| BackgroundGlioma accounted for35.26%and60.96%of intracranial primary tumor, an average of44.69%is the most common primary intracranial tumor. Especially, the mean survival time of glioblastoma showed as only3months. It’s difficult to avoid the recurrent because of its invasive growth, the unclear boundaries from the normal brain tissue, and other high malignancy characteristics. Until now, surgery with radiotherapy and chemical drug therapy still was generaly considered as the common therapeutic plan for the glioma, in which the chemotherapy pays an important role in glioma therapy. However, the normal venous system administration of chemotherapeutic drugs will exposure some shortages such as a dose-dependent bone marrow suppression, the toxic effects of liver toxicity, pulmonary fibrosis, difficulting to pass the blood-brain barrier (BBB) and so on.To solve the problem above, many scholars explored the mode of chemotherapy delivery methods and ways in order to improve the therapeutic effect and patients’ quality of life. Glioma recurrence often happened at primary site, therefore, the local treatment with antineoplastic agent was considered to be able to effectively prevent or delay the tumor recurrence. Recently, some of new therapeutic ways about local administration for glioma were arised, such as the local biological therapy with "Gliasite I125balloon interstitial radiotherapy", the immune treatment by glioma-intracavitary administration of lymphokine activated killer (LAK), and so on. Single dose of administration into the tumor cavity is a much more effective method among the local chemotherapy ways. The gelatin sponge was commonly used as a carrier to set the drug into the tumor cavity, which showed the advantages including simple operation, low cos, and rejection reaction, ect.It was well known that the ACNU played an obvios role as soon as it was localy used in glioma therapy. Studies have shown that topical application of the ACNU on glioma by using gelatin sponge dipped with a reasonable dose of ACNU solution to set on local glioma region, might inhibit tumor cell growth, and reduce the side effects of systemic chemotherapy. However, in this course of treatment, there were some actual troubles such as the toxical side-effect to the normal cerebral tissue at the same time during the local therqapy of glioma. Until now, it still lacks the relevant evaluating indexes as soon as the ACNU contacting to normal brain tissue, during glioma therapy with ACNU localy.Many types of anticancer drugs containing the ACNU, showed the different adverse reactions because of their various pharmacological effects, which might cause the different effects on body systems and organs, and thus exhibited the virous performances. Common adverse reactions of anticancer drugs were summaried as below.(1) Bone marrow suppression. The vast majority of anticancer drugs have varying degrees of toxic effects on the hematopoietic system. The sensitivity of blood cells to chemotherapy drugs mainly depends on the half-life of of these drugs. The half-life of white blood cells (WBC) is only6h, the platelet (PLT) as5-7d, and the red blood cell (RBC) up to120d. Therefore, the suppressed degree of bone marrow hematopoietic cells showed the order in turn as white blood cells (especially granulocytes), platelets, and the hemoglobin. The final result is the whole blood reducing.(2) Gastrointestinal reactions. The main manifestations include the nausea, vomiting, anorexia, acute gastritis, diarrhea, constipation, severe gastrointestinal bleeding, intestinal obstruction, intestinal necrosis, as well as varying degrees of liver injury. These side-effect made the influence not only on the patient’s mood and eating, but only on the disturbance about nutritional, metabolic and other complications. And also the body weight also will be impacted.(3) Reactions of nervous system. Some of abmormal peripheral nerve symptoms, including numbness and paresthesia, reversible peripheral neuritis, disappearance of deep tendon responses, lower limb weakness, might appeared. On the other hand, some abnormal CNS signs such as the short-term language barriers, confusion/loss consciousness, drowsiness, and rare convulsions also may happen. The abnormal autonomic nerve functions including the constipation and abdominal distension caused by intestinal paralysis will appeared following the administration of anticancer drugs. The auditory nerve obstacle generally displays the tinnitus, deafness, dizziness, and the severe high-frequency hearing loss. As a common and effective anti-glioma chemotherapy drugs. ACNU will result in the characteristics above. Especialