Method for creating biological model of moderate growth inhibition of tumour and metastases in lewis lung carcinoma with prolonged cyclophosphanine-induced leukopenia in mice

FIELD: medicine.

SUBSTANCE: what is involved is simulating moderate growth inhibition of tumour and metastases in Lewis lung carcinoma with prolonged cyclophosphanine-induced leukopenia in mice by intraperitoneal introduction of cyclophosphane in 1/3 ADR - 3 times, 83.3 mg/kg each on 6th, 12th and 18th post-transplantation days. On the 3rd day after each introduction, peripheral blood is analysed (total leukocyte count, leukogram) - the lowest WBC count is determined. The clinical effectiveness is assessed at the end of the experiment on the 21st post-transplantation day as shown by tumour weight, a percentage of growth inhibition, a metastasis rate, the number of lung metastases, a metastasis inhibition index.

EFFECT: new biological model of carcinoma with comorbid prolonged leukopenia enables weighing the contribution of substances of different nature to the anti-cancer clinical effectiveness and to the elimination of white blood cell toxicity when the above substances are included into the therapy.

1 ex, 1 tbl

 

The invention relates to medicine, specifically to Oncology, and can be used for preclinical studies of substances that enhance antitumor and antimetastatic effects of the action of drugs and reducing their toxicity on white blood cells.

In modern clinical Oncology chemotherapy is one of the main methods of treatment of patients with malignant neoplasms, particularly in the later stages of the development of tumor in the presence of extensive metastasis [1].

Most anticancer drugs drugs have side effects and affect not only cancer cells but also healthy with a high growth fraction, first of all, blood cells, causing the development of Hypo - and aplastic States. Such violations are a major limiting factor for chemotherapy. One of the widely used drugs in the Oncology clinic is cyclophosphamide, which along with the cytostatic effect on tumor has a number of toxic effects (impaired hematopoiesis, immune depression)that limits its continued use in high doses for the treatment of patients with tumors. Thus, increasing the antitumor and antimetastatic effects activity of cyclophosphamide by reducing the th toxicity is relevant.

In the literature there is evidence that after a single intraperitoneal administration to mice of cyclophosphamide at a dose of 125 mg/kg (1/2 of the maximum tolerated dose, MTD) significantly inhibited the growth of primary tumor and metastases of carcinoma of the lung Lewis. There leukopenia with minimum values of 3 and 4 days, and recovery of peripheral blood counts with 5 d after injection of cyclophosphamide [2].

It is known that 2-fold introduction of cyclophosphamide at a dose of 60 mg/kg to mice with Lewis lung carcinoma leads to a significant inhibition of tumor growth (63%) and metastases (index inhibiting metastasis equal to 82%) [3].

In these biological models, there is a pronounced inhibition of tumor growth and metastasis, in which it is impossible to assess the contribution to improving the efficiency of cytostatic therapy substances of different nature when they are in treatment.

Given the fact that in clinical practice cytotoxic therapy is applied courses (usually 3 times lower), arising from long-leukopenia is a barrier to full treatment.

Thus, our proposed model of moderate inhibition of growth of primary tumor and metastases in the development of carcinoma, Lewis lung in mice with concomitant prolonged leukopenia, you the bathroom 3x introduction of cyclophosphamide, can be used in the preclinical study of substances that increase the efficacy of chemotherapy and reduce the toxic effect of drugs on white blood cells.

In the analysed literature adequate prototype not found.

The objective of the invention is to provide a new biological model of moderate inhibition of tumor growth and metastasis associated with prolonged leukopenia.

The problem is solved by repeated introduction of animals of cyclophosphamide. What's new is that as a model course use of cytostatic agents used 3-fold intraperitoneal administration to mice C57B L/6 with inoculated intramuscularly with 4 million cells of Lewis lung carcinoma of cyclophosphamide at a dose of 83.3 mg/kg (1/3 MTD) at 6, 12 and 18 days after transplantation of the tumor. The first time the cyclophosphamide is administered at 6 days after inoculation of the tumor due to the fact that by this time already laid metastases of carcinoma of the lung Lewis and it is possible to evaluate the influence of cytostatic agents on their development [4]. Further, the cyclophosphamide is administered at 12 and 18 days after transplantation of the tumor, in order to maintain a moderate inhibitory effect of cytostatic agents on the tumor growth during the experiment. In addition, the cyclophosphamide is administered three times with an interval of 6 days to reduced the cytotoxic effects of the amount of glue is OK white blood remained at the same level for a long time. With moderate impact of cytostatic to tumor development and concomitant prolonged leukopenia possible to assess the contribution in enhancing the effectiveness of cancer treatment and toxicity reduction in white blood cells included in the regimen substances of different nature.

