CN114712350A

CN114712350A - Application of DTTZ in preparation of medicine for preventing and treating chemotherapy injury

Info

Publication number: CN114712350A
Application number: CN202111636019.1A
Authority: CN
Inventors: 徐文清; 周晓靓; 杨雨薇; 龙伟; 唐海康
Original assignee: Institute of Radiation Medicine of CAMMS
Current assignee: Institute of Radiation Medicine of CAMMS
Priority date: 2021-12-28
Filing date: 2021-12-28
Publication date: 2022-07-08
Anticipated expiration: 2041-12-28
Also published as: CN114712350B

Abstract

The invention discloses an application of DTTZ in preparing a medicament 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 tract injury and hepatorenal toxicity caused by clinical chemotherapeutic agents. Particularly, DTTZ exhibits an outstanding high safety and a clear pharmacological effect.

Description

Application of DTTZ in preparation of medicine for preventing and treating chemotherapy injury

Technical Field

The invention belongs to the technical field of biological medicines, and particularly discloses application of DTTZ in preventing and treating liver, intestine and kidney diseases and organism injury caused by chemotherapy.

Background

Currently, chemotherapy remains the first choice for medical oncology treatment, mainly including platinum (cisplatin), alkylating agents (cyclophosphamide), antimetabolites (gemcitabine), anticancer antibiotics (doxorubicin), plant species (paclitaxel), hormones, and the like. The medicines can inhibit or kill tumor cells by acting on different links of growth and reproduction of the tumor cells, thereby achieving the aim of eliminating tumors.

Cisplatin (cis-diamminedichloroplatinum) is a platinum-containing anticancer drug, has the advantages of wide anticancer spectrum, effectiveness of hypoxic cells, strong action and the like, and is widely used for treating various cancers. Cisplatin, which is a cell-nonspecific chemotherapeutic drug, has an action mechanism that mainly causes cross-linking through binding with DNA, thereby interfering with the repair and transcription of DNA. Cyclophosphamide has no anticancer activity in vitro, and needs to be hydrolyzed by excessive amount of phosphoramidase or phosphatase in liver or tumor in vivo to be activated into phosphoramide mechlorethamine with broad-spectrum antitumor effect. Although the chemotherapeutic drug has obvious antitumor activity, the lack of tumor tissue specificity causes the chemotherapeutic drug to produce serious toxic and side effects on normal tissues while eliminating tumors, thereby causing bone marrow suppression, hepatotoxicity, gastrointestinal reactions, neurotoxicity and the like. Cytoprotective agents were administered clinically prior to cisplatin treatment, but toxicity due to cisplatin was still observed. The accumulation of toxicity caused by these chemotherapeutic drugs or radiation therapy can limit their effectiveness in tumor therapy, preventing further tumor treatment regimens. How to reverse the toxic and side effects of chemotherapy or radiotherapy on normal tissues while not interfering with tumor therapy is a difficult problem in tumor therapy.

Cytoprotective agents are a class of protective drugs that do not possess anti-tumor activity themselves, but when used in combination with chemoradiotherapy, selectively protect normal cells without interfering with the efficacy of the chemoradiotherapy. Ideally, the cytoprotective agent should have several characteristics: the product is nontoxic or has less toxicity to normal tissues; when the chemotherapy medicament is applied, the multi-organ failure of the organism can be prevented, and the toxic and side effects of the radiotherapy and chemotherapy medicament are reduced; the anti-tumor curative effect of the chemotherapeutic drug is not influenced; has selectivity to normal cells and cancer cells. Currently, amifosine (also known as WR2721) is a cell protective agent approved by FDA for clinical use, and exerts chemoprotective effect by selectively dephosphorylating alkaline phosphatase into a sulfhydryl-containing activated metabolite WR1065 through the content difference of alkaline phosphatase on the cell surfaces of normal tissues and cancer tissues. World patent PCT/US1998/026096 to Stotgonif et al discloses the use of amifostine and other aminothiol compounds for the treatment or reversal of radiation or chemotherapy-induced damage. The research finds that DTTZ has obvious prevention and treatment effects on mouse nephrotoxicity and bone marrow suppression caused by cisplatin and cyclophosphamide, and has reversal and treatment effects on bone marrow suppression and intestinal injury caused by gamma-ray. More importantly, earlier stage toxicology studies of DTTZ hydrochloride indicate that it is administered by intraperitoneal injection and oral administration of LD in mice₅₀560 + -14 mg/kg, 1092 + -22 mg/kg, which are higher than the amifosine at 321mg/kg (intraperitoneal injection) and 842 mg/kg (oral administration), so that the amifosine is safer and has better effect than the amifosine.

