5 2.0? 412 4.7 3.2 2.3 1,28 0.75 85+3 7.8 1.6 5.1 2.0 0 +0011a)””6.2 7! ? , 5 8, 7 10.7 −b+”° 3.1 2.7 3.6 2.5 3.5 - Number of rats/Il! Tumor: 14/ +7 Arithmetic mean 4,7 3 2.1 1.5 1.2 82 Fluctuation range 0.2-7.8 0-730-150-8.7 0-10.5 0-100F, "<0.01 <0.01 <0.01 <0.01P,. >0.05 <0.01 <0 ．． 01 <0.01 <0.01 Note '100% for 11 tumors, 50% or more for 4 tumors Above, 21!1 tumor had 0% decline.

”:P,’”== Comparison with initial data for each week.

”: P, Comparison between χ1 control group and experimental group for one-paired data.

-9′″: a), b) = 1 Indicates that the rat had several tumors.

Table 3. Anti-l! 10 g/kg of dimethyltestosterone, a drug that exhibits tumor activity. and DL-valine at a dose of 550 snow/kg in randomly bred white mice. Originated breast cancer (conditional tumor size in cm').

Mouse initial interval Number Data Week 1 Week 2 Week 3 Week 4 '11 Control group (no administration) +4 7.8 20.2 37.3 Death 2 3.9 5.7 7.0 +3 ．． 3 20.23a) 6.0 10.2 16.0 25.1 Death b) 5 ．． 0 5.8 5.3 8.245.16.67+1.88.1 5 7.3 12.5 19.0 30.2 42.06 8.0 9.6 2 0,0 36.0 Death arithmetic mean 5.3 8.7 11.6 20.2 2 ( 1,7 Fluctuation range 3.8-8.0 4.5-12.5 5.3-20 7.8-3 7.3 8.0-42.0P" <0.05 <0.01 <0.01 <0. 01 Judgment Progress Mouse initial interval decline Number Data 1 week 2 weeks 3 weeks 4 weeks <%) Actual Ugf (DL-valine and Methyltestosterone) 6 6.7 4. +2.1 0.9 0.6 95 calculation Operative mean 6.3 5.4 3.6 2.1 14 80 Variation range 4.2-8.2 3.0-8.6 0.7-6.9 0.8-4.1 0-2.9 6l-10 0P' >0.05 <0.01 <0.01 <0.01 Note: 10 for 2 tumors 0%, with less than 50% decline in all others.

Judgment Decline 0, P = comparison with initial data for each week.

Experimental group (all animals had tumor decline) 1 220 230 240 245 250 +302 260 265 270 270 275 +153 2 40 225 260 260 265 +254 200 210 2+5 220 220 + 205 2 (10210220235240+406 16 0 180 185 190 195 ++57 200 210 215 2 20 230 +308 240 240 245 250 260 +209 220 220 230 235 240 +2010 240 255 2 60 260 255 +15 If 170 180 190 190 200 +30P””　　　　　0.05　＞O,Q5　　　＜0.05　Control group (progress (with lines) 5 200 190 IO219018020+go -40-20P""> O, [lS　>0.05　>0.05　<0.05Table 5. Induced milk treated with DL-valine and methylteslostero7 Whitening spikes associated with decline of intestinal tumors in cancer-bearing female rats 1f) 1 processing method is based on Wilfox/-7)-Witney's 1 base width. average value and This indicates the range of fluctuation).

hemoglobin (Not administered) llIs 02 4291422 057 Note, 10 increase, = decrease Small, ~ No change Table 5 (continued) Normal 2.9 3.4 3B, 7 5.6 52.2 Abscess 2.6 7 ．． 2 62 1,7 27.8 Arithmetic mean 9.1 14.5 20,7 25, 5 32.1 Fluctuation range 3.4-12.5 5.7-22.18.2-36.49 ．． 6-42.612.2-50.8P””　＜0.05　＜0.05　＜0.0 5　<0.01　<0.01　-Note 1=When 2 to 3 tumors are fused, Statistical analysis was performed as 2 or 3 tumors.

Note 2: Tumors with a size equal to 0 were counted as one tumor.

1: Necrosis °0 Displayed number of tumors are fused 1°′″: P - comparison with the initial magnitude for each week.

