Research Progress on Mechanism of Action of DHODH in Progression of Malignant Tumors / 肿瘤防治研究

Dihydroorotate dehydrogenase (DHODH) is a flavin-dependent metabolic enzyme that oxidizes dihydroorotate acid to orotic acid in the de novo synthesis pathway of pyrimidine metabolism. DHODH is located in mitochondria, closely related to cellular oxidative phosphorylation, and an important suppressor of the ferroptosis pathway. This study investigates the influence of DHODH on the progression of malignant tumors, including its important role in the de novo synthesis of pyrimidine, oxidative phosphorylation, and ferroptosis. The objective is to present evidence that DHODH is a potential target for the clinical treatment of tumors.

Effect of uridine on mitochondrial function / 生物工程学报

Uridine is one of the essential nutrients in organisms. To maintain normal cell growth and intracellular metabolism, the uridine must be maintained at certain concentration. Recent studies have shown that uridine can reduce inflammatory response in organisms, participate in glycolysis, and regulate intracellular protein modification, such as glycosylation and acetylation. Furthermore, it can protect cells from hypoxic injury by reducing intracellular oxidative stress, promoting high-energy compounds synthesis. Previous studies have shown that the protective effects of uridine are closely related to its effect on mitochondria. This review summarizes the effect of uridine on mitochondrial function.

A new pyrazolo4,3-i/pyriinidine derivative-. Synthesis and anti-inflammatory activity / 中国药理学通报

Aim To design and synthesizea new pyrazolo[4,3-d] pyrimidine derivative for the purpose of developing novel anti-inflammatory agents, and to revealthe possible anti-inflammatory mechanisms of thenew compound using preliminary studies. Methods The changes of the cell morphology were investigated via the microscope. The influence of title compound on the NO production of the L P S - stimulated RAW264. 7 cells was measured by Griess assay. The gene relative transcription levels of TNF-a, IL - 6 and IL-lß were evaluated by qRT-PCR. COX-2 expression was measured by qRT-PCR and western blot. NF-KB/NLRP3 inflammasome signaling pathway were investigated by Western blot. The changes of lung tissue were observed by HE staining in vivo experiments of mice. Results Preliminary mechanism researches revealed that the ti - tle compound could inhibit nitric oxide (NO) generation as well as the expression of COX-2, TNF-a, IL - 6, and IL - lβ by NF-KB/NLRP3 inflammasome signaling pathway in RAW264. 7 cells. Furthermore, it could simultaneously improve the morphology of the cells and relieve acute lung injury in mice. Conclusions The new pyrazolo [4, 3-α] pyrimidine derivative has anti-inflammatory activity through NF-KB/NLRP3 inflammasome signaling pathway.

Caprini model for prevention of venous thromboembolism in coma patients after surgery for severe traumatic brain injury / 中国基层医药

Objective:To analyze the preventive effect of Caprini model on venous thromboembolism (VTE) in coma patients after severe craniocerebral trauma.Methods:A total of 190 patients with severe craniocerebral trauma who received treatment in Lishui City People's Hospital, China between January 2015 and April 2019 were randomly divided into a control group and an observation group ( n = 95/group). Patients in the control group underwent the conventional strategy to prevent lower extremity VTE. Patients in the observation group were subjected to individualized strategies to prevent lower extremity VTE based on Caprini model assessment. The drop-out rate and treatment outcome were compared between the control and observation groups. The proportion of patients developing VTE during treatment in Department of Intensive Care Unit and the changes in coagulation indexes relative to before treatment were compared between the two groups. Results:There was no significant difference in drop-out rate between the control and observation group [10.53% (10/95) vs. 8.42% (8/95), χ2 = 0.245, P < 0.05]. The proportion of patients developing VTE in the observation group was significantly lower than that in the control group [2.30% (2/87) vs. 10.59% (9/85), χ2 = 4.935, P < 0.05]. At 7 days after surgery, the coagulation indices D-dimer, platelet count, prothrombin time, activated partial thromboplastin time in the observation group were (2.27 ± 0.43) mg/L, (281.62 ± 37.29) × 10 9/L, (12.93 ± 2.87) seconds and (34.35 ± 7.19) seconds, respectively, which were (3.31 ± 0.68) mg/L, (303.28 ± 39.96) × 10 9/L, (11.24 ± 2.46) seconds and (31.16 ± 6.82) seconds, respectively in the control group. The coagulation indices in the observation group were significantly superior to those in the control group ( t = 10.013, 3.070, -3.463, -2.493, all P < 0.05). Conclusion:The Caprini model is effective in preventing VTE in patients with coma after surgery for severe traumatic brain injury. It deserves to be clinically applied.

