CN114712350B - Application of DTTZ in preparation of medicines for preventing and treating chemotherapy injury - Google Patents
Application of DTTZ in preparation of medicines for preventing and treating chemotherapy injury Download PDFInfo
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- CN114712350B CN114712350B CN202111636019.1A CN202111636019A CN114712350B CN 114712350 B CN114712350 B CN 114712350B CN 202111636019 A CN202111636019 A CN 202111636019A CN 114712350 B CN114712350 B CN 114712350B
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Abstract
The invention discloses an application of DTTZ in preparing a medicine for preventing and treating organism injury diseases caused by chemotherapy. DTTZ and pharmaceutically acceptable salts thereof can be used for preparing medicines for preventing and treating bone marrow suppression, gastrointestinal damage and hepatorenal toxicity caused by clinical chemotherapeutic agents. In particular, DTTZ exhibits outstanding high safety and definite pharmacological effects.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly discloses an application of DTTZ in a medicament for preventing and treating organism injury caused by liver, intestine and kidney diseases and chemotherapy.
Background
Currently, chemotherapy remains the first choice for oncology therapies, mainly including platinum (cisplatin), alkylating agents (cyclophosphamide), antimetabolites (gemcitabine), anticancer antibiotics (doxorubicin), plants (paclitaxel), hormones, etc. The medicines can inhibit or kill tumor cells through acting on different links of growth and propagation of the tumor cells, thereby achieving the purpose of eliminating tumors.
Cisplatin (cis-diamminedichloroplatinum) is a platinum-containing anticancer drug, has the advantages of wide anticancer spectrum, effective hypoxic cells, strong action and the like, and is widely used for treating various cancers. Cisplatin action mechanism mainly causes cross-linking through combination with DNA, thereby interfering with DNA repair and transcription, and is a cell nonspecific chemotherapeutic drug. Cyclophosphamide has no anticancer activity in vitro, and can be activated into phosphamide mustard with broad-spectrum antitumor effect after hydrolysis by excessive phosphatases or phosphatases in liver or tumor in vivo. Although the chemotherapeutic has remarkable anti-tumor activity, due to the lack of tumor tissue specificity, the chemotherapeutic can produce serious toxic and side effects on normal tissues while eliminating tumors, thereby causing bone marrow suppression, hepatorenal toxicity, gastrointestinal tract reaction, neurotoxicity and the like. Clinical use of cytoprotective agents administered prior to cisplatin treatment has been shown to result in toxicity observed with cisplatin. The accumulation of toxicity caused by these chemotherapeutics or radiation can limit their effectiveness in tumor treatment, preventing further tumor treatment regimens. Reversing the normal tissue toxic side effects caused by chemotherapy or radiotherapy while not interfering with tumor treatment is a difficult problem faced in tumor treatment.
The cytoprotective agent is a protective drug which does not have anti-tumor activity per se, but can selectively protect normal cells without interfering with the curative effect of chemoradiotherapy when being combined with chemoradiotherapy. The ideal cytoprotective agent should possess several characteristics: is non-toxic or less toxic to normal tissues; the application of the chemotherapeutic medicine can protect multiple organs of the organism from failure and reduce the toxic and side effects of the chemotherapeutic medicine; the anti-tumor curative effect of the chemotherapeutic medicine is not affected; has selectivity to normal cells and cancer cells. Currently, amifostine (also known as WR 2721) is an FDA approved cytoprotective agent for clinical useThrough the difference of the alkaline phosphatase content on the cell surface of normal tissues and cancer tissues, the alkaline phosphatase can be selectively dephosphorylated into an activated metabolite WR1065 containing sulfhydryl groups, thereby playing a role in chemoprotection. World patent PCT/US1998/026096 to Stogonev et al discloses amifostine and other aminothiol compounds for the treatment of damage induced by torsional or chemotherapy. We have found that DTTZ has obvious preventive and therapeutic effects on mouse nephrotoxicity and bone marrow suppression caused by cisplatin and cyclophosphamide, and has reversing and therapeutic effects on bone marrow suppression caused by gamma-rays and intestinal injuries. More importantly, pre-toxicology studies of DTTZ hydrochloride indicate that it is LD injected intraperitoneally and orally in mice 50 560.+ -.14, 1092.+ -.22 mg/kg, respectively, which is higher than 321mg/kg (intraperitoneal injection) and 842 mg/kg (oral administration) of amifosine, so that it has higher safety and better effect than amifosine.
