Anti-tumor agent benzamide

FIELD: medicine, oncology, pharmacy.

SUBSTANCE: invention relates to an anti-tumor agent representing benzoic acid amide (benzamide). Benzamide is used in the range of doses from 25 to 100 mg/kg.

EFFECT: expanded assortment of agents of indicated designation.

2 cl, 1 tbl

 

The invention relates to medicine and veterinary medicine, namely to the tool benzamid (I)

(benzoic acid amide), as well as pharmaceutical compositions containing this substance. The tool according to the invention can be used in medical or veterinary practice as an anticancer drug.

Analogues benzamide and its derivatives by themselves (without radiation or anticancer drugs) have antitumor activity [1-3], whereas the benzamide antitumor properties are not described. Benzamid, its analogues and derivatives with a joint introduction with anticancer remedies [4-14] and used to inhibit the growth of tumors with ionizing radiation [15-25] increase their effectiveness.

It is believed that benzamid, its analogues and derivatives with a stand-alone application (without radiation or anticancer drugs) not only do not possess antitumor activity [26], but can even enhance the action of carcinogens [27-30].

In our patent RF №2205009 from 27.05.03 benzamid described as an antiemetic. According to the patent benzamid in the dose range from 5 to 150 mg/kg can be used in medical or veterinary practice for the prevention and treatment of nausea and vomiting of various etiologies, in particular due to the impact is the influence of ionizing radiation or cytotoxic drugs.

Experimental studies have shown that the scope of benzamide in Oncology practice may not be limited to his appointment as an antiemetic.

The aim of the invention is the use of benzamide in medical, veterinary and pharmaceutical practice as antitumor agents.

We found that benzamid able to significantly delay tumor growth. According to the invention benzamid offered in a range of doses from 25 to 100 mg/kg

To achieve the desired effect benzamid you can enter in a clinically reasonable quantities by any means, for example, oral, rectal or parenteral. On its basis can be developed drugs, containing in addition to the active ingredient necessary pharmaceutical additives and components.

Such means may constitute the drugs in dosage form and prepared by any method known in the art Pharmacopoeia. In all of these methods provides the stage of combining the active substance with a carrier that includes one or more auxiliary components.

Benzamide can be used as an anticancer drug in combination with other therapeutic agents used in Oncology.

Below is experimentally example illustrates but do not limit the claims of the applicant.

Specific activity

The ability benzamide to provide an antitumor effect installed in the experiments of 52 mice hybrids F1 (CBA×C57BL), weighing 18-20 g in 2 series of experiments on the model of transplantable Ehrlich carcinoma.

Tumor cells in quantities of 1 million on the mouse in 0.15 ml of Hanks solution transplanted into the muscle of the leg. During the whole experiment through the day, a measurement was performed three perpendicular diameters of the tumor and, taking the shape of the tumor for the ellipsoid was calculated its volume using the formula: V=(π/6)×d1×d2×d3where V is the volume of the tumor, d1d2d3linear sizes of the three axes of the ellipsoid.

Benzamid at a dose of 25, 50 or 100 mg/kg was administered orally, for 5 days, starting from the 4th day after inoculation carcinoma. The antitumor effect of the drug was assessed by the impact on the growth of carcinoma. The observation was continued up to 30 days after inoculation of the tumor.

The results of the experiments are subjected to statistical processing carried out by standard methods of calculating mean values and the arithmetic mean of errors. The reliability of the results was evaluated using a t-student test.

Research has shown that the introduction into the leg muscle of the mice 1 million cells of transplantable Ehrlich carcinoma leads the development of 100% animal tumor formation is ellipsoidal. Tumor volume was increased in proportion to the period of time elapsed from the moment of inoculation, and by the end of the observation averaged 9.3±0.4 cm3(table).

