RU2365370C1 - Method of lung cancer treatment - Google Patents

Abstract

FIELD: medicine; oncology.

SUBSTANCE: Etoposide, Cisplatin, Aranose are administered one after another, in intraperitoneally, in a dose of 1/4 from the maximum tolerated dose with an interval of 10-20 minutes at a double or triple administration regimen.

EFFECT: inhibition of tumour growth at the expense of complex action of preparations and treatment tolerance increase.

4 tbl, 5 ex

Description

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

Known methods of treating lung cancer using combination chemotherapy with the inclusion of cisplatin: etoposide + cisplatin; gemcitabine + cisplatin; irinotecan + cisplatin; paclitaxel + cisplatin; docetaxel + cisplatin. However, the effectiveness of modern treatment regimens for disseminated lung cancer is low: one-year survival rarely reaches 60% [1, 2, 4, 5].

Closest to the claimed is a method of treating lung cancer with a combination of etoposide and cisplatin (EP), which is selected as a prototype. Its essence lies in the fact that etoposide and cisplatin were administered intraperitoneally to mice at the maximum tolerated doses on the 10-11th day after transplantation of Lewis epidermoid carcinoma of the lung (LLC). Etoposide was used at a dose of 40 mg / kg of animal weight once, cisplatin - fractionally at a dose of 2 mg / kg 4 times a day with an interval of 4 hours (total dose of 8 mg / kg). The therapeutic effect (34%) was less than after etoposide monotherapy (57%) with high toxicity leading to the death of animals [6].

The disadvantages of the treatment method with a combination of EP when using drugs in the most tolerated doses are: high toxicity and low antitumor effect.

The objective of the invention is to provide a method for the treatment of lung cancer with higher efficiency with satisfactory tolerance.

The problem is solved in that the claimed method uses a combination of three antitumor drugs: etoposide + cisplatin + aranose (EPAr). The inventive method of treatment is as follows. Animals with transplantable tumors are exposed to the combined effects of drugs in doses close to ј maximum tolerated. Single doses of etoposide were 5 or 10 mg / kg; cisplatin - 2.5 or 3 mg / kg; aranoses - 100 or 200 mg / kg. The drugs were administered intraperitoneally once a day, sequentially, starting with etoposide, then cisplatin and aranose. The interval between drug administrations was 10-20 minutes.

The results of studies of the antitumor effect of the proposed method on transplantable tumors of mice and humans are presented. In experiments on male BDF ₁ mice that received LLC subcutaneously or intramuscularly, the efficacy and tolerability of a combination of EPAr preparations was studied.

Treatment was started after tumor transplantation with subcutaneous inoculation of the LLC after 48 hours or with intramuscular inoculation on day 7. The technique of tumor transplantation is standard [3].

The effectiveness of the treatment was evaluated according to standard criteria:

inhibition of tumor growth (SRW,%; minimum criterion for efficacy ≥50%), increase in life expectancy (VLP,%; minimum criterion for efficacy ≥25%) and cure (absence of a tumor for 2-3 months) in comparison with control groups of untreated mice .

Treatment tolerance was evaluated by the behavior and condition of the mice during and after treatment, as well as by the results of an autopsy of the dead or slaughtered mice and the weight of the spleen.

The effectiveness and tolerability of the proposed method of treatment is demonstrated by examples 1, 2, 3, 4, 5.

Example 1. The effectiveness of the claimed method of treatment was studied in mice with subcutaneous transplanted LLC. The drugs were administered intraperitoneally on the 2nd, 3rd, 4th day after LLC transplantation, sequentially: etoposide, then cisplatin and aranose. The dose of etoposide was 5 mg / kg (total dose of 15 mg / kg), cisplatin - 3 mg / kg (total dose of 9 mg / kg); aranoses - 200 mg / kg (total dose of 600 mg / kg). The claimed method of treatment led to the cure of 11 out of 11 mice: on the 65th day after the end of treatment, no signs of tumor were detected in animals.

Example 2. Comparison of the effectiveness of the proposed method of treatment (EPAr) was carried out with a method of treatment with a combination of etoposide + cisplatin (EP) in mice with subcutaneous transplanted LLC. The drugs were administered intraperitoneally on the 2nd, 3rd, 4th day after LLC transplantation, sequentially: first etoposide was administered, then cisplatin and aranose. The dose of etoposide was 5 mg / kg (total dose of 15 mg / kg), cisplatin - 2.5 mg / kg (total dose of 7.5 mg / kg); aranoses - 100 mg / kg (total dose 300 mg / kg). The results of treatment with combinations of EPAr and EP (BDF ₁ , males) are presented in Table 1 (* - reliability in relation to control, p <0.05; ** - reliable in relation to combination EP and control; minimal criteria for TPO≥50 effectiveness %, UPZ≥25%).

The inventive method of treatment was effective, 11 of 13 mice were cured. The method of treating mice with a combination of EP drugs was ineffective, in no case was there a cure, there was only inhibition of tumor growth within 23 days after the end of treatment and a slight increase in the life expectancy of mice (TPO was 88-42% (p <0.05), UPZ 2%).

In the treatment of the claimed method, there was a significant decrease in body weight and spleen mass, which did not lead to the death of animals.

Example 3. The effectiveness of the treatment of the claimed method EPAr was studied in 13 mice with a developed LLC tumor after intramuscular transplantation. The results of the treatment of intramuscularly transplanted Lewis epidermoid carcinoma of the lung with a combination of EPAr (BDF ₁ , males, IM LLC) are presented in Table 2 (* - reliably with respect to the control, p <0.05).