Data essential features not identified from the medical-scientific and patent literature. They explicitly do not follow from the prior art for professionals. Offered as the invention of the model term use of cyclophosphamide can be used for pre-clinical study of substances that increase the efficacy of chemotherapy and reduce the toxic effect of cytostatics in respect of white blood cells.

Based on the foregoing, it should be considered the present invention with the relevant conditions of patentability: Novelty", "Inventive step", "Industrial applicability".

This model was experimental research in laboratories Oncohematology and pathological physiology and experimental therapy NII pharmacology" SB RAMS Tomsk.

The study was conducted on a three-month mice-female line C57B L/6 mass 19-20, as a model of malignant growth used hematogenous the metastatic Lewis lung carcinoma (3LL), perelevayuschimsya 4 million tumor cells in the mouse. For modeling course chemotherapy regimens used 3-fold intraperitoneal administration of cyclophosphamide (1/3 MTD - of 83.3 mg/kg at 6, 12, 18 days after inoculation of the tumor).

For detection of antitumor and antimetastatic actions, as well as toxic effects on the peripheral blood in animals (total leukocyte, neutrophil and eosinophil granulocytes, lymphocytes, monocytes) with 3-fold introduction of cyclophosphamide at a dose of 83.3 mg/kg was delivered the following experiment.

Example

Animals were divided into following groups:

1. Background (n=10) healthy mouse.

2. "Control" (n=6) - untreated mice with Lewis lung carcinoma.

3. "Cyclophosphamide (n=6) mice with Lewis lung carcinoma treated with cyclophosphamide intraperitoneally at a dose of 83.3 mg/kg at 6, 12, 18 days of tumor development.

1 day before tumor inoculation and 3 days after 1, 2 and 3 injection of cyclophosphamide (9, 15, 21 days after transplantation of the tumor) from the tail vein of mice were collected peripheral blood was determined by its indicators (total number of leukocytes, leukocyte formula) standard hematological methods [5]. The peripheral blood was determined at 3 days after each injection of cyclophosphamide in connection with the fact that this term is found as low as possible the number of white blood cells.

At the end of the experiment (21 days after Tran the plantations of the tumor) was determined by the mass of the tumor, the percentage inhibition of its growth, the frequency of metastasis, the number and size of lung metastases, the index of inhibition of metastasis [6, 7]. Processing of the obtained results was performed using non-parametric criterion of Wilcoxon-Mann-Whitney. The differences were considered significant at P<0,05 [8].

The experiment revealed that the 3-fold intraperitoneal administration of cyclophosphamide at a dose of 83.3 mg/kg had a moderate inhibitory effect on the growth of primary tumor and metastases. So, by the end of the experiment, the inhibition of tumor growth was 34%, the number of metastases decreased 4.7 times (P<0.01), and decreased the area of metastatic lung lesions compared with the control values, the frequency of metastasis was 100%, as in the control (table 1).

The study of peripheral blood in mice of the control group (with tumors) showed increased content of total number of cells at all time observations regarding this indicator in healthy animals (Background), mainly due to the increase in the number of neutrophilic granulocytes (table 2). The most pronounced leukocytosis was observed for 21 days of the experiment, when the total number of leukocytes increased 1.5 times (P<0.01), and by increasing the number of segmented neutrophils 4.3 times (P<0.01) compared with that in the background is ISA.

Depression of the white blade of blood, caused 3-fold by the introduction of cyclophosphamide, was reflected in the decrease in the total number of leukocytes in peripheral blood of mice throughout the study period: 3 days after 1, 2, 3 the introduction of cyclophosphamide - 3.4; 3,2; 5.9 times (P<0,01), respectively, relative to those in animal control. At the same time, surveillance observed a decrease in the number of segmented neutrophils (7.9; 2.5 and 5.8 times, P<0.01) and lymphocytes (3.0; 3.6 and 6.1-fold, P<0,01) against these indicators in the control (table 2).

