RU2414894C1 - Method of treating lung cancer - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to oncology and can be applied for treatment of lung cancer. Essence of claimed method lies in the following: topotecan and aranose are introduced intraperitoneally in doses: for topotecan 0.5 mg/kg or 1 mg/kg, for aranose 100 mg/kg sequentially with interval 10-15 min twice or thrice.

EFFECT: application of method makes it possible to increase efficiency of lung cancer treatment due to inhibition of tumor growth, increase of life duration and reduction of toxicity under impact of topotecan and aranose combination.

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Description

The invention relates to medicine, namely to antitumor therapy, and relates to a method for the treatment of lung cancer; it can be used alone or in combination with surgical or radiation treatments.

A known method of treating lung cancer with topotecan. The drug is used in monotherapy as a standard treatment in the 2nd line of chemotherapy for small cell lung cancer. However, the effectiveness of modern schemes of the second line of chemotherapy for small cell lung cancer chemotherapy is low: the frequency of remissions does not exceed 25%, and the annual survival rate is about 30% [1, 2].

Closest to the claimed method is a method of treating lung cancer with topotecan, which is selected as a prototype. Its essence is that topotecan was used orally in mice with a xenograft of non-small cell lung cancer obtained from A549 cell culture at a dose of 1.5 mg / kg five times. The therapeutic effect was evaluated by tumor volume and compared with the control group. As a result of the study, it was revealed that topotecan therapy in this mode did not lead to significant inhibition of tumor growth [3].

The main disadvantage of prototype treatment was a low antitumor effect: no significant inhibition of tumor growth was noted.

The objective of the invention is to provide a more effective method of treating lung cancer.

The problem is solved in that the claimed method uses a combination of two antitumor drugs: topotecan + aranose (TAg). The inventive method of treatment is as follows. Animals with transplantable tumors (the number of mice in groups is 8-11) are exposed to the combined effects of the above drugs. Single doses of topotecan were 0.5 mg / kg or 1.0 mg / kg, a dose of aranose - 100 mg / kg. The drugs were administered intraperitoneally once a day, sequentially, starting with topotecan. The interval between drug administrations was 10-15 minutes. A control group of mice was injected with 0.9% sodium chloride solution.

The study was conducted on male BDF ₁ mice, which were transplanted subcutaneously with Lewis epidermoid lung carcinoma (LLC), and the efficacy and tolerability of the TAr combination was studied.

Treatment began 48 hours after LLC subcutaneous transplantation. The tumor transplantation technique is standard [4].

Treatment efficacy was evaluated according to generally accepted criteria: inhibition of tumor growth (TPO%, minimum criterion of effectiveness ≥50%), increase in life expectancy (VL%, minimum criterion of effectiveness ≥25%) and cure (absence of a tumor within 3 months after treatment). Control groups of mice did not receive specific treatment [4, 5]. Statistical processing of data was carried out according to the standard Student's method using confidence intervals of the average compared values, the differences were considered significant at p <0.05.

Treatment tolerance was assessed by the condition and behavior of mice during and after treatment, as well as by the results of autopsy of dead or killed mice and the mass of the spleen - an indirect sign of hematological toxicity [5].

The effectiveness and tolerability of the proposed method of treatment is demonstrated by examples 1 and 2.

Example 1. Comparison of the effectiveness of the proposed method of treatment (TAr) and the prototype was carried out on mice with subcutaneous transplanted LLC. The groups included 8-11 animals. Topotecan and aranose were administered on the 2nd, 3rd and 4th day after LLC transplantation sequentially: the first was administered topotecan, the second - aranose. A single dose of topotecan was 1 mg / kg (total dose - 3 mg / kg), a single dose of aranose was 100 mg / kg (total dose - 300 mg / kg). The results of treatment with a combination of TAr compared with topotecan therapy are presented in table 1.

It is shown that the claimed method of treating TAr is more effective than the prototype. During treatment with topotecan, VLD and cure of mice were not observed; a short-term antitumor effect was obtained within 14 days. In the group of 8 mice treated with TAr, a long antitumor effect was achieved for 30 days, a significant prolongation of the life of 6 mice (VLP = 90%) and cure of 2 mice. TPO in groups of mice that received topotecan and TAr was 69-98% and 98-100%, respectively, p <0.05.

The tolerance of the proposed method is comparable with the tolerance of treatment with the prototype topotecan. The condition and behavior of animals in both groups were not changed. The average spleen mass in mice treated with TAr and mice treated with topotecan did not significantly differ: 130 [77–183] mg and 144 [107–181] mg, respectively.

Example 2. Comparison of the effectiveness of the proposed method and prototype on 26 athymic male mice Balb / c nude with a subcutaneous xenograft of non-small cell lung cancer RL-4, obtained from cell culture A549.

The groups included 8-9 animals. Topotecan and aranose were administered intraperitoneally once a day sequentially with an interval between administrations of 10-15 minutes on the 2nd and 4th day after tumor transplantation. Topotecan was used in a single dose of 0.5 mg / kg (total dose of 1 mg / kg), aranose in a single dose of 100 mg / kg (total dose of 200 mg / kg). When using the proposed method of treatment on the 22nd day after its completion, a reliable TPO = 65% was achieved (p <0.05). The effect at the level of SRW> 50% was maintained thereafter for 30 days after the end of treatment. While topotecan did not show a significant antitumor effect, TPO≤24% (p> 0.05). The treatment results are presented in table 2.

Technical result

The technical result of the proposed method for the treatment of lung cancer is to achieve:

- growth inhibition of subcutaneous xenograft of human lung cancer (line A549) on immunodeficient mice with higher efficiency compared to the prototype.

- increased life expectancy compared with the prototype by 74% and cured 25% of mice with subcutaneous transplanted lung carcinoma LLC with satisfactory tolerance.

The inventive method of treating lung cancer with a combination of TAr preparations is more effective in comparison with topotecan therapy.

Information sources

1. Eckardt JR, von Pawel J., Pujol JL, Papai Z., Quoix E., Ardizzoni A., Poulin R., Preston AJ, Dane G., Ross G. Phase III Study of Oral Compared With Intravenous Topotecan As Second -Line Therapy in Small-Cell Lung Cancer // J. Clin. Oncol. - 2007 .-- Vol.25. - P.2086-2092.

2. O'Brien M., Eckardt J., Ramlau R. Recent Advances with Topotecan in the Treatment of Lung Cancer // The Oncologist. - 2007 .-- Vol.12. - P.1194-1204.

3. Hardman W.E., Mover M.P., Cameron I.L. Efficacy of treatment of colon, lung and breast human carcinoma xenografts with: doxorubicin, cisplatin, irinotecan or topotecan // Anticancer Res. - 1999. - Vol.19. - P.2269-2274.

4. Guidance on the experimental (preclinical) study of new pharmacological substances. / Ed. R.U. Khabrieva, 2nd ed. - M .: Medicine. - 2005. - S.637-651.

5. Larionov L.F. Chemotherapy of malignant tumors. - M .: Medgiz, 1962 .-- 464 p.

Claims (1)

A method of treating lung cancer by parenteral administration of topotecan, characterized in that aranose is added, while topotecan and aranose are administered intraperitoneally in doses: for topotecan 0.5 mg / kg or 1 mg / kg, for aranose 100 mg / kg sequentially with an interval of 10 -15 min twice or three times.