Benzamid when using an oral dose of 25 mg/kg, without changing the proportion of animals with developed cancer had a significant impact on the dynamics of tumor volume. In his introduction to this dose was slowing tumor growth at different periods of observation. Significant differences between the control group mice and animals treated with basamid at a dose of 25 mg/kg, occurred in the period from 16th to 18 th day, as well as from the 25th through the 30th day (table). Benzamid dose of 50 mg/kg, compared with the dose of 25 mg/kg, had a less pronounced inhibitory effect on the growth of Ehrlich carcinoma. In these mice for a long time (16 x 30 days) tumor sizes were smaller than in the control group, but the differences were not significant (table). With further increase in dose benzamide up to 100 mg/kg of the nature of its influence on the dynamics of tumor volume was similar to that at the dose of 50 mg/kg of a slowdown in benzamido tumor growth, marked with a 16 x 20 days and 25 th to 28 th day of observation, can only be described as a trend (table).

Therefore, the obtained results indicate that in mice, benzamid has protivoop alevai activity against transplantable Ehrlich carcinoma.

td align="center"> 2,3±0,3
Table

The effect of benzamide (introduced per os) on growth of transplantable Ehrlich carcinoma in mice
GroupQty animalsTumor volume, cm3
4 d.for 6 days.8 d.12 d.14 days.16 d.18 days.20 day.22 d.25 d.28 d.30 days.
Control140,005±0,0010,3±0,020,7±0,041,4±0,12,2±0,12,8+0,253,4±0,24,1±0,245,2+0,36,8±0,38,5±0,59,3+0,4
Benzamid 25 mg/kg130,002±0,0010,4±0,030,8±0,051,7±0,21,8±0,21,9±0,2*2,0±0,4*2,9±0,74,0±0,94,6±0,8*5,6+0,8*6,4±0,9*
Benzamid 50 mg/kg140,002±0,0010,4±0,040,8±0,081,8±0,242,4+0,352,8±0,43,4±0,64,5±0,95,7±0,67,1±0,98,1±1,0
Benzamid 100 mg/kg110,002±0,0010,4+0,050,8±0,131,7±0,32,3±0,42,5±0,53,1±0,74,0±0,55,4±0,66,2±0,88,4±1,0a 9.5±1,0
Note: * - differences significant (p≤0,05) with the control

References

1. International patent WO 03 /042191.

2. U.S. patent US 6447748.

3. Cookson M.R., Ince p, Shaw P.J. Peroxynitrite and hydrogen peroxide induced cell death in the NSC34 neuroblastoma x spinal cord cell line: role of poly (ADP-ribose) polymerase // J. Neurochem., 1998, v.70, n.2, p.501-508.

4. European patent EP 0305008.

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7. M.R. Horsman, Brown D.M., D.G. Hirst, Brown J.M. The effects of purine nucleoside analogs on the response of the RIF-1 tumor to melphalan in vivo // Int. J.Radiat. Oncol. Biol. Phys., 1986, v.12, n.5, p.801-806.

8. M.R. Horsman, Brown D.M., D.G. Hirst, J.M. Brown Changes in the response of the RIF-1 tumour to melphalan in vivo induced by inhibitors of nuclear ADP-ribosyI transferase // Br. J.Cancer, 1986, v.53, n.2, p.247-254.

9. M.R. Horsman, D.G. Hirst, D.M. Brown, Brown J.M. Modification of alkylating agent cytotoxicity by cisplatin // In. J. Radiat. Oncol. Biol. Phys., 1984, v.10, n.9, p.1669-1673.

10. Brown, D.M., M.R. Horsman, D.G. Hirst, J.M. Brown Enhancement of melphalan cytotoxicity in vivo and in vitro by inhibitors of poly (ADP-ribose) polymerase // Int. J. Radiat. Oncol. Biol. Phys., 1984, v.10, n.9, p.1665-1668.

11. Institoris E., B.W. Fox, Palyi I. Benzamide potentiation of the cytotoxicity of bifunctional galactitol [correction of galacticol] in resistant P388 leukemia correlates with inhibition of DNA ligase II // Cancer. Chemother. Pharmacol., 1992, v.30, n.4, p.325-329.

12. Sakamoto H., Kawamitsu h, Miwa M., et. al. Enhancement of antitumor activity of bleomycin by benzamide in vitro and in vivo // J. Antibiot. (Tokyo), 1983, v.36, n.3, p.296-300.

13. Ludwig A., Dietel M., Schafer, G., et. al. Nicotinamide and nicotinamide analogues as antitumor promoters in mouse skin // Cancer Res., 1990, v.50, n.8, p.2470-2475.