5. Compared to other cytostatic drugs, the alleged formulation was not traced during the experiment. As I said, excitability to pain is 1! ! Rf rise in value, and as a result The analgesic effect of reducing the animal's sensitivity to pain during the process of tumor decline. can be demonstrated. In the absence of decline, there is no analgesic effect, which suggests that It can be used clinically to evaluate therapeutic effects.

6. In contrast to its original form, the alleged preparation partially reduces sensitivity to anandrogens. It exerts a cell growth inhibitory effect on carcinomas that proliferate for a long time after losing their target or completely. 75, but this could serve as an experimental model for a clinically abandoned cancer process. can. In this case, this anti-inflammatory preparation contains protein homologs in a mixture with DL-valine. Methanodorostea ONO, a chemical drug, and its conventional use as an anti-tumor drug Contains futibazide, a previously unknown anti-tuberculosis drug. In this composition, Experimentally induced large, confluent (2-3 ft.) tumor and one giant (2 A novel anti-tumor product that exhibits a cell growth inhibitory effect on tumors (different from 4,0 cm') of tumors, often accompanied by necrosis! Causes ¥ depreciation. In this case, liquid structureless Il! The tumor mass drains and healing of the IT tissue begins at this site (Table 6).

7. Morphological lesions that occur in the MI tissue that lead to lower back decline also have their own unique characteristics. i.e. the effects of damaging therapeutic effects of any chemical drugs and even radiation. Significant fibrosis occurs even under Il. Tumor 1 (lysis of parenchymal and interstitial cells of the tissue, a change caused by necrotic lysis) tion with subsequent absorption (Figure 1).

1-3 Based on own experimental data and, in particular, the framework of completed pharmacological preclinical studies. In the midst of all this, the complete non-hazardous nature of new anti-tumor preparations tested and confirmed in normal animals. In view of this, we aim to treat narumono-sensitive carcinoma in female F. 4g FDI) L-valine, an amino acid, and 0.020 to 0.025 g per day. A novel anti-inflammatory drug consisting of a mechanical mixture with non-therapeutic administration of steroids Oncology drugs and treatment of carcinomas that have partially or completely lost their receptivity. Target 2-4g of I) L-valine per day and O,OQS~0.010 Mechanical reaction between 0g of Methanodorostea and 03-0.5g of methyl, ++' H! for clinical application of medicines consisting of mixtures! sing.

The daily dose for clinical use of a proposed drug is the dose used experimentally. It is calculated from.

Therefore, the dosage for DL-valine is 500 kg/111 kg of animal body. An experimental dose of ~・550 lIg/kg, and at least Calculated to be 2-4g, taking into account the strength of amino acid metabolism in humans, which is 10 times lower. As a result, the human body [approximately 50 to 55 mE/kg per 11 kg, and body weight 11,150 to 70 kg) 2 to 4 g of DI, -valine is used per day for humans. It will be done.

The dosage of hormones is determined by the sensitivity of humans and animals to them due to differences in metabolic intensity. Since these are often uncorrelated, they were calculated using different methods.

Methyltestosterone 20-251g or 0.020-0.025g per day The dosage (4-5 tablets) was calculated based on experimental and clinical data; According to it, its experimental non-therapeutic administration 1 (75 mg per 11 kg of body) is five times lower than the therapeutic value of 251 g/kg of animal body weight. breast cancer Andugen therapy in clinical cases requires a methyl test of +00 g or more per day. stipulates the dosage of steroids [Y, M, Bruskin: r milk Hormone Therapy of Cancer J, Medlzlna Publishing House, 1969, pp. 69-73 The non-therapeutic dose should be about 20-25 B per day. Must be. The dosage of Methanodorostea 0 is that it is used as an anti-Hcancer drug. Since this has never been the case, it can be produced based on the tumor's susceptibility to it. Because of this, the literature [M, D, Mashkovsky: r medicine], Medi zlni Publishers, 1985, Part 1, page 317] and administered to volunteers. Calculated from data from direct clinical observations. In this way, the tumor In abandoned cases that have completely lost their susceptibility to 5 to long doses per day in combination with futivazide to enhance the conduction effect of the hormone It has been established that it is necessary to use For futibazides, small mammals Compared to humans, the daily dosage is 10%, taking into account the lower metabolic intensity. It was calculated from the empirical data. The dose for experimental animals (rats) is approximately 1kg body weight. If the average weight was 45 to 50 g, it would be 4.5 g per kg of body weight for humans. 5 to 5 g, or a human body weighing 60 to 80 g or more. For comparison, it would be about 300-500sg (0.3-0.5g) per day. cormorant.