One-pot three-component synthesis of new triazolopyrimidine derivatives bearing indole moiety as antiproliferative agents

A new series of triazolopyrimidine derivatives was produced via three-component reactions of suitable aromatic orheteroaromatic carboxaldehyde, 3-amino-1,2,4-triazole, and 3-indolyl-3-oxopropanenitrile in triethylamine as a catalyst.The new compounds have been interpreted using elemental analysis, infrared, mass spectrometry, and nuclear magneticresonance spectroscopy. Antiproliferative effects of the new compounds have been screened on four human cancer types andone human noncancerous type (retinal pigment ephitilial-1) via the 3-(4,5-Dimethylthiazol-2-yl)-2,5-DiphenyltetrazoliumBromide assay. Compounds 4a and 4h have moderate activity against the human colon cancer; most of the compoundswere active toward human lung cancer; compounds 4i, 4h, and 4g were highly active on hormone-dependent human breastcancer, while compounds 4c, 4b, 4h, and 4e were the most active on the hormone-independent human breast. The resultsof this study offer a source for further investigation of selected triazolopyrimidine derivatives as antiproliferative agents.

Synthesis and biological evaluation of novel substituted pyrrolo[2,3-d]pyrimidines as anticancer agents

Pyrrolopyrimidines are well known scaffold, which play a critical role as anticancer agents, so it thought of interest tosynthesize a series of novel substituted pyrrolo[2,3-d]pyrimidines having diverse groups at position C4 and N7 of thepyrrolo[2,3-d]pyrimidine core and performed in vitro screening against MDA-MB-468 (breast cancer cell line) cellline. The details of the synthetic methods and characterization data of the synthesized compounds have been presentedin this study. Compounds 8a, 8h, 8j, 9h, 9i, 9j, 9m, 9n, and 9o showed the excellent anticancer activity compared tostandard doxorubicin with an IC50 value of 6.17 µM/ml against MDA-MB-468 (breast cancer cell line), which wasnon-toxic to normal vero cell line.

Exploring the hydrophobic channel of NNIBP leads to the discovery of novel piperidine-substituted thiophene3,2-pyrimidine derivatives as potent HIV-1 NNRTIs

In this report, a series of novel piperidine-substituted thiophene[3,2-]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket (NNIBP) by incorporating an aromatic moiety to the left wing of the lead . The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells and inhibitory activity to HIV-1 reverse transcriptase (RT). Most of the synthesized compounds exhibited broad-spectrum activity toward wild-type and a wide range of HIV-1 strains carrying single non-nucleoside reverse transcriptase inhibitors (NNRTI)-resistant mutations. Especially, compound exhibited the most potent activity against wild-type and a panel of single mutations (L100I, K103N, Y181C, Y188L and E138K) with an EC ranging from 6.02 to 23.9 nmol/L, which were comparable to those of etravirine (ETR). Moreover, the RT inhibition activity, preliminary structure-activity relationship and molecular docking were also investigated. Furthermore, exhibited favorable pharmacokinetics (PK) profiles and with a bioavailability of 33.8%. Taken together, the results could provide valuable insights for further optimization and compound holds great promise as a potential drug candidate for the treatment of HIV-1 infection.

Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.

Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.

Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.

Design and synthesis of 2-aryl-4-(trans-4-hydroxycyclohexanylamino)-5-ethyl- 7H-pyrrolo2, 3-dpyrimidines and Mer tyrosine kinase inhibitory activity evaluation / 国际药学研究杂志