In 1979, song Xiaoying et al, in the national academy of medicine, 1979,1 (2): 147-53; the academy of Chinese medical science (academy of sciences) 1980,2 (4): 241-5 et al report that DTTZ hydrochloride has a preventive effect on damage caused by acute ionizing radiation, particularly on bone marrow suppression caused by lethal doses of ionizing radiation when used before receiving X-rays and gamma rays, and improves survival rate of mice. Among them, DTTZ is not mentioned as having a preventive and therapeutic effect on injury of human organs caused by chemotherapeutic drugs.
The mechanism of injury for preventing and treating chemotherapeutic drugs is different from that of ionizing radiation. Preventing and treating the injury of the chemotherapeutics promotes the repair and regeneration of the injury of each target organ. The accumulation toxicity mechanism of platinum chemotherapeutics in vivo is mainly as follows: after the platinum is hydrolyzed and activated in cells, the platinum is very easy to combine with amino acid side chains containing S donors and proteins in the body through coordination bonds (such as copper transporter CTRI, ATP7A/ATP7B and the like), so that the cell functions controlled by the proteins are affected. As a weak acid-like Lewis acid, cisplatin has a high affinity for electron donor atoms having weak base properties, so Pt (II) preferentially binds to soft base compounds containing S donors. And the sulfhydryl generated by DTTZ metabolism in vivo can competitively remove coordination action between cisplatin and protein, and assist in restoring normal cell functions.
CAS number of DTTZ: 19351-18-9, which has the following structural formula:
the term prophylaxis as used herein refers to the administration prior to the administration of chemotherapy; the treatment is administered one or more days after the occurrence of the one or more toxicities.
The organism comprises human and animal; wherein the animal comprises in particular a mammal.
Disclosure of Invention
The DTTZ comprises a DTTZ compound, and/or pharmaceutically acceptable salts and/or hydrates thereof.
The invention aims to provide the application of DTTZ and/or pharmaceutically acceptable salts and/or hydrates thereof in preparing medicaments for preventing and treating the damage of an anti-tumor chemotherapeutic agent to organisms, including but not limited to the application of medicaments for treating diseases such as related liver, intestine, kidney, bone marrow inhibition and the like, in particular to the treatment or prevention of toxic effects of normal tissues of the organisms caused by the treatment modes of the anti-tumor chemotherapeutic agent and the like in the tumor chemotherapy process.
The anti-tumor chemotherapeutic agent is selected from alkylating chemotherapeutic agents, antimetabolite chemotherapeutic agents, anti-tumor biotin chemotherapeutic agents, plant chemotherapeutic agents, hormone chemotherapeutic agents, platinum chemotherapeutic agents and combinations of two or more of the above. Wherein the alkylating chemotherapeutic agent comprises nimustine, cyclophosphamide and maryland; antimetabolite chemotherapeutic agents include the class of tabine, methotrexate; antitumor biotin chemotherapeutics include dactinomycin, bleomycin, doxorubicin hydrochloride; the plant chemotherapeutic agent comprises paclitaxel, vinblastine and vincristine; hormonal chemotherapeutic agents include medroxyprogesterone, farinacol; platinum-based chemotherapeutic agents include cisplatin, carboplatin, cisplatin, platinum oxalate, and combinations of two or more of the foregoing.
The organism injury disease of the invention comprises: renal disease associated with anti-tumor chemotherapy, liver disease associated with anti-tumor chemotherapy, gastrointestinal disease associated with anti-tumor chemotherapy, mucosal injury associated with anti-tumor chemotherapy, xerostomia associated with anti-tumor chemotherapy, myelosuppressive disease associated with anti-tumor chemotherapy, neurotoxicity associated with anti-tumor chemotherapy, cardiotoxicity associated with anti-tumor chemotherapy, ototoxicity associated with anti-tumor chemotherapy, alopecia associated with anti-tumor chemotherapy, pulmonary fibrosis associated with anti-tumor chemotherapy.
Another object of the present invention is to provide a method for selectively treating lesions caused by chemotherapy comprising DTTZ and pharmaceutically acceptable salts thereof, without affecting the tumor inhibiting effect of chemotherapeutic agents while reversing normal tissue lesions.