The cytostatic properties of this new drug were tested in clinical settings, primarily in incurable volunteer patients. From the study of sex, the following data have been obtained that distinguish it from its original form.

1. Mechanical mixing of Dl,-barrier with non-therapeutic low doses of methyltestosterone The direct antitumor effect of the proposed drug under the influence of low-dose methyl test Other than DL-Barrier in combination with steroids, patients who received no specific medications in the preoperative period In a case of adenocarcinoma of the uterine body of a female applicant who did not receive the drug, the uterine cavity was affected after administration of this drug. This is substantiated by the results of aspiration Hashimoto's cytological examination. All nine members This administration resulted in a significant reduction in tumor size as well as pain and An outage occurred. from several of these patients at different intervals (1, 0 days, 2 weeks). , 4 weeks), we found significant cytoplasmic and nuclear vacancies. Adenocarcinoma cells malnourished with vesiculation, “eroded” contours of the nucleus, Ikukka We found dissolution of the rod and significant malnutrition of the vacuole (Fig. 2).

2. In abandoned cases recognized as completely incurable, DL-barrier and methyltestosterone or with methanotrosterone and methyl2-do Administration of this new formulation as a mixture of objective cell growth inhibitory effect, i.e., tumor degradation and patient survival. A significant extension of the term of existence has occurred.

3. The early action of this new antitumor drug, within the first 7 to 10 days, is due to its strong narcotic effect. Cases where anesthetics are only helpful for a limited period of time, such as bone metastases. Even in some abandoned cases, pain symptoms were completely eliminated.

4. The action of this new drug during the course of administration includes signs of toxicity (hemodynamic disorders). It is not accompanied by nausea, vomiting, or nausea.

5 In the process of administering this new drug, improvements in peripheral blood composition, weight gain, Even in the incurable, resistance is shown by increased appetite and increased work capacity. Ill tumor resistance was increased.

6. A significant advantage of this new drug is that outpatient physicians will be able to use it for success in medical institutions. As a result, this new drug may exhibit serious side effects and This eliminates the majority of known chemotherapeutic drugs that require hospitalization for application. markedly distinct.

1 ri Since this new drug is harmless, there are no serious complications. at low doses Long-term administration of methyltestosterone (up to 2 months) produces mild episodes of virilization. may occur, but this disappears quickly after methyltestosterone administration is discontinued. do.

If this new drug is administered in excessive doses and a protein-rich diet is not observed.

Minor nausea, loss of appetite, and weight loss may occur. Amino acid imbalance These symptoms can be alleviated by reducing the 8th dose of DL-valine and increasing the protein patient diet. disappears after strong obedience.

Okiya 1. Prior androgenotherapy In such cases, low doses of methyltestosterone in the first treatment regimen may Unable to realize its effect as a DL-valine conductor to the cells of the tissue, There is also no effect of inhibiting cell growth. Second treatment regimen (Methanotroste/Ron and Flu) (using Tibad) can be used.

2. Presence of metastasis to the lungs The reason is that the rapid decline of tumors can lead to defects in the walls of large blood vessels, which can be life-threatening. This is because such bleeding may occur.

3. Various forms of C stress on patients and mechanical damage prior to administration Surgical interference, burns, fractures, etc. may cause DL-Bubble to the damaged tissue rather than the tumor tissue. It is linked to the property of preferential transport of amino acids called RI.

Therefore, the application of this new drug is important for complete tissue healing W1 (20-25 days after surgery). i&) and possible only after cessation of stress conditions. Blood transfusions (especially multiple transfusions) blood) also exerts an effect on metabolic processes similar to that of stress. therefore, Administration of this medication must be discontinued during this period.

4. During administration, use of diuretics that affect salt metabolism must be avoided.

5. During administration, no other anti-tumor drugs should be given in conjunction with this new drug. stomach.

6. During the administration of this new drug, the hormones, adaptogens, phytotherapy, and Administration of drugs that stimulate hematopoiesis and cardiac activity must be stopped.

K Tanega The present invention is illustrated by the following specific examples regarding the anti-tumor properties of the claimed novel medicines. do.