In 1979, Song Xiaoying et al, proceedings of Chinese academy of sciences, 1979, 1 (2): 147-53; proceedings of the Chinese academy of medical sciences 1980, 2 (4): 241-5, et al report that DTTZ hydrochloride has a preventive effect on acute ionizing radiation damage, particularly on myelosuppression caused by a lethal dose of ionizing radiation when used before X-rays and gamma-rays are received, thereby improving the survival rate of mice. Among them, DTTZ is not mentioned as having preventive and therapeutic effects on organ damage of human body caused by chemotherapeutic drugs.

The damage mechanism of the prevention and treatment of chemotherapy drugs is different from the damage mechanism of ionizing radiation. Preventing and treating the damage of chemotherapeutic drugs, and promoting the repair and regeneration of the damage of each target organ. The accumulation toxicity mechanism of the platinum chemotherapeutic drugs in vivo is mainly as follows: after being activated by intracellular hydrolysis, platinum is easily combined with amino acid side chains of S-donor-containing proteins and proteins in vivo through coordination bonds (such as copper transport proteins CTRI, ATP7A/ATP7B, and the like), thereby influencing the cell functions controlled by the proteins. As a Lewis acid of weak acidic nature, cisplatin has a high affinity for donor atoms of weak basic nature, so Pt (II) preferentially binds to soft base compounds containing S donors. And the sulfhydryl generated by the metabolism of DTTZ in vivo can competitively remove the coordination between cisplatin and protein, and assist in recovering normal cell function.

CAS number of DTTZ: 19351-18-9, which has the following structural formula:

the prevention of the present invention means that the chemotherapy is performed before the chemotherapy is performed; said treatment is carried out one or more days after the onset of said one or more toxicities.

Organisms described herein, including humans, animals; wherein the animal particularly includes a mammal.

Disclosure of Invention

The DTTZ of the present invention includes DTTZ compounds, and/or pharmaceutically acceptable salts thereof, 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 organism damage caused by antitumor chemotherapeutic agents, including but not limited to medicaments for treating diseases such as relevant liver, intestine, kidney, bone marrow inhibition and the like, and particularly treating or preventing toxic effects of normal tissues of organisms caused by treatment modes such as the antitumor chemotherapeutic agents in the process of tumor chemotherapy.

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 agent chemotherapeutic agent comprises nimustine, cyclophosphamide and kalimeris; antimetabolite chemotherapeutic agents include the decitabine class, methotrexate; the antitumor biotin chemotherapeutic agent comprises dactinomycin, bleomycin, and doxorubicin hydrochloride; the plant chemotherapeutic agent comprises paclitaxel, vinblastine, and vincristine; hormonal chemotherapeutic agents include medroxyprogesterone, farnesyl; platinum chemotherapeutic agents include cisplatin, carboplatin, leplatin, oxaliplatin, and combinations of two or more thereof.

The organism injury disease of the invention comprises: kidney diseases related to antitumor chemotherapy, liver diseases related to antitumor chemotherapy, gastrointestinal diseases related to antitumor chemotherapy, mucosal injury related to antitumor chemotherapy, xerostomia related to antitumor chemotherapy, myelosuppressive diseases related to antitumor chemotherapy, neurotoxicity related to antitumor chemotherapy, cardiotoxicity related to antitumor chemotherapy, ototoxicity related to antitumor chemotherapy, alopecia related to antitumor chemotherapy, and pulmonary fibrosis related to antitumor chemotherapy.

The invention also aims to provide the DTTZ and the pharmaceutically acceptable salts thereof, which have selective treatment effect on the injury caused by chemotherapy, and do not influence the tumor inhibition effect of chemotherapeutic drugs while reversing the normal tissue injury.

The effective dose of DTTZ in the invention is 10mg/m in terms of body surface area²-2000mg/m²。

The invention provides a DTTZ or a pharmaceutically acceptable salt or hydrate thereof pharmaceutical composition for use according to the invention. The invention provides a safe and efficient preventive or therapeutic agent, the active ingredient of which is DTTZ, and the DTTZ can be prepared into various pharmaceutical compositions with one or more pharmaceutically acceptable carrier, adjuvant, auxiliary agent or diluent or other medicines, such as various solid and liquid preparations of tablets, capsules, granules, injections and the like; in particular tablets, capsules, injections, emulsions, nanoparticles, pills, inhalants, gels, powders, suppositories, suspoemulsions, creams, jellies, sprays, and the like. The pharmaceutical composition of the invention also comprises.