The effective dose of the DTTZ is 10mg/m according to the body surface area 2 -2000mg/m 2 。
The invention provides a pharmaceutical composition of DTTZ or pharmaceutically acceptable salt or hydrate thereof for the use of the invention. The invention provides a safe and efficient preventive or therapeutic agent, the active ingredient of the preventive or therapeutic agent is DTTZ, and the DTTZ can be prepared into various pharmaceutical compositions, such as various solid and liquid preparations of tablets, capsules, granules, injections and the like, together with one or more pharmaceutically acceptable medium carriers, auxiliary agents or diluents or other medicaments; in particular tablets, capsules, injections, emulsions, nanoparticles, pills, inhalants, gels, powders, suppositories, suspoemulsions, creams, jellies, sprays, etc. The pharmaceutical composition also comprises.
The DTTZ can be used as an active ingredient alone or in combination with other medicines. Other medicaments comprise anti-chemotherapy injury medicaments, liver, intestine, kidney and other organ protection medicaments to form a pharmaceutical composition. The medicine can be prepared into various dosage forms by combining with other effective components of traditional Chinese medicines, and can be used for treating or reversing toxic effects of liver, intestine and kidney diseases and bone marrow suppression caused by various treatment modes of normal tissues of an organism through different administration routes.
Drawings
FIG. 1 is a graph of cell selectivity of DTTZ for chemotherapy lesions examined by neutral red assay: A. cisplatin-induced chemotherapy damage; B. chemotherapy injury caused by doxorubicin (cells: HIEC-6, CHO, MCF-7, A549, hela, respectively, from left to right);
fig. 2 is a graph of EdU staining examining the protective effect of DTTZ chemotherapy protection against normal cellular DNA synthesis processes: A. HIEC-6; MCF-7 (green region in the figure is DNA synthesis phase cells stained with EdU-488; blue is DAPI stained nuclei);
FIG. 3 shows the inhibition of the clonogenic activity of DTTZ and the positive control WR2721 on 4 cells.
FIG. 4 is an Annexin V-FITC apoptosis experiment examining the protective effect of DTTZ on cisplatin leading to normal apoptosis: HIEC-6; MCF-7 (lower left hand corner of the figure: normal cells; lower right hand corner: early apoptotic cells; upper right hand corner: late apoptotic cells; upper left hand corner: necrotic cells);
FIG. 5 is the protective effect of DTTZ on Cyclophosphamide (CP) induced hematopoietic system in mice: average body weight (a) (B) bone marrow DNA content (C) bone marrow nucleated cell number (D) spleen index (E) thymus index (F) spleen nodule number (G) lymphocyte single cell gel electrophoresis 0live tail moment and (H) tail DNA content (%);
fig. 6 shows that DTTZ does not affect the tumor-inhibiting effect of cisplatin on tumor-bearing mice: (a) average body weight (B) tumor volume (C) tumor inhibition (D) liver index (E) kidney index (F) colon length;
fig. 7 is a graph showing the effect of DTTZ on protecting against radiation and chemotherapy injury: (A) Small intestine crypt cell count (B) HE staining of small intestine tissue, liver tissue and kidney tissue.
Figure 8 shows the 30 day survival results of cisplatin, a DTTZ protected chemotherapeutic, on mice.
Detailed Description
The invention is further illustrated below in connection with the following examples:
EXAMPLE 1 neutral Red assay to detect cell selectivity and optimal action concentration for DTTZ hydrochloride chemoprotection
Selecting normal cells including human intestinal epithelial cells (HIEC-6), hamster ovaryThe nest Cells (CHO) and cancer cells comprise 5 kinds of cells such as human breast cancer (MCF-7), human non-small cell lung cancer (A549) and human cervical cancer (Hela) to examine the normal cytoprotective effect of DTTZ on chemotherapeutic drugs such as cisplatin and doxorubicin. DMEM culture with 10% foetal calf serum was used for the cells at 37℃with 5% CO 2 Culturing in an incubator. Each cell was seeded at 5000 cells/well in 96 well plates, incubated for 15min in advance after 24h with DTTZ or positive control WR2721, then incubated with chemotherapeutic drug (cisplatin or doxorubicin) and washed 2 times per well in PBS after 24h, and the protective effect of DTTZ chemotherapy was examined using a neutrophil proliferation and cytotoxicity detection kit.
