CN111298122A

CN111298122A - Pharmaceutical composition for treating small cell lung cancer and application thereof

Info

Publication number: CN111298122A
Application number: CN201911231857.3A
Authority: CN
Inventors: 高原; 雒江菡; 王福玲
Original assignee: Harbin University of Commerce
Current assignee: Harbin University of Commerce
Priority date: 2019-12-04
Filing date: 2019-12-04
Publication date: 2020-06-19
Anticipated expiration: 2039-12-04
Also published as: CN111298122B

Abstract

The invention relates to a pharmaceutical composition for treating small cell lung cancer and application thereof, belonging to the field of medicines. Which include lurbinedin and selective NA reuptake inhibitors. The mass ratio of the lurbinectin to the selective NA reuptake inhibitor in the pharmaceutical composition is 1: 0.01-1.

Description

Pharmaceutical composition for treating small cell lung cancer and application thereof

Technical Field

The invention relates to a pharmaceutical composition for treating small cell lung cancer and application thereof, belonging to the field of medicines.

Background

Lung cancer is the first malignant tumor with global morbidity and mortality. In recent years, the incidence and mortality of lung cancer in China have rapidly increased. Lung cancer is classified into non-small cell lung cancer (NSCLC) and Small Cell Lung Cancer (SCLC), with SCLC accounting for about 15-20% of all lung cancers.

SCLC is a systemic disease with a poor prognosis with a 5-year survival rate of less than 5%. At present, the first-line treatment of SCLC generally adopts operation and is mainly assisted by chemotherapy or radiotherapy. The chemotherapy drugs mainly comprise etoposide and cisplatin and irinotecan and cisplatin, and except chemotherapy, patients in a limited period are improved in survival by using a chest radiotherapy department. Survival can also be significantly improved by subjecting patients in a limited period of time to a Prophylactic (PCI) therapy directed at chemotherapy to achieve complete or partial remission.

Unlike NSCLC, SCLC has few new breakthroughs beyond existing chemoradiotherapy treatment methods, and especially has far inferior effect on SCLC compared to NSCLC in terms of targeted drugs and immunotherapy.

Recently, the U.S. Food and Drug Administration (FDA) awards a lurbinactedin (PM1183) orphan drug designation, which has been shown based on studies to have an Objective Remission Rate (ORR) of 39.3% in patients with advanced Small Cell Lung Cancer (SCLC) after chemotherapy, and a median Overall Survival (OS) of 11.8 months in patients. This brings new therapeutic promise to SCLC patients.

lurbinectin is an ecteinascidin derivative which is independently developed by PharmaMar, is an inhibitor of RNA polymerase II, can selectively inhibit a trans-activated RNA polymerase II-mediated transcription process, has no influence on the activities of RNA polymerase I and mitochondrial RNA polymerase, and also has no influence on the normal transcription process of mRNA. RNA polymerase II is often over-activated in the transcription process of tumor cells, and lubrinectedin can distort and die the tumor cells in the mitosis process and finally reduce the cell proliferation. In some types of tumors, tumor cells, which are particularly sensitive to lurbinedin, rely on a high-speed running transcriptional process to support their proliferation. The tumors comprise small cell lung cancer, BRCA1/2 mutant breast cancer, platinum drug-resistant ovarian cancer, sarcoma caused by chromosome translocation and the like.

However, in clinical application, the lurkinectin is found to have a relatively obvious bone marrow suppression effect, so that the search for a lower drug administration amount is the key for drug development around the lurkinectin.

Disclosure of Invention

In a first aspect of the invention, a pharmaceutical composition for the treatment of a tumor comprises a lurbinedin and a selective NA reuptake inhibitor.

In one embodiment of the invention, the mass ratio of lurbinedin to selective NA reuptake inhibitor in the pharmaceutical composition is 1: 0.01-1.

In another embodiment of the invention, the mass ratio of lurbinedin to selective NA reuptake inhibitor in said pharmaceutical composition is 1: 0.01-0.2. In a preferred embodiment, the mass ratio of lurbinedin to selective NA reuptake inhibitor in the pharmaceutical composition is 1: 0.05.