The treatment was carried out on the 7th, 8th, 9th day after the transplantation of the tumor with an average tumor volume of 1219 [1026 ÷ 1572]. In the claimed method of treatment, the drugs were administered daily intraperitoneally in the previously indicated sequence: etoposide in a single dose of 5 mg / kg (total dose of 15 mg / kg), cisplatin 3 mg / kg (total dose of 9 mg / kg) and aranose in a single dose of 150 mg / kg (total dose 450 mg / kg). As a result of using the proposed method of treatment, a stable high therapeutic effect was achieved on the 6th, 9th, 12th, 16th day after the end of treatment: TPO was 83, 84, 84, 69%, respectively (p <0.05). Treatment tolerance is satisfactory: the weight loss of mice after administration of drugs did not exceed 15%.

Example 4. The effectiveness of the proposed method of treatment was studied on strain RL-4, obtained as a result of subcutaneous implantation of A549 human lung adenocarcinoma cell culture by immunodeficient (nude) 8-week-old Balb / c nude female mice weighing 20 g. Results of treatment of lung cancer xenograft human RL-4 in immunodeficient mice with a combination of EPAr (Balb / c nude) are presented in table 3.

The drugs were administered intraperitoneally once a day sequentially with an interval between administrations of 10-20 minutes. The treatment regimen is double with an interval of 48 hours: on the 5th and 7th day after tumor transplantation. The drugs were administered in doses close to ј of the maximum tolerated doses: etoposide - in a single dose of 10 mg / kg (total dose of 20 mg / kg), cisplatin - in a single dose of 2.5 mg / kg (total dose of 5 mg / kg) and aranose - in a single dose of 100 mg / kg (total dose of 200 mg / kg). The total doses of cisplatin and aranose, which determine the degree of hematological toxicity of the combination, are reduced by reducing the number of injections to prevent complications in immunodeficient mice. It was shown that as a result of combined chemotherapy for xenograft of human lung cancer according to the EPAr regimen on the 4th day after treatment, a reliable therapeutic effect of TPO = 73% (p <0.05) was achieved, which remained for 11 days at the level of TPO 73-37 % Treatment tolerance is satisfactory.

Example 5. Comparison of the effectiveness of the proposed method was carried out with a treatment method using a combination of EP in 31 nude male Balb / c nude mice with a subcutaneously transplanted xenograft of non-small cell lung cancer A549. The results of the treatment of subcutaneous xenograft of human lung cancer RL-4 in immunodeficient mice with combinations of EP and EPAr (Balb / c nude) are presented in table 4 (* - reliably with respect to the combination of EP, p <0.05).

The drugs were administered intraperitoneally once a day sequentially with an interval between administrations of 10-20 minutes on the 2nd and 4th day after tumor transplantation. Etoposide was used in a single dose of 5 mg / kg (total dose of 10 mg / kg), cisplatin in a single dose of 2 mg / kg (total dose of 4 mg / kg) and aranose in a single dose of 100 mg / kg (total dose of 200 mg / kg). When using the claimed method on the 27th day after the end of treatment, the SRW was 77%. This effect continued for 39 days after the end of treatment. In the treatment method with the combination of EP TPO, did not exceed 34% (p> 0.05). The tolerance of the proposed method was satisfactory and comparable with that of mice treated with the combination of EP.

Technical result

The technical result of the proposed method of treatment is:

- the ability to cure mice with subcutaneous transplanted LLC in the early stages of tumor development with satisfactory tolerance;

- the possibility of prolonged inhibition of the growth of a developed massive tumor;

- the possibility of inhibiting the growth of a subcutaneously transplanted xenograft of human lung cancer (line A549) in immunodeficient mice with higher efficiency compared to the prototype with satisfactory tolerance.

The inventive method of treating lung cancer with a combination of etoposide, cisplatin, aranose (EPAR) is more effective than the prototype (EP) with satisfactory tolerance.

Information sources

1. Gorbunova V.A., Marenich A.F., Mikhina Z.P. et al. Conservative treatment of lung cancer. - M., Litterra. - 2005 .-- 127 p.

2. Guidelines for chemotherapy for tumor diseases. / Ed. N.I. Perevodchikova, 2nd ed. - M .: Practical medicine. - 2005. - S.203-208.

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

4. Mori K., Ohta S., Kishiro I. et al. Phase II study ofinfusional cisplatin in combination with etoposide in the treatment of small cell lung cancer. // Eur J. Cancer. - 1995. - V.11. - P.1781-1784.

5. Anticancer drugs development guide / Edt. by B.A. Teicher, P.A. Andrews, 2nd edition. - Totowa-New Jersey, Humana Press. - 2004 .-- p.450.

6. Zupi G., Greco C., Sacchi A. et al. Etoposide prior to cis-diamminedichloroplatinum in combination chemotherapy: in vitro and in vivo studies. // Eur J. Cancer Clin Oncol. - 1985. - V.21. - N.12. - P.1501-1506.

Claims (1)

A method for the treatment of lung cancer by intraperitoneal administration of etoposide and cisplatin, characterized in that aranose is added to the treatment regimen, all drugs being administered at a dose of ј of the maximum tolerated, sequentially: etoposide, cisplatin, aranose with an interval of 10-20 minutes with a double or triple administration mode.