As shown in FIG. 1, DTTZ at 0.1mM concentration resulted in clear cell selectivity for cytotoxicity caused by cisplatin and doxorubicin, protection against HIEC-6 and CHO cells, and substantially no protection against MCF-7, A549 and Hela cancer cells.
EXAMPLE 2 EdU staining to examine the protective Effect of DTTZ hydrochloride chemotherapy protection against the DNA Synthesis procedure in Normal cells
EdU (5-ethylyl-2 '-deoxyuridine), chinese name 5-ethynyl-2' -deoxyuridine, is a novel thymidine (thymidine) analogue, and can be incorporated into newly synthesized DNA in place of thymidine during DNA synthesis. If DNA synthesis is inhibited, the incorporation of EdU is also inhibited. Therefore, the inhibition effect of the drug on the DNA synthesis of the cells can be judged according to the number of the cells infected by the EdU obtained by detection. HIEC-6 and MCF-7 were seeded at a density of 50,000 cells/well in 24 well plates for 24h, followed by 15min incubation of cells in advance with DTTZ or positive control WR2721, continued incubation with cisplatin, a chemotherapeutic drug, 24h, and treatment of cells with BeyoClickTM EdU-488 assay kit and observation by photographing under an inverted fluorescence microscope.
As shown in FIG. 2, DTTZ hydrochloride at a concentration of 0.1mM has a protective effect against the DNA synthesis inhibition effect of normal cells caused by cisplatin, but has no protective effect against cancer cells.
EXAMPLE 3 cloning experiments to investigate the cytotoxicity of DTTZ and the positive control WR2721
Cell clonogenic assays are important technical methods for detecting cell proliferation capacity, invasiveness, population dependence, and the like. The drug reflected in the rate of colony formation is more sensitive to the effects of cell proliferation than in cell survival experiments (e.g., MTT assay). In the event that the cytogenetic material is disturbed by drugs, it will not be possible for individual cells to undergo a mitotic process to form clonal populations. Thus, the toxicity of the drug to cells can be examined using a clonogenic assay.
The cytotoxicity of DTTZ and positive control WR2721 was examined by selecting 4 kinds of normal cells including human intestinal epithelial cells (HIEC-6), human renal epithelial cells (293T) and cancer cells including human breast cancer (MCF-7) and human cervical cancer (Hela). Cells were resuspended as a single cell suspension using 10% complete medium, seeded into 12-well plates at a cell density of 500 cells/well, and gently rotated to disperse the cells uniformly and cultured in an incubator for 24h. After the cells were attached, incubation was continued for 24h with 0.1mM DTTZ or WR2721, respectively, and after 2 careful rinsing with PBS, the cells were further cultured for 1-2 weeks. It is often observed that the culture is terminated when macroscopic clones appear in the culture dish. The supernatant was discarded and carefully rinsed 2 times with PBS. Adding 4% paraformaldehyde to fix cells for 15min, removing the fixing solution, adding a proper amount of crystal violet staining solution to dye for 10-30min, and then slowly washing out the staining solution with ddH20 and airing.
As shown in FIG. 3, DTTZ showed no clone inhibitory effect on cells at 0.1mM, while WR2721 showed significant inhibition on clone formation in all four cells. The results indicate that DTTZ is safer at effective concentrations for this protective effect than the positive control WR 2721.
EXAMPLE 4 Annexin V-FITC apoptosis experiment investigating the protective Effect of DTTZ on cisplatin-induced apoptosis of Normal cells
Apoptosis is a mode of apoptosis, regulated by a series of genes, proteins. Phosphatidylserine is mainly distributed inside cell membranes, and in the early stage of apoptosis, different types of cells can evert phosphatidylserine to the cell surface so as to be selectively combined by Annexin V, so that the Annexin V is an early apoptosis mark. Propidium Iodide (PI) can stain necrotic cells or cells that lose cell membrane integrity late in apoptosis. HIEC-6 and MCF-7 were seeded at a density of 200,000 cells/well in 12 well plates for 24h, followed by 15min incubation of cells in advance with DTTZ or positive control WR2721, continued incubation with cisplatin, a chemotherapeutic drug, and treatment of cells with Annexin V-FITC apoptosis assay kit after 24h, and flow cytometry detection of apoptosis rate.