1,,! Pitch name: G, A, Melnikova, 75 years old, case No. 12763 No. 7a. Exploratory laparotomy on May 31, +977 at the Rostov Oncology Institute Gynecology Department was carried out. Extracting metastases from the outline and histological analysis No. 104847-84 It was set as No. 8. The patient had solid ovarian abdominal pain.

Clinical diagnosis: 8I! Tumor invasive disease and explantation, omentum and liver metastasis. 111112 Stage 4 ovarian cancer due to migration and accumulation of fallen water in the 111112.

During the postoperative period, one course of chemical therapy (thiotepa muscle stimulation) was administered, and as a result, the abdominal The water accumulation disappeared, but the tumor continued to grow. In July, the patient was discharged from the hospital and treated symptomatically. prescribed the law.

In late July 1977, as a volunteer, I was a patient (body weighing 154 kg) for 1 day. 25 mg (0,025 g) or in combination with 5 tablets of methyltestostero Administering the alleged medicine in two forms of a mixture of 2 g of DL-valine, and strictly following the insecticide diet. The daily dose was started divided into 4 doses to be taken before meals. i.e. , DI via enteral route in warm milk - 170.5g and 1 tablet via sublingual route of methyltestosterone/4 times and 1 tablet of methyldesterosterone sublingually was administered during the day without DI, -valine. This cool 1I! The duration is 2 months there were.

During this period, the pain in the inferior part and the area of the liver completely disappears, and the gastrointestinal tract functions (Constipation and bleeding disappeared to normal), appetite improved, and weight gain was 4.5 kg. and regained strength and work capacity. - No ulcer was palpated.

Because of this condition, the patient is admitted to the hospital after 1 or 1 and then undergoes a second course of chemotherapy. Teva was administered intramuscularly (total dose: 200 mg). Gynecological examination revealed neoplasia. I didn't meet it.

In March and July 1978, two more courses of Thioteva were administered prophylactically to improve safety. Qualitative leukopenia occurred.

In August 1978, the second course of the proposed drug was administered using the same treatment plan for one month. He pitched 11 times. ml fluid analysis was normal. On the 7th day of tIA, the hepatic I felt severe pain in the area that lasted for 24 hours but then completely disappeared.

Gynecological examination revealed no neoplasia. The patient was feeling well. April next year Although we did not administer anything, her general condition was satisfactory, she had gained some weight, and Nothing was found in the medical examination.

In April-May 1979, the fifth course (prophylactic) of thiotepa was administered internally, and the Tolerated.

In June 1979, a third course (preventive) of a new drug was administered, but the weight decreased within two years. has changed significantly (from 54 kg to 68 kg), i.e. 14 kgN! addition Therefore, different doses were used. DL-barrier 3g and methyltestosterone 25 The mixture with g was administered in four doses daily in the same diet. This cool is It continued for 2 months. Signs of virilization appear and the patient becomes anxious due to the development of libido. I made it to t.

For this reason, the patient declined further prophylactic administration of this new drug. 1979 later in the year, and in the spring and fall of 1980, three more times with /chlorophosphano. A course of prophylactic chemotherapy was administered, which was more difficult to tolerate.

In February and March 1981, Mr. Φ suffered two attacks. The living person has a second shot. The woman died at the hospital, but there were no signs of neoplasia, indicating that the woman had died before her death. This was confirmed during a medical examination. Relatives refused an autopsy.

Conclusion II! ! active treatment for up to four years after the person's condition is recognized as completely incurable. The increase in life span cannot be attributed to the success of conventional cancer chemotherapy alone. do not have.

The new drug not only corrects the side effects of chemical drugs, but also suppresses cell growth. clearly promoted.

2 Patient name: M, A, Tkachenko, 28 years old, case No. 11518/ No. She was admitted to the Rostov Institute of Oncology and Gynecology on August 15, 1989. Condition at the time of hospitalization O: Significant enlargement of U area within 2 months, significant weight loss, evening body temperature approximately 39℃ , dyspnea, and chest X-ray showed metastasis to the lung pleura. Opening multiple types of endolymph chemotherapy started, but did not improve the patient's condition.

August 1989 3181 Aspirated 151 fluids from the abdominal cavity and approximately 21 fluids from the thoracic cavity. - An exploratory laparotomy was performed.