Objective: To design and synthesize a series of 2-aryl-4-(trans-4-hydroxycyclohexanolamine)-7H-pyrrolo[2, 3-d] pyrimidine derivatives and test their inhibitory activity against Mer tyrosine kinase(MerTK)and tumor cell proliferation. Methods: 2, 4-Dichloro-7H-pyrrolo[2, 3-d]pyrimidine(1)was used as starting material to synthesize the target compounds via iodination, protection with p- Tosyl(Ts), nucleophilic substitution, Stille coupling, vinyl reduction, Suzuki coupling and deprotection of Ts. The MerTK inhibitory activity was tested by the Kinase-Glo Plus luminescence method. The antiproliferation activity was assayed using MV- 4-11, A549, MDA-MB-231, KB, and KB-vin tumor cell lines by the CCK8 and SRB methods. Molecular docking of MerTK and 6h was conducted using the DS3.0 software. Results: Nine compounds were synthesized, and their structures were confirmed by 1H NMR and MS. Compound 6h exhibited certain inhibitory effect on MerTK, with the(6.7±0.3)μmol/L of IC50 value, and could selectively inhibit the growth of MV-4-11 tumor cells, with the(6.6±1.1)μmol/L of GI50 value that was approximately 3-fold to 6-fold more potent than the GI50 value of 6h on the other tested tumor cells. Molecular docking showed that 6h could interact with MerTK on the binding site of UNC569 and overlapped well with the original ligand UNC569, but its binding energy was higher than the binding energy of UNC569. Conclusion: Compound 6h showed a selective inhibitory effect on the MV-4-11 cell growth, which might be further investigated via more biological experiments to explore whether the inhibitory effect is related to the inhibition of MerTK by 6h. The molecular docking results in the present study have suggested that further structural modification on the 2 and 5 position of 7H-pyrrolo[2, 3-d] pyrimidine skeleton could likely improve the MerTK inhibitory activity.

Molecular Docking Study Of Six Pyrimidine Derivatives As Egfr (EPIDERMAL Growth Factor Receptor) And Ca Ix (CARBONIC Anhydrase Ix) Inhibitor

Objective: The present study was carried out to discover whether these pyrimidine derivatives have the potential to be used as epidermal growth factor receptor (EGFR) and carbonic anhydrase (CA) IX inhibitors through structure-based in silico study. Methods: Docking was performed on 6 pyrimidine analogs; cetuximab and curcumin were taken as reference drug. The structure of the target protein retrieved from the RCSB Protein databank and the protein-ligand docking was performed using Pyrx AutoDock wizard with MGL tools 1.5.6 by using Lamarckian algorithm. Results: All the compounds have shown lower binding energy and inhibition constant (Ki) value than reference drug cetuximab and curcumin. Out of the 6 inhibitors analyzed vkh has shown minimum binding energy against the target protein EGFR and CA IX respectively. Smaller Ki value shows stronger interaction. The scoring value of the interaction of vkh i. e-10.74 and-9.93 Kcal/mol and Ki 13.17ɳM and 53.04ɳM against the target protein EGFR and CA IX respectively while the reference drug cetuximab has shown binding energy-6.09 Kcal/mol with Ki value 34.44 µM and curcumin has shown binding energy-6.02 kcal/mol with Ki value 38.60 µM. Conclusion: It can be concluded that the molecule vkh could have potential to be used as an EGFR inhibitor and CA IX inhibitor.

Synthesis of some novel pyrimidine, thiophene, coumarin, pyridine and pyrrole derivatives and their biological evaluation as analgesic, antipyretic and anti-inflammatory agents

Pyrimidine derivative 3 was afforded through the reaction of compound (1) with 5-ureidohydantion (2). Product 3 underwent a cyclization to produce fused pyrimidine derivative 7, although the latter product 7 was synthesized through one step via the reaction of compound (1) with 5-ureidohydantion (2) using another catalyst. Compound 3 was oriented to react with cyclic ketones 8a,b in the presence of elemental sulfur, salicylaldehyde (10), aryldiazonium chlorides 12a,b and ω-bromo-4-methoxy- acetophenone (14), which afforded, fused thiophene derivatives 9a,b, coumarin derivative 11, arylhdrazono derivatives 13a,b and 4-methoxyphenyl butenyl derivative 15, respectively. The latter product 15 was reacted with either potassium cyanide (16a) or potassium thiocyanide (16b) to form cyano and thiocyano derivatives 17a,b, respectively. Compound 17a underwent further cyclization to afford pyridopyrimidine derivative 19. Compound 15 was reacted with either hydrazine (20a) or phenylhydrazine (20b) to produce hydrazo derivatives 21a,b and these products were cyclize to produce pyrrole derivatives 23a,b. Finally, 5-ureidohydantion (2) was reacted with compounds 24a,b,c to afford pyrimidine derivatives 25a,b,c. The structures of the synthesized compounds were confirmed using IR, 1H NMR, 13C NMR and mass spectrometry techniques. Compounds 11 and 19 have promising as analgesic and antipyretic activities

Synthesis and JAK2 inhibitory activities of 4-phenyl-pyrrolo[2, 3-d] pyrimidine derivatives / 中国药科大学学报