As shown in FIG. 4, DTTZ has a remarkable protective effect on normal apoptosis caused by cisplatin at a concentration of 0.1mM, but has no protective effect on cancer cell MCF-7.
EXAMPLE 5 treatment of cyclophosphamide-induced hematopoietic injury in mice with DTTZ hydrochloride
After the C57BL/6 mice reached the quality required for the experimental requirements, they were randomly divided into 4 groups of 10 animals each, which were a blank control group (control), a cyclophosphamide group (100 mg/kg CP), a dosing group (250 mg/kg DTTZ hydrochloride+100 mg/kg CP), and a positive control group (250 mg/kg WR2721+100mg/kg CP). Cyclophosphamide mice were given 100mg/kg of CP three consecutive days; 250mg/kg of DTTZ was administered to the mice for 5 consecutive days in the dosing group, wherein the mice were given a further DTTZ 30min after the first three days of intraperitoneal injection of cyclophosphamide; the positive control group was dosed in the same manner as the dosed group. Each reagent adopts an intraperitoneal administration route, and the injection volume is 0.2mL of each mouse; control group was intraperitoneally injected with 0.2mL of physiological saline. Peripheral blood, bilateral femur, liver, spleen and thymus were collected from mice three days after drug withdrawal. Bone marrow nucleated cell number (BMNC) was measured using a cytometer, and bone marrow DNA content was measured using an ultraviolet spectrophotometer.
(1) Blood cell parameters: three days after drug withdrawal, each group of mice was weighed and data recorded, and peripheral blood collected from the eyeballs was collected after anesthesia into 1.5mL anticoagulation tubes for separation of lymphocytes in the peripheral blood. Single cell gel electrophoresis experiments of lymphocytes: lymphocytes were isolated (within 4 hours as much as possible) using a peripheral blood lymphocyte separation kit, and then analyzed by gel electrophoresis.
(2) Bone marrow nucleated cell number (BMNC): each group of mice was sacrificed by cervical removal after removal of peripheral blood collected from the eyeballs, and femur on both sides of lower limb was removed from each mouse. One of them was taken, both proximal and distal femur were cut off, bone marrow cells were gently rinsed with 10ml CaCl2, filtered with gauze and checked for BMNC using a cytometer. The other femur was used for index (3).
(3) Bone marrow DNA content: the bone marrow cells of the other femur in index (2) are gently rinsed with 1mLPBS, kept at 4 ℃ for half an hour, the supernatant is removed by centrifugation, 5mL of freshly prepared perchloric acid is added, and kept in a water bath box at 90 ℃ for 15min, and the filtrate is taken out of the centrifuge tube for filtration and measured for ultraviolet absorption wavelength at 268 nm.
(4) Organ index of spleen and liver: after the neck-removed and sacrificed mice were dissected, spleen and liver were taken, and weighed and recorded separately, in addition to peripheral blood and bilateral femur. Liver (or spleen) index = liver (or spleen) weight (mg)/total weight (g) of the rat
(5) Spleen nodule number (CFU-S): the spleen in index (4) was weighed and placed in a prepared fixative (45 mL picric acid, 3mL glacial acetic acid and formaldehyde 15 mL), and after 24 hours, washed clean, and the number of nodules on the specimens was counted visually.
As shown in FIG. 5, the DTTZ treatment can raise the weight loss of mice caused by cyclophosphamide, increase the number of bone marrow cells of the mice and remarkably reduce the degree of DNA damage, which indicates that the DTTZ can reduce the apoptosis of bone marrow cells induced by cyclophosphamide. Organ index of organs related to hematopoiesis-spleen and liver index was reduced in all mice groups treated with cyclophosphamide, whereas in mice injected with DTTZ and positive control WR2721, there was a different degree of return of spleen index. The number of spleen nodules is an important indicator of spleen hematopoietic function, and mice normally have few spleen nodules, and when a stress response occurs, the present hematopoietic stem cells in the spleen migrate to the organ surface and proliferate as spleen nodules. Cyclophosphamide treated mice were stress-induced, and treatment of spleen nodules with DTTZ and positive control WR2721 after cyclophosphamide treatment was further increased in number, indicating that existing hematopoietic stem cells migrate into the spleen to proliferate and differentiate in increased numbers, demonstrating that DTTZ can alleviate and restore hematopoietic damage caused by chemotherapeutics.