14. Wielckens K., Delfs T. Glucocorticoid-induced cell death and poly[adenosine diphosphate(ADP)-ribosyl]ation: increased toxicity of dexamethasone on mouse S49.1 lymphoma cells with the poly(ADP-ribosyl)ation inhibitor benzamide // Endocrinology, 1986, v.119, n.5, p.2383-2392.

15. International patent WO 86/06628.

16. U.S. patents US 5032617, 5041653 and 5215738.

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18. Virag L., Szabo C. therapeutic potential of Poly(ADP-Ribose) polymerase inhibitors // Pharmacol. Rev., 2002, v.54, n3, p.375-429.

19. Gradzka I., Iwanenko So, Kruszewski M., et al. Modulation of the effect of camptothecin in x-irradiated L5178Y-R and L5178Y-S cells by benzamide // Radiat. Environ. Biophys., 1996, v.35, n.3, p.185-191.

20. M.R. Horsman, Brown D.M., Lemmon M.J., et. al. Preferential tumor radiosensitization by analogs of nicotinamide and benzamide // Int. J.Radiat. Oncol. Biol. Phys., 1986, v.12, n.8, p.1307-1310.

21. G.P. Raaphorst, E.I. Azzam Poly(ADP-ribose) synthetase inhibitors increase radiation and thermal sensitivity but do not affect thermotolerance // Radiat. Res., 1988, v.116, n.3, p.442-452.

22. Szwniel I., Wlodek D., Johanson K.J. Differential effect of benzamide on NAD+ content and the fequency of chromatid aberrations in X-irradiated L5178Y-R and L5178Y-S cells // Acta Oncol., 1988, v.27, n.6b, p.851-855.

23. Ben-Hur E. Involvement of poly (ADP-ribose) in the radiation response of mammalian cells // Int. J.Radiat. Biol. Relat. Stud. Phys. Chem. Med., 1984, v.46, n.6, p.659-671.

24. Kjellen e, Pero, R.W., Nilsson P. Comparison of low dose nicotinamide versus benzamide, administered per os, as radiosensitizers in a C3H mammary carcinoma // Radiother. Oncol., 1988, v.12, n.4, p.327-331.

25. Thraves P.J., K.L. Mossman, T. Brennan, Dritschilo A. Differential radiosensitization of human tumour cells by 3-aminobenzamide and benzamide: inhibitors of poly(ADP-ribosylation) // Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med., 1986, v.50, n.6, p.961-972.

26. Vartanyan L.A., Rusanov A.M., Kolosova MB and other Recovery processes in tumor cells when exposed purine inhibitors of reparation // Restore. and the compensator. processes in the beam. the lesions. Proc. 7th Uses. scient. Conf., 1979". L., 1979, 57-58.

27. Durkacz B.W., Lunec J., Grindley, H. et al. Murine melanoma cell differentiation and melanogenesis induced by poly(ADP-ribose) polymerase inhibitors // Exp. Cell. Res., 1992, v.202, n.2, p.287-291.

28. Burkle, A., Heilbronn, R., zur Hausen H. Potentiation of carcinogen-induced methotrexate resistance and dihydrofolate reductase gene amplification by inhibitors of poly(adenosine diphosphate-ribose) polymerase // Cancer Res., 1990, v.50, n.18, p.5756-5760.

29. Kasid U.N., Stefanik D.F., R.A. Lubet, et. al. Relationship between DNA strand breaks and inhibition of poly (ADP-ribosylation): enhancement of carcinogen-induced transformation // Carcinogenesis, 1986, v.7, n.2, p.327-330.

30. Kun, E., Kirsten E., Milo, G.E., et al. Cell cycle-dependent intervention by benzamide of carcinogen-induced neoplastic transformation and in vitro poly(ADP-ribosyl)ation of nuclear proteins in human fibroblasts // Proc. Natl. Acad. Sci. USA, 1983, v.80, n.23, p.7219-7223.

1. Antitumor agent, wherein the pharmacologically active agent is benzamid.

2. The tool is .1, characterized in that benzamid used at doses of 25÷100 mg/kg



 

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