The DTTZ for the application can be used as an active ingredient alone or can form a medicinal composition with other medicines. Other medicines comprise chemotherapy injury resisting medicines and liver, intestine, kidney and other organ protecting medicines to form a medicinal composition. They include glutathione, metoclopramide, mercapto sodium sulfonate and other typical medicine, and may be also prepared into different forms together with other Chinese medicine components for treating and reversing the toxic effect of liver, intestine and kidney diseases and bone marrow suppression of body's normal tissue caused by different treating modes.

Drawings

Figure 1 is a graph of cell selectivity of DTTZ on chemotherapy injury examined by neutral red assay: A. cisplatin-induced chemotherapy injury; B. chemotherapy injury caused by doxorubicin (cells from left to right: HIEC-6, CHO, MCF-7, A549, Hela, respectively);

FIG. 2 is a graph of the protective effect of EdU staining on the DNA synthesis process of normal cells in DTTZ chemotherapy protection: A. HIEC-6; MCF-7 (green region in the figure is EdU-488 stained DNA synthesis phase cells; blue is DAPI stained nuclei);

FIG. 3 shows the inhibition of the colony formation of 4 cells by DTTZ and the positive control WR 2721.

FIG. 4 is an Annexin V-FITC apoptosis assay to investigate the protective effect of DTTZ on cisplatin-induced apoptosis in normal cells: HIEC-6; MCF-7 (lower left corner: normal cells; lower right corner: early apoptotic cells; upper right corner: late apoptotic cells; upper left corner: necrotic cells);

figure 5 is a graph of the protection of Cyclophosphamide (CP) -induced hematopoietic system in mice by DTTZ: (A) average body weight (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 is a graph showing that DTTZ does not affect the tumor-inhibiting effect of cisplatin on tumor-bearing mice: (A) mean body weight (B) tumor volume (C) tumor inhibition rate (D) liver index (E) kidney index (F) colon length;

figure 7 is a graph of the effect of DTTZ on protection against chemoradiotherapy injury: (A) small intestine crypt cell count (B) HE staining of small intestine tissue, liver tissue and kidney tissue.

Figure 8 is a 30 day survival rate result of DTTZ protective chemotherapeutic cisplatin from mice toxicity.

Detailed Description

The invention is further illustrated below with reference to an embodiment:

example 1 neutral Red assay to determine cell selectivity and optimal concentration of DTTZ hydrochloride chemoprotectant

Selecting 5 cells such as normal cells including human intestinal epithelial cells (HIEC-6), hamster ovary Cells (CHO) and cancer cells including human breast cancer (MCF-7), human non-small cell lung cancer (A549) and human cervical cancer (Hela) to examine the normal cell protection effect of DTTZ on chemotherapeutic drugs such as cisplatin and doxorubicin. The cells are cultured by DMEM (DMEM) containing 10% fetal calf serum at 37 ℃ and 5% CO₂Culturing in an incubator. And (3) performing seed sowing on each cell in a 96-well plate at the density of 5000 cells/well, incubating the cells for 24h in advance for 15min by adopting DTTZ or positive control WR2721, adding a chemotherapeutic drug (cisplatin or doxorubicin) for continuous incubation, washing each well of PBS for 2 times after 24h, and inspecting the DTTZ chemotherapy protection effect by adopting a neutral erythrocyte proliferation and cytotoxicity detection kit.

As shown in the attached FIG. 1, DTTZ has definite cell selectivity on the cytotoxicity caused by cisplatin and doxorubicin at the concentration of 0.1mM, and protects HIEC-6 and CHO cells, while basically not displaying protection effect on MCF-7, A549 and Hela cancer cells.

Example 2 EdU staining to detect the protective Effect of DTTZ hydrochloride on the DNA Synthesis Process of Normal cells in chemoprotection

EdU (5-ethyl-2 '-deoxyuridine), named 5-ethynyl-2' -deoxyuridine in Chinese, is a novel thymidine (thymidine ) analogue, and EdU can be incorporated into newly synthesized DNA instead of thymidine during DNA synthesis. Incorporation of EdU is inhibited if DNA synthesis is inhibited. Therefore, the inhibition effect of the drug on the DNA synthesis of the cell can be judged according to the number of the cells stained by the EdU. HIEC-6 and MCF-7 were seeded in 24-well plates at a density of 50,000/well for 24h, then DTTZ or the positive control WR2721 were pre-incubated for 15min, cisplatin was added as a chemotherapeutic drug for further incubation, and 24h later cells were treated with the BeyoClickTM EdU-488 detection kit and visualized by taking pictures under an inverted fluorescence microscope.