A series of 4-phenyl-pyrrolo[2,3-d] pyrimidine derivatives were synthesized through modifying the structure of the lead compound ruxolitinib by molecular hybridization strategy.It was synthesized from pyrimidine-4,6-diol by Vilsmeier-Haack reaction,SNAr reaction,cyclized,dehydration,Suzuki coupling and finally acylated to give 12 new compounds(12a-121).All structures of the synthesized compounds were confirmed by 1H NMR,13C NMR,and HRMS analysis.The biological activities were evaluated in vitro.Their JAK2 inhibitory activities were studied using JAK2 enzymatic and TF1-GMCSF cellular assays.The results indicated that compounds 12b,12e and 12h showed moderate activity.The anti-tumor activities were studied against JAK2-independent A549 cell line by the MTT assay.Results showed that the tide compounds exhibited potent antiproliferative effect on A549,especially compound 12c(IC50 =0.12 μmol/L),suggesting that this series compounds might be promising anti-tumor agents for futher investigation.

Pyrrolidine dithiocarbamate alleviated rat cervical intervertebral disc degeneration via reducing tumor necrosis factor α and matrixmetalloproteinase 9 expression and its underlying mechanism / 中国药理学通报

Aim To observe the effect of pyrimidine dithiocarbamate (PDTC) on the variance of disc morphology and the expressions of TNF-α, MMP-9 in the cervical disc in cervical dynamic equilibrium rat models, and to investigate the roles of PDTC in the process of intervertebral disc degeneration and the mechanism involved.Methods Fifty-four SD rats were divided into three groups randomly, then the dynamic equilibrium rat model was established by cutting the nuchal superficial and deep muscle of the rats.The dynamic equilibrium rats with PDTC solution intraperitoneal injection after operations were defined as PDTC group (group A), the models with saline intraperitoneal injection after operations as saline group (group B), the rats of fake operation with saline intraperitoneal injection as blank group (group C), and the animals were sacrificed in batches 10 weeks, 12 weeks, 16 weeks respectively after operation.The C5, C6 vertebrae and C5/6 discs were harvested, and the disc morphology was observed.TNF-α, MMP-9 mRNA expressions were detected by q-PCR and protein expression was observed by Western blot.Results Compared with the saline group, the morphology of disc in PDTC group was destructed slightly and fiber ring arranged orderly.TNF-α, MMP-9 gene and protein expressions had no obvious changes (P>0.05) in blank group (group C) at each time point.The expressions of IL-6, MMP-9 mRNA increased with time in group B, but the amount increased fast firstly, and slow lately, reaching peak in 12 weeks.The expression of TNF-α, MMP-9 protein became steady in group B from 10 weeks compared with other time points(P>0.05).TNF-α, MMP-9 genes and proteins expression decreased obviously in PDTC group (group A) compared with saline group (group B) (P<0.01) at each time point, but higher than blank group C(P<0.01) at each time point.Conclusions TNF-α and MMP-9 are important inflammatory factors involved in rat cervical disc degeneration, PDTC relieves the degeneration of rat cervical disc by reducing the expression of TNF-α and MMP-9 via disturbing the NF-κB signal pathway probably, and PDTC may become potential medicine for disc degeneration.

Design, synthesis and antitumor activities of oxazolo[5, 4-d] pyrimidine derivatives / 中国药科大学学报

A series of oxazole[5,4-d] pyrimidine derivatives were designed and synthesized to discover novel compounds with antitumor activity.Compounds 8a-8m were synthesized using acetamidine hydrochloride as the start material.The structures of synthesized compounds were confirmed by IR,1H NMR,EI-MS and elemental analysis.The antiangiogenesis activities of the synthesized compounds were determined by MTT in human umbilical vein endothelial cell (HUVEC).The in vitro antitumor activities of the synthesized compounds were determined by MTT assay in A549,HepG2 and U251.Compounds 8c,8d,8g,8i and 8l were found to inhibit the proliferation of all the tested cell lines.Compound 8l exhibited noteworthy activities in A549,HepG2 and U251 cell lines with IC50value lower than the positive reference sunitinib,suggesting that compound 8l might be the promising antitumor agent for further investigation.

Pyrimidinethione derivatives with tosyl substitution: Synthesis, and antimicrobial property investigation.