In the present invention, the selective NA reuptake inhibitor is selected from one or more of maprotiline, mianserin and reboxetine.

In yet another embodiment of the invention, the pharmaceutical composition further comprises one or more of etoposide, cisplatin and irinotecan. The mass ratio of the lurbinedin to the selective NA reuptake inhibitor to the cisplatin is 1:0.01-0.2: 0.1-0.5; preferably 1:0.05: 0.3.

The second aspect of the invention provides the application of the pharmaceutical composition in preparing a medicament for treating tumors.

In one embodiment, the tumor is selected from small cell lung cancer, breast cancer, or ovarian cancer. Further, the tumor is preferably small cell lung cancer.

Selective NA reuptake inhibitors can block Norepinephrine (NA) reuptake by the central presynaptic membrane, but cannot block the reuptake effect of 5-hydroxytryptamine (5-HT). Is generally used for treating depression clinically. The invention unexpectedly discovers that when the compound is used together with lurbinedin, the compound generates an obvious synergistic effect on the aspect of treating the small cell lung cancer, and can play a certain role in relieving the mental stress of a patient while realizing the treatment of the cancer.

Detailed Description

The invention may be further understood by reference to the following examples, which illustrate some methods of making or using. However, it is to be understood that these examples do not limit the present invention. Variations of the invention, now known or further developed, are considered to fall within the scope of the invention as described herein and claimed below.

Example 1 screening of Lurbinectedin in combination with antidepressants on a cell model of SCLC

Taking logarithmPreparing small cell lung cancer cell line H446 cells in a growth period into cell suspension by using an RPMI1640 culture medium; cells were diluted to a density of 4X 10⁴Per ml; then, 96-well plates were inoculated, and 200ul of cell suspension was added per well and cultured in an incubator. After 24h of incubation, a grouping experiment was performed:

administration group 1 was supplemented with 5. mu.g/ml of lurbinactedin (final concentration);

dosing group 2 added maprotiline at 0.5ug/ml (final concentration);

in the administration group 3, imipramine (final concentration) was added at 0.5 ug/ml;

the administration group 4 was supplemented with 0.5ug/ml of cloxetine (final concentration);

in the administration group 5, 0.5ug/ml of venlafaxine (final concentration) was added;

dosing group 6 added 5ug/ml lurbinedin +0.5ug/ml maprotiline (final concentration);

in the administration group 7, 5ug/ml of lurbinectin +0.5ug/ml of imipramine (final concentration) was added;

dosing group 8 added 5ug/ml lurbinedin +0.5ug/ml chloricetin (final concentration);

administration group 9 was supplemented with 5ug/ml lurbinedin +0.5ug/ml venlafaxine (final concentration).

The control group was given the same amount of medium, cultured for 24h, and the proliferation inhibition rate of each group of cells was measured by MTT method, the proliferation inhibition rate being (control OD value-administration OD value)/control OD value × 100%

The specific results are as follows:

	proliferation inhibition ratio (%)
		Administration group 1	45.3±1.9
Administration group 2	3.9±0.7
		Administration group 3	11.2±2.4
Administration group 4	8.6±1.8
		Administration group 5	5.7±1.1
Administration group 6	67.1±2.2
		Administration group 7	56.5±1.6
Administration group 8	49.8±1.4
		Administration group 9	51.7±2.1

To screen whether there is a synergistic effect of lurbinactin and an antidepressant in treating SCLC. We screened representative drugs of different antidepressant mechanism pathways, such as the selective NA reuptake inhibitor maprotiline, the tricyclic antidepressant imipramine, the selective 5-HT reuptake inhibitor (SSRI) cloxetine, and the 5-hydroxytryptamine-norepinephrine reuptake inhibitor vindolac, at the same weight ratio. From the results, only imipramine in the antidepressant medicaments has certain effect of inhibiting the proliferation of SCLC cells, and other antidepressant medicaments have no obvious inhibition effect on small cell lung cancer cells when being singly administered. After the antidepressant drug and the lurbinedin are combined, the maprotiline has obvious synergistic effect, and the combination effect of other antidepressant drugs is poor.