As shown in FIG. 2, DTTZ hydrochloride had a protective effect against the inhibition of DNA synthesis in normal cells by cisplatin, but not against cancer cells, at a concentration of 0.1 mM.

Example 3 cloning experiments DTTZ and the Positive control WR2721 were examined for cytotoxicity

Cell clonogenic experiments are important technical methods for detecting cell proliferation capacity, invasiveness, population dependence, and the like. The drug, as reflected by the clonogenic rate, is more sensitive to the effects of cell proliferation than is the case in cell survival assays (e.g., MTT assays). If the cytogenetic material is disturbed by a drug, it will not be possible to form a clonal population from a single cell undergoing mitotic processes. Therefore, the toxicity of the drug to cells can be examined using a colony formation experiment.

Selecting 4 cells such as normal cells including human intestinal epithelial cells (HIEC-6), human renal epithelial cells (293T) and cancer cells including human breast cancer (MCF-7), human cervical cancer (Hela) and the like to examine the cytotoxicity of DTTZ and positive control WR 2721. The cells were resuspended in a 10% complete medium to a single cell suspension, seeded into 12-well plates at a cell density of 500 cells/well, and gently rotated to disperse the cells evenly, and cultured in an incubator for 24 h. After the cells are attached to the wall, 0.1mM DTTZ or WR2721 is respectively given, the incubation is continued for 24h, and after 2 times of careful immersion washing by PBS, the cells are continuously cultured for 1-2 weeks. It was frequently observed that when macroscopic colonies appeared in the culture dish, the culture was terminated. The supernatant was discarded and carefully rinsed 2 times with PBS. Adding 4% paraformaldehyde to fix cells for 15min, removing the fixing solution, adding appropriate amount of crystal violet staining solution, staining for 10-30min, slowly washing with ddH20 to remove the staining solution, and air drying.

The results are shown in figure 3, DTTZ has no clone inhibition effect on cells at 0.1mM concentration, while WR2721 has significant inhibition on clone formation of four cells. The result shows that DTTZ has higher safety compared with positive control WR2721 at the effective concentration of the protective effect.

Example 4 Annexin V-FITC apoptosis assay to investigate the protective Effect of DTTZ against cisplatin-induced apoptosis in Normal cells

Apoptosis is a programmed cell death mode and is regulated by a series of genes and proteins. Phosphatidylserine is mainly distributed on the inner side of a cell membrane, and in the early apoptosis stage of cells, different types of cells can turn the phosphatidylserine out to the cell surface, so that the phosphatidylserine is selectively combined by Annexin V, and the Annexin V is a marker for the early apoptosis stage. Propidium Iodide (PI) stains necrotic cells or cells that lose cell membrane integrity late in apoptosis. HIEC-6 and MCF-7 are planted in a 12-well plate at the density of 200,000/well for 24h, then DTTZ or positive control WR2721 incubate cells for 15min in advance, add chemotherapy drug cisplatin to continue incubation, after 24h, use Annexin V-FITC apoptosis detection kit to process cells, and detect the apoptosis rate by a flow cytometer.

The result is shown in figure 4, DTTZ has obvious protective effect on cisplatin-induced normal apoptosis at the concentration of 0.1mM, but has no protective effect on cancer cell MCF-7.

Example 5 DTTZ hydrochloride treatment of cyclophosphamide induced hematopoietic Damage in mice

After the C57BL/6 mice reached the required mass, the mice were randomly divided into 4 groups of 10 mice, each group was a blank control group (control), a cyclophosphamide group (100mg/kg CP), an administration group (250mg/kg DTTZ hydrochloride +100mg/kg CP), and a positive control group (250mg/kg WR2721+100mg/kg CP). The cyclophosphamide group mice were continuously given 100mg/kg of CP for three days; the administration group continuously gives 250mg/kg of DTTZ to the mice for 5 days, wherein the DTTZ is given to the mice 30min after the first three days of intraperitoneal injection of cyclophosphamide; the positive control group was administered in the same manner as the administration group. Each agent adopts an intraperitoneal administration route, and the injection volume is 0.2mL per mouse; the control group was injected intraperitoneally with 0.2mL of physiological saline. Three days after drug withdrawal, peripheral blood, bilateral femurs, livers, spleens and thymuses of mice were collected. The bone marrow nucleated cell number (BMNC) was measured with a hemocytometer and the bone marrow DNA content was measured with an ultraviolet spectrophotometer.