Diagnosis: Tumor explantation into the intestine, and major, liver, peritoneal, and Im membranes (metastatic 11 inflammation) Stage 4 ovarian cancer with metastasis to. Histological analysis No. 261362. Double capillary carcinoma.

On September 13, 1989, a platinum preparation was inoculated into the glandular cavity. After this, the patient's condition remained stable. The patient's condition worsened and was considered incurable, so he was discharged from the hospital in a near-terminal state.

On September 26, 1989, as a volunteer, I began administering a new drug to patients in the outpatient department. It started. The daily dose (for a person weighing approximately 70 kg) is methyltestosterone. 25-g (0°025 g or 5 tablets) was used in combination with 3 g of DL-valine. Day The next dose was divided into three doses (Q! DL-valine Ig via the intestine in milk) , and lt via sublingual! 1 of methyltestosterone/3 times daily on an empty stomach and 1 tablet of methyltestosterone before meals and via sublingual route without DL-valine. twice during the previous day). Patients should be treated with no more than 1 to 2 tablespoons of vegetable oil daily and excess protein. white matter, limited amounts of carbohydrates and completely eliminated animal fats and phospholipids II ( The patient strictly adhered to a diet consisting of fish eggs and egg yolks.

Within the first 10-15 days of administration of the new drug, the following changes in the patient's condition occur: did, i.e. 1. Vomiting stopped and 18 vomitings from the intestine occurred independently.

2. Body temperature has become normal.

3. The color of the urine has become lighter (previously dark beer color) 4. The color of the skin has changed from gray-green to yellowish-white It changed to

5. My liver became slightly enlarged and I experienced periodic pain.

6. Occasional tachycardia occurred.

7 showed good appetite and interest in life.

Since the patient was thought to be curable, the treatment course was set to one month, and in 1989 The patient was rushed to the hospital on October 23rd, and repeated intraperitoneal injections of platinum preparations were administered. patient tolerated the platinum injection more easily than the first time, but again showed signs of cardiopulmonary insufficiency. A phenomenon appeared.

After discharge, on November 9, 1989, the patient again underwent a 2-month course (II 1989). ~December) [Started receiving medication. Changes during this period are as follows: Ori.

1. Signs of pulmonary insufficiency disappeared.

2. Periodic pain in the liver has stopped, but the liver is still enlarged. there was.

3. There were no signs of ascites in either the Ill or thoracic cavity.

4. Appetite remained good, and weight increased by 4 kg.

5. The patient wanted to enjoy the active parts of life and go to work, but quickly became tired. I worked hard.

In January 1990, I received a 3-week course of systemic chemotherapy (internal administration of thiotepa). The patient was admitted to the hospital for treatment and was well tolerated, with no hemodynamic compromise and no symptoms of nausea or There was no vomiting. However, due to severe allergic edema in Quince pear, tartar The project was aborted without completion. At this point, pain was felt in the left and right hypochondriacs.

At the beginning of February 1990, the new drug was administered for a two-month course (February to March) as before. The patient was started at the same dose. The situation after cooling is as follows.

10 Objective condition: M1 As shown in the medical examination, in the small pelvis, there is a small ( All tumor formations other than fist-sized (in children) II tumors degrade and show signs of metastatic pleurisy. There were no cases.

2. Subjective condition g: Subjective condition is good. plan to get married. Ending in early April Marriage. He refused all treatments during April and May. Menstruation for 8 months from May 1st There wasn't.

However, in mid-May 1990, symptoms of metastatic pleurisy, including dyspnea and The chest of the left lung up to the bone was exposed. There were no changes in the small pelvis.

Starting May 18, 1990, a full course of cyclophosphane was administered in the outpatient treatment room. Although physical chemotherapy was administered, there was no result, and the pleurisy progressed (the chest was affected by the fifth rib). reached the bone).

On June 4, 1990, 3 g of DL-valine and 3 tablets (0,015 g) of medicinal We started the fourth course of treatment with a new drug at a dose of chilltestosterone. , the reason is that due to extremely elevated lipid levels, the patient takes 5 tablets a day (o, 025 g) because he refused to take it or would have stopped all treatment. Ru. After 2 weeks of administration, the pleurisy decreased and reached the third rib again), and breathing became easier. It was.