Substitution of tosyl group on hydroxyacetophenones orhydroxybenzaldehyde and their subsequent condensation yielded several tosyloxy substituted chalcones which were derivatized to obtain the corresponding pyrimidinethione derivatives. The synthesized compounds were characterized by spectroscopic techniques like FT-IR, 1H NMR, 13C NMR, and mass spectrometry. These compounds were subjected to initial screening for their bioactivity using zone of inhibition method and were found moderately active against the tested microorganisms, viz. Mycobacterium smegmatis, Staphylococcus aureus, Escherichia coli, and Candida albicans.

Insights into the pyrimidine biosynthetic pathway of human malaria parasite Plasmodium falciparum as chemotherapeutic target

Malaria is a major cause of morbidity and mortality in humans. Artemisinins remain as the first-line treatment for Plasmodium falciparum (P. falciparum) malaria although drug resistance has already emerged and spread in Southeast Asia. Thus, to fight this disease, there is an urgent need to develop new antimalarial drugs for malaria chemotherapy. Unlike human host cells, P. falciparum cannot salvage preformed pyrimidine bases or nucleosides from the extracellular environment and relies solely on nucleotides synthesized through the de novo biosynthetic pathway. This review presents significant progress on understanding the de novo pyrimidine pathway and the functional enzymes in the human parasite P. falciparum. Current knowledge in genomics and metabolomics are described, particularly focusing on the parasite purine and pyrimidine nucleotide metabolism. These include gene annotation, characterization and molecular mechanism of the enzymes that are different from the human host pathway. Recent elucidation of the three-dimensional crystal structures and the catalytic reactions of three enzymes: dihydroorotate dehydrogenase, orotate phosphoribosyltransferase, and orotidine 5′-monophosphate decarboxylase, as well as their inhibitors are reviewed in the context of their therapeutic potential against malaria.

Synthesis and antitumor activities of 8-aminobenzofuran3, 2-d pyrimidine derivatives / 中国药学杂志

OBJECTIVE: To synthesize the derivatives of 8-amino benzofuran[3, 2-d] pyrimidine and study their anticancer activiies. METHODS: The target compounds were synthesized through a series of reactions, and their anticancer activities in vitro were evaluated against COLO205, MCF-7 and K562 cell lines by MTT as assay. RESULTS: Nine title compounds were synthesized and confirmed by EI-MS, 1H-NMR and 13C-NMR. Compounds 2, 3d and 5c had good inhibition effect against COLO205, MCF-7 and K562 cells. The inhibition rates of compound 5c against COLO205, MCF-7 and K562 cells were 99.58%, 78.75% and 98.68% respectively at 10-4 mol · L-1. CONCLUSION: The anticancer activity of benzofuran[3, 2-d] pyrimidine derivatives is worthy of further study.

Changes of coagulation and fibrinolysis function and PLT in patients with lung cancer before and after ;chemotherapy / 中国基层医药

Objective To investigate the changes of blood coagulation and fibrinolytic function and PLT in patients with lung cancer before and after chemotherapy,and to investigate the changes of the patients with lung cancer and the influence of the changes with lung cancer and the prognosis.Methods 40 patients with lung cancer(observation group)treated in our department from March 2012 to May 2014 were selected as the research subjects.The changes of coagulation and fibrinolytic activity,PT(PTINR),APTT,thrombin time(Fib),thrombin time(D -D),thrombin time (TT),D -D,and PLT were analyzed.The relationship between the parameters and the lung cancer staging was analyzed. Results Before chemotherapy,the levels of Fib,PLT,D -D,PT,PTNR,APTT,TT,PLT were (11.34 ±1.14)s, (1.01 ±0.07),(24.34 ±4.53)s,(2.54 ±0.45)g/L,(184.31 ±10.88)×109 /L,(143.35 ±23.45)ng/mL, (14.55 ±4.56)s.After chemotherapy,the levels of Fib,PLT,D -D,PT,PTNR,APTT,TT,PLT were (11.57 ± 1.36)s,(1.03 ±0.05),(24.52 ±5.32)s,(3.63 ±0.65)g/L,(210.45 ±11.24)×109 /L,(126.56 ±26.55)ng/mL, (14.34 ±4.17)s.The contents of Fib and PLT after chemotherapy were higher than before chemotherapy(t =0.024, 0.025,all P 0.05).Compared with patients with stage Ⅰ ~Ⅱ lung cancer,Fib level in stage Ⅲ ~Ⅳ lung cancer was higher (t =0.01,P 0.05).Conclusion PLT and Fib were increased,but D -D decreased after chemotherapy,the tumor remission rate was higher in D -D group,which indica-ted that the levels of Fib and D -D should be changed in the course of clinical chemotherapy.