Parameters of blood cells: three days after drug withdrawal, each group of mice was weighed and data recorded, peripheral blood collected from the eyeballs was collected after anesthesia and used to isolate lymphocytes in the peripheral blood in a 1.5mL anticoagulation tube. Single cell gel electrophoresis experiments on lymphocytes: lymphocytes were isolated using a peripheral blood lymphocyte separation kit (as long as 4 hours) and then analyzed by gel electrophoresis.

Bone marrow nucleated cell number (BMNC): each group of mice was sacrificed by cervical dislocation after removal of peripheral blood collected from the eyeball, and each mouse was given femoral bones on both sides of the lower limb. One of them was removed, the proximal and distal femur was cut off, bone marrow cells were gently washed out with 10mL CaCl2, gauze filtered and tested for BMNC with a hemocytometer. The other femur is used as index.

③ DNA content of bone marrow: in the index II, bone marrow cells of the other femur are slightly washed out by 1mL PBS, the mixture is kept for half an hour at 4 ℃, the supernatant is removed by centrifugation, 5mL of perchloric acid which is prepared in situ is added, the mixture is kept for 15min in a 90 ℃ water bath box, a centrifugal tube is taken out, and the filtrate is filtered to determine the ultraviolet absorption wavelength at 268 nm.

Spleen and liver organ index: after dissection of decapitated mice, spleen and liver were also taken in addition to peripheral blood and bilateral femurs and weighed separately for recording. Liver (or spleen) index ═ liver (or spleen) weight (mg)/total weight of the mouse (g)

Number of splenic nodules (CFU-S): the spleen in the index IV is weighed and then placed into prepared fixing solution (45 mL of picric acid, and 15mL of glacial acetic acid and formaldehyde in 3 mL), and the solution is washed clean after 24 hours, and the knot number on the specimen is counted by naked eyes.

The results are shown in figure 5, the DTTZ treatment can increase the mice weight loss caused by cyclophosphamide, increase the number of bone marrow cells of the mice and obviously reduce the DNA damage degree, which indicates that the DTTZ can reduce the bone marrow cell apoptosis induced by cyclophosphamide. Organ-spleen and liver indices associated with hematopoiesis, spleen and liver indices were decreased in all groups of mice treated with cyclophosphamide, while spleen indices were raised to varying degrees in mice injected with DTTZ and the positive control WR 2721. The number of spleen nodules is an important index of spleen hematopoiesis, and the mice have few spleen nodules in normal conditions, and the hematopoietic stem cells in the spleen now migrate to the surface of organs and proliferate as spleen nodules when stress reaction occurs. Cyclophosphamide treatment of mice caused stress, and treatment of spleen nodules with DTTZ and the positive control WR2721 further increased after cyclophosphamide treatment, indicating that the number of proliferating and differentiating existing hematopoietic stem cells migrating into the spleen increased, demonstrating that DTTZ can alleviate and restore hematopoietic system damage caused by chemotherapeutic drugs.

Example 6 DTTZ hydrochloride does not affect the tumor inhibition effect of cisplatin on tumor-bearing mice, and has treatment and reversal effects on liver, kidney and gastrointestinal toxicity caused by cisplatin

After Balb/c nude mice reach the quality required by the experiment, 2x10 is inoculated subcutaneously⁷0.2mL of MCF-7 cell suspension, and after the tumor diameter is more than 8mm, the tumor-bearing mice are randomly divided into 4 groups, 6 mice in each group are respectively a blank control group (control), a cisplatin group (10mg/kg), an administration group (250mg/kg DTTZ +10mg/kg cisplatin) and a positive control group (250mg/kg WR2721+10mg/kg cisplatin). Cisplatin group mice were given 10mg/kg of cisplatin for three consecutive days; the administration group is injected with 10mg/kg cisplatin in abdominal cavity for 3 consecutive days, and is administered with 250mg/kg DTTZ 30min later; the positive control group was administered in the same manner as the administration group. Each agent adopts an intraperitoneal administration route, and the injection volume is 0.2mL per mouse; the control group was injected intraperitoneally with 0.2mL of physiological saline. Each group of mice was weighed and data recorded, the tumor minor (a) and major (b) diameters were measured with a vernier caliper, and the tumor volume was calculated: tumor volume (mm)³)＝0.52*a²B. Tumor inhibition was calculated starting on the first day of administration and on the fifth day of initial administration: tumor inhibition rate (control group-administered group)/control group 100%. Kidney and liver organ index (mg) liver (or kidney)/total weight of the mouse (g)