At the request of the doctor in charge, chemotherapy with cyclophosphane (2 weeks) and new medicine Treatment with (2 weeks) was administered alternately. After two such shifts, the patient He refused further chemotherapy from the 90th grader, but this , very allergic nature of the external labia and larynx that is not relieved by new medicines. This is because 7[ has occurred.

Patients received independent administration of the new drug for 1 year (August 1991 to August 1991). The patients received the same dose for 1 to 2 months, approximately 1 month apart. death However, the generalization of the process continued slowly: metastases appeared in the left chest; In the area of the membrane there was a buildup of thorax, which was removed three times during this period.

By the end of the year, the malignant neoplasia that had filled the small pelvis had become unresponsive to hormones. August 1991, as it seemed clear that he had completely lost his receptivity. On the 13th of the month, administration of a mechanical mixture, i.e. 3 g of DL-valine per day, methand Administration of Rostea 0.005 g and Butibud 0.3 g was started. mixture All items were 1.5g of DL-barrier with warm milk and methane at the time of emptying. Consisting of 1/72 tablet of Drostenolo and 1/2 tablet of Futibud, taken twice in the morning and evening. Divided into quantities.

This is a one month cool.

This administration apparently caused the formation of large necrotic metastases within the interpleural space and By evening, his temperature had risen, he developed a severe cough, and breathing became difficult. Vomiting is 1~ It occurred once every 2 days, and the vomit contained dark, structureless masses. After that, the fever It decreased and breathing became easier, but the coughing did not stop.

In September 1991, at the patient's request, methyltestosterone 0.015 A one-month course of DL-valine (3 g) in combination with g was restarted. Cough now The symptoms decreased and the vomiting stopped, but the generalization of the process persisted. Chest metastasis into the back muscles and began to proliferate.

In early October, 1′)■, -valine, methandrostea 0no and fuchibud Another course at the same dosage with a mixture of was started. Cough increases and nitrile Symptoms occurred frequently, and attempts to suction the chest showed its absence. clearly, The thoracic cavity was filled with a turret. Heart weakness increased. There was no pain . Due to difficulty climbing stairs, the patient rarely left the house, but At home, the monk read, wrote, and wandered around the room freely.

On November 8, 1991, the patient died of a heart attack that lasted 30-40 minutes. the patient, He lived more than two years longer than he was thought to be incurable.

Conclusion: ■ The successful extension of this young girl's active life was demonstrated by the patient's Has he undergone courses of conventional chemotherapy that he could not tolerate each time? cannot be associated solely with the administration of new drugs.

2. The turning point towards new emulsification in this process is when all treatments are discontinued4. It was ~May. This should not have been canceled. Our treatment is voluntary We had no right to claim it because it was Ru.

3. In our opinion, DL-valine, methandrostea and futibud The use of the mixture was too late, and perhaps the time for its optimal effect was I had lost it.

Initially, in the form 11 of a mixture of DL-Vari/ and low doses of methyltestosterone. This new drug, which has antitumor activity of The study was conducted on 33 patients (volunteers) with malignant genital H tumors. The breakdown is evil Sexual ovarian cancer: 9 patients, uterine corpus ablation in 121 patients, fallopian tube cancer in 1 patient, cervical cancer: 2 patients be.

If you have cancer of the uterine body in stages 2 to 3, but in the period before surgery, you have cancer in the first stage. With the exception of 9 patients for whom the new drug was used as treatment, all other patients The patient is in the third to fourth stage of the disease, and by the time of new drug administration, the patient has not received conventional treatment or chemotherapy. A large and fixed collection of abscesses in the small pelvis occurred after receiving only physical therapy without any effect. , or had significant intraluminal exudate. In some patients, combination therapy may be ineffective. Some people saw recurrence of the disease after.

Most of the patients given the new drug had good results (the tumor had resolved) or adequate It worked. Complete lack of effect was observed in only 5 patients. That's right In four patients, MS was clearly caused by hormone-insensitive cervical cancer, fallopian tube cancer, or sarcoma of the uterine body. Therefore, the fifth patient was in a very serious condition due to rapid emulsification of the process and was not treated for treatment. I visited the hospital.

The proposed drug is effective against metastases within the bones and explants into the muscles of the skin of the chest. The study was also conducted on 5 patients with incurable breast cancer who had cancer, but these patients showed no efficacy. After irradiation of the fruit and 10-1z courses of chemotherapy, the patient is in a very serious condition. He was discharged to receive symptomatic treatment.