EXAMPLE 6 DTTZ hydrochloride does not affect the tumor inhibiting effect of cisplatin on tumor-bearing mice and has therapeutic and reversing effects on cisplatin-induced liver, kidney, and gastrointestinal toxicity
Balb/c nude mice reach realityAfter testing the required quality, subcutaneous inoculation is 2x10 7 After the tumor diameter is more than 8mm, tumor-bearing mice are randomly divided into 4 groups of 6 MCF-7 cell suspension (0.2 mL), and the groups are respectively a blank control group (control), a cisplatin group (10 mg/kg), a dosing group (250 mg/kg DTTZ+10mg/kg cisplatin) and a positive control group (250 mg/kg WR2721+10mg/kg cisplatin). Cisplatin group mice were given 10mg/kg of cisplatin for three consecutive days; the administration group was intraperitoneally injected with 10mg/kg of cisplatin for 3 consecutive days, and 250mg/kg of DTTZ was administered after 30 min; the positive control group was dosed in the same manner as the dosed group. Each reagent adopts an intraperitoneal administration route, and the injection volume is 0.2mL of each mouse; control group was intraperitoneally injected with 0.2mL of physiological saline. Each group of mice was weighed and data recorded, vernier calipers measured tumor minor (a) and major (b), and tumor volumes were calculated: tumor volume (mm) 3 )＝0.52*a 2 * b. The tumor inhibition rate was calculated starting on the first day of dosing and calculating on the fifth day of initial dosing: tumor inhibition rate= (control-dosing group)/control 100%. Organ index of kidney and liver = liver (or kidney weight (mg)/total weight of the rat (g)
As shown in fig. 6, after cisplatin administration, the body weight of the tumor-bearing mice was significantly reduced (fig. a), and DTTZ and the positive control WR2721 had a certain effect of alleviating the body weight decrease of the mice, and the effect of alleviating DTTZ was more significant. Meanwhile, tumor volume (graph B) and tumor inhibition rate (graph C) at the 5 th day of administration show that DTTZ and WR2721 do not affect the inhibition effect of cisplatin on tumors after 30min of cisplatin. Cisplatin treatment group resulted in a certain hepatorenal toxicity (fig. D, E), which was manifested by a reduction in organ index and a reduction in colon length in mice, while DTTZ administration resulted in significant relief of cisplatin-induced reduction in liver and kidney organ index, while restoring colon length in mice and reducing the occurrence of colonic inflammation. The results of organ HE staining show (FIG. 7) that DTTZ has remarkable protective effect on intestinal, kidney and liver injuries caused by chemotherapy after administration, and remarkably reduces crypt cell injuries caused by the chemotherapy.
EXAMPLE 7 protection of DTTZ hydrochloride against toxicity of mouse chemotherapeutic drugs
C57BL/6J mice are adaptively fed for 2-3 days, 36 mice are randomly divided into 3 groups (12 mice in each group), and the groups are respectively a blank control group (control), a simple cisplatin group (10 mg/kg/day) and a cisplatin plus drug administration group (500 mg/kg/day DTTZ), and the cisplatin group is continuously perfused with stomach cisplatin for two days; cisplatin + dosing mice were separately gavaged with DTTZ hydrochloride saline solution 30min before and 24h after cisplatin dosing, and the blank control was only gavaged with 0.2mL saline.
The results are shown in figure 8, DTTZ significantly prolonged survival in 30 days in the case of chemotherapy mice.
Claims (3)
- Use of dttz or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention and treatment of damage to an organism by a cisplatin anti-tumor chemotherapeutic, wherein the damage to an organism is: renal disease related to anti-tumor chemotherapy, liver disease related to anti-tumor chemotherapy, and gastrointestinal disease related to anti-tumor chemotherapy.
- 2. The use according to claim 1, wherein the organism is: a human or an animal.
- 3. The use according to claim 1 or 2, wherein the DTTZ therapeutically effective dose is 10mg/m, calculated as body surface area 2 —2000 mg/m 2 。
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