Thus, 3-fold intraperitoneal administration of cyclophosphamide at a dose of 83.3 mg/kg to mice with Lewis lung carcinoma leads to moderate inhibition of tumor growth, metastasis and is accompanied by prolonged radiation throughout the study period. Moderate effect of cyclophosphamide on the tumor growth and prolonged leukopenia will identify the possibility of increasing the antitumor and antimetastatic effects of the action of cytostatics and correction of its toxic effects when introduced into the regimen of substances of different nature.

Proposed biological model will allow us to investigate the possibility of using drugs-correctors cytotoxic therapy for cancer clinic.

Table 2
Dynamics of the content of the total number of leukocytes and their individual forms (×109g/l) in the peripheral blood of mice with Lewis lung carcinoma in conditions 3 injections of cyclophosphamide at a dose of 83.3 mg/kg (X±m)
The monitoring group, dose × the number of introductions (number of animals)The total number of leukocytesNeutrophilic granulocytesLymphocytesEosinophilsMonocytes
Palocco-nuclearSegment-nuclear
The original background (1 day before inoculation 3LL)
A. Background (n=10)8,75±0,70,03±0,021,2±0,227,34±0,550,09±0,020,08±0,02
3 days after 1 injection of cyclophosphamide, 83 mg/kg (9 days)
1. Control (n=6)10,83±1,840,06±0,04 1,75±0,388,75±1,50,08±0,040,19±0,06
2. Cyclophosphamide, 83 mg/kg ×1 (n=6)3,21±0,480,01±0,010,22±0,072,92±0,420±00,06±0,03
1-2P<0,011-2P<0,011-2P<0,01
3 days after the 2nd injection of cyclophosphamide, 83 mg/kg (15 days)
1. Control (n=6)9,00±1,230±02,05±0,216,70±1,20,06±0,030,17±0,03
2. Cyclophosphamide, 83 mg/kg ×2 (n=6)2,79±0,320±00,81±0,151,86±0,20,02±0,010,10±0,03
1-2P<0,011-2P<0,01
1-2P<0,01
3 days after 3 introduction the deposits of platinum, 83 mg/kg (21 day)
1. Control (n=6)13,08±1,160,10±0,075,20±0,58a 7.62±0,670,14±0,070,03±0,03
A-1P<0,01A-1P<0,01
2. Cyclophosphamide, 83 mg/kg ×3 (n=6)2,21±0,610,01±0,010,90±0,331,25±0,280,01±0,010,05±0,03
1-2P<0,011-2P<0,011-2P<0,01

References

1. Guidelines for chemotherapy of neoplastic diseases / edited Nieremontowany. - M.: Practical medicine, 2005. - P.26.

2. Abramova E.V. Influence of the extract of Scutellaria baicalensis on the regeneration of hematopoiesis in terms of chemotherapy: author. Diss.... Kida. the honey. Sciences., Tomsk, 1992. - P.10, 15.

3. Patent for invention No. 2270682 of the Russian Federation. Method of enhancing antitumor and antimetastatic activity of cyclophosphamide in the experiment / Kokorev O.V., Cherdyntseva NV, Zuikova O.V. Published: 27.02.2006, bull. No. 6.

4. the owner's manual on experimental (preclinical) study of new pharmacological substances / Under Rugarama. - M.: Medicine, 2005. - S.

5. Goldberg ED, Digi A.M., Shah V.P. Methods of tissue culture in Hematology. - Tomsk: Publishing house of Tomsk University, 1992. - S, 214.

6. Arkhipov S.A., Junker V.M., gruntenko EV change in the intensity of metastasis in the lungs of transplantable tumors in mice depending on the value Leno dose of tumor cells // Research on induction and metastasis of tumors in experimental animals. - Novosibirsk, 1984. - P.29.

7. Experimental evaluation of anticancer drugs in the USSR and the USA / edited Spoofing, Abberline (USSR), Agostina, Alaina (USA). - M.: Medicine, 1979. - P.131.

8. Gubler E.V. Computational methods of analysis and recognition of pathological processes. - L.: Medicine, 1978. - S.

The method of modeling a moderate inhibition of growth of primary tumor and metastases of carcinoma of the lung Lewis with prolonged leukopenia in mice, characterized in that the cyclophosphamide is administered intraperitoneally in 1/3 MTD - of 83.3 mg/kg 3 times at 6, 12, 18 days after inoculation.



 

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