The results are shown in figure 6, after cisplatin administration, the tumor-bearing mice significantly reduced body weight (figure A), DTTZ and the positive control WR2721 had a certain relieving effect on the mice weight loss, and the DTTZ relieving effect was more significant. Meanwhile, the tumor volume (panel B) and the tumor inhibition rate (panel C) at the 5 th day after the administration of the DTTZ and WR2721 after 30min of the cisplatin do not influence the tumor inhibition effect of the cisplatin. The cisplatin treatment group caused a certain hepatotoxicity and kidney toxicity (fig. D, E), which is shown as the reduction of the visceral index and the reduction of the colon length of the mice, but after DTTZ administration, the cisplatin-caused reduction of the hepatotoxicity and kidney visceral index can be remarkably alleviated, the colon length of the mice can be recovered, and the occurrence of colonic inflammation can be reduced. The result of organ HE staining (figure 7) shows that DTTZ has a remarkable protection effect on intestinal tract, kidney and liver injury caused by chemotherapy after administration, and meanwhile, crypt cell injury caused by chemotherapy is remarkably relieved.

Example 7 protective Effect of DTTZ hydrochloride on toxicity of chemotherapeutic drugs in mice

C57BL/6J mice are adaptively raised for 2-3 days, 36 mice are randomly divided into 3 groups (each group comprises 12 mice), which are respectively a blank control group (control), a pure cisplatin group (10 mg/kg/day) and a cisplatin + administration group (500 mg/kg/day DTTZ), and the cisplatin group is continuously irrigated with cisplatin for two days; the mice in the cisplatin + administration group are respectively gavaged with DTTZ hydrochloride physiological saline solution 30min before and 24h after cisplatin administration, and the blank control group is only gavaged with 0.2mL of physiological saline.

The results are shown in fig. 8, DTTZ significantly extended the survival of chemotherapy mice for 30 days.

Claims

Use of DTTZ and/or a pharmaceutically acceptable salt and/or a hydrate thereof for the preparation of a medicament for preventing or treating damage of an anti-tumor chemotherapeutic agent to an organism.
2. The use according to claim 1, wherein the anti-tumor chemotherapeutic is selected from the group consisting of 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 thereof.
3. The use of claim 2, wherein said alkylating chemotherapeutic agents comprise nimustine, cyclophosphamide, malignan; antimetabolite chemotherapeutic agents include the decitabine class, methotrexate; the antitumor biotin chemotherapeutic agent comprises dactinomycin, bleomycin, and doxorubicin hydrochloride; the plant chemotherapeutic agent comprises paclitaxel, vinblastine, and vincristine; hormonal chemotherapeutic agents include medroxyprogesterone, farnesyl; platinum chemotherapeutic agents include cisplatin, carboplatin, leplatin, oxaliplatin, and combinations of two or more thereof.
4. The use of claims 1-3, wherein the organism is injured, comprising: kidney diseases related to antitumor chemotherapy, liver diseases related to antitumor chemotherapy, gastrointestinal diseases related to antitumor chemotherapy, mucosal injury related to antitumor chemotherapy, xerostomia related to antitumor chemotherapy, myelosuppressive diseases related to antitumor chemotherapy, neurotoxicity related to antitumor chemotherapy, cardiotoxicity related to antitumor chemotherapy, ototoxicity related to antitumor chemotherapy, alopecia related to antitumor chemotherapy, and pulmonary fibrosis related to antitumor chemotherapy.
5. The use of claim 1, wherein said organism comprises: human and animal.
6. The use of claims 1-3, wherein said DTTZ is in a therapeutically effective dose of 10mg/m on a body surface area basis²-2000mg/m²。
7. A pharmaceutical composition comprising DTTZ and/or a pharmaceutically acceptable salt thereof and/or a hydrate thereof for the use of claims 1-3.
8. The pharmaceutical composition of claim 7, further comprising: other medicines with chemotherapy injury resisting effect, and organ protecting medicine.
9. The pharmaceutical composition of claim 7, further comprising one or more pharmaceutically acceptable vehicles, adjuvants or diluents.
10. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition is in a dosage form comprising: injection, emulsion, nanoparticle, tablet, capsule, pill, inhalant, gel, powder, suppository, suspoemulsion, cream, jelly, and spray.