In one of these cases, after prolonged hospital treatment, the skull, pelvis and Metastases to the ribs led the patient to a near-terminal state, and the patient was sent out of the hospital on a stretcher. It was. Dosing of a mechanical mixture of 2 g DL-valine and 20 mg methyltestosterone The effects were both subjective and objective. Usually like that 1. by trimeperinone hydrochloride (promedol), accompanied by a metastasis. 5～ The most severe pain, which could only stop for 2 hours, was relieved from the third day of administration. It started and disappeared completely within two weeks. As a result, the living were able to get out of bed within a month. , gradually became involved in active life. Every two months, examine the affected part of the skeleton. The minutes were examined by X-ray. Signs of bone tissue repair beginning to be seen in the skull and pelvis. It was done. Patients are treated in an outpatient treatment room for 8 months at short intervals of 1 to 1.5 weeks. administration, at which point the result of long-term unrestricted intake of calcium chloride for 3 months. The patient died from thromboembolism.

Until the last day, the patient did household chores, went shopping, and went to the market. Ru.

In three cases, mechanical mixing of DL-valine, methyltestosterone and futibazide A temporary but sufficiently significant subjective improvement in the patient's condition as a result of administration of the compound , which eventually ended after another course of chemotherapy, but the reason for this was This was because the patient was readmitted to the Rostov Institute of Oncology Chemistry and Hormone Therapy. be.

■ In cases, such a subjectively significant improvement does not occur suddenly during the administration of the proposed drug. The reason for this was that the patient was under stress due to personal problems. This is because it occurred in This person was not hospitalized.

From the observations carried out by the inventors, the administration of the proposed drug is different from the conventional practice. Even after effective chemo-group 11 therapy, it has been shown to yield largely satisfactory results. It was done.

The technical achievements of the present invention are as follows.

Hormone sensitivity of proposed drugs to breast cancer induced in rats and normal animals Pharmacological properties studied experimentally in layered tumors, as well as in volunteers in incurable cases. The data obtained clinically in the treatment show that it is completely harmless and well-defined. It has remarkable cell growth inhibiting properties, along with simultaneous stimulation of the body's defenses and analgesic effect. I'm testifying.

Explanation of drawings/ Figure 1. DMB^-induced mammary carcinoma in rats.

1. Control group, solid adenocarcinoma of mammary gland of rats (not administered). Magnification: Xl602, experimental group : After administration of DL-”phosphorus in a mixture with methyltestosterone (decline). The tumor cells exhibit prominent dystrophic malnutrition lesions, i.e., extensive vacuolization of the cytoplasm; Both cough and cytoplasmic lysis are observed. Double fissure: x 200 Figure 2. human uterine corpus adenocarcinoma. Aspirate from the uterine cavity (cytology).

1. Before administration: Rosette structure with typical cylindrical elongated cells. Magnification x 200 2. Two weeks of administration of DL-valine and methyltestostero/. tumor cell cells π and nuclear vacuolization ((kirate x 600. liquid man).

3. DL--valine and methyltestosterone administration for 4 weeks. prominent vacuoles Malnutrition, i.e. fusion of small vacuoles in the cytoplasm and nucleus of abscess cells (magnification x 60 0, immersion).

Administration for 410 days. The malnourished and altered layers of cancer cells, the ``eroded'' nucleus. Contours and dissolution of individual coughs (magnification x600. liquid).

Engraving (no changes to the content) Human endometrial adenocarcinoma Aspirate specimen from uterus (cytology) 2. Two weeks of treatment with DL valine and methyltestosterone combination Cytoplasmic and nuclear vacuolization of tumor cells.

Table 7 DMBL-induced breast cancer 1. Control: Rat glandular-solid mammary carcinoma (no effect). (Magnification: X160) Procedure correction Calligraphy, maple, October 14, 1994

Claims (1)

[Claims] 1. A drug that exhibits antitumor activity and is effective in treating hormone-sensitive carcinomas in women. For therapeutic purposes, 2-4 g of DL-valine and 0.020-0.025 g of non-containing Mechanical mixture with therapeutic low doses of methyltestosterone, as well as hormone/sensitivity 2-4 g DL-valine, 0.00 for the treatment of non-susceptible carcinomas 5-0.010 g methandrostenolone and 0.3-0.5 g futivazide A medicine consisting of a mechanical mixture of.