Example 2 weight ratio screening of Lurbinectedin in combination with maprotiline on a cell model of SCLC

The test method is the same as that in example 1, the related medicaments with different dosages are added into each group, and the specific results are as follows:

from the results, the lurbinedin and the maprotiline can generate obvious synergistic effect under different weight ratios, wherein the synergistic effect is most obvious when the ratio is 1: 0.05. In addition, we repeated the above experiments in other small cell lung cancer cell lines H20 and H69, which gave results consistent with those in the H446 cell line, which also fully demonstrates the certainty that lurbinedin and maprotiline produce synergistic effects in treating SCLC.

EXAMPLE 3 Effect of pharmaceutical compositions on mouse Small cell Lung cancer model

Collecting about 20g of C57BL mice, half of each, randomly grouping after feeding for 24H, wherein the mice in the model group and the administration group are subcutaneously inoculated with small cell lung cancer cells H4462X 10⁶In each control group, an equal amount of physiological saline was injected. Administration was started one day after lung cancer cell inoculation, and the control group and the model group were injected with physiological saline, and the administration schedule of the administration group was as follows:

administration group 1: intraperitoneal injection of 2.5mg/kg lurbinedin is carried out once a day;

administration group 2: intraperitoneal injection of 0.125mg/kg maprotiline is carried out once a day;

administration group 3: intraperitoneal injection of 0.75mg/kg cisplatin is carried out once a day;

administration group 4: intraperitoneal injection of 2.5mg/kg lurbinedin and 0.125mg/kg maprotiline is carried out once a day;

administration group 5: intraperitoneal injection of 2.5mg/kg lurbinedin, 0.125mg/kg maprotiline and 0.75mg/kg cis-platinum is carried out once a day;

mice were sacrificed 14 days after continuous administration, tumor bodies of each group of tumor-bearing mice were removed, and tumor growth inhibition rates were calculated after weighing, the inhibition rates being (average tumor weight in model group-average tumor weight in administration group)/average tumor weight in model group × 100%

The results are as follows:

	tumor weight (g)	Inhibition ratio (%)
			Model set	3.31±0.54
Administration group 1	2.44±0.37**	26.4
			Administration group 2	3.14±0.43	5.1
Administration group 3	2.91±0.49*	11.9
			Administration group 4	1.71±0.33**	48.7
Administration group 5	1.35±0.36**	59.3

This summary merely illustrates some embodiments which are claimed, wherein one or more of the features recited in the claims can be combined with any one or more of the embodiments, and such combined embodiments are also within the scope of the present disclosure as if they were specifically recited in the disclosure.

Claims

1. A pharmaceutical composition for treating a tumor comprising a lurbinedin and a selective NA reuptake inhibitor.

2. The pharmaceutical composition according to claim 1, wherein the mass ratio of lurbinedin to selective NA reuptake inhibitor in the pharmaceutical composition is 1: 0.01-1.

3. The pharmaceutical composition according to claim 2, wherein the mass ratio of lurbinedin to selective NA reuptake inhibitor in the pharmaceutical composition is 1: 0.01-0.2.

4. The pharmaceutical composition of claim 1, wherein the selective NA reuptake inhibitor is selected from one or more of maprotiline, mianserin, and reboxetine.

5. The pharmaceutical composition of claim 1, further comprising one or more of etoposide, cisplatin, and irinotecan.

6. The pharmaceutical composition according to claim 5, wherein the mass ratio of lurbinedin to selective NA reuptake inhibitor to cisplatin is 1:0.01-0.2: 0.1-0.5.

7. Use of a pharmaceutical composition according to claims 1-6 for the preparation of a medicament for the treatment of tumors.

8. The use according to claim 7, wherein the tumor is selected from the group consisting of small cell lung cancer, breast cancer and ovarian cancer. Further, the tumor is preferably small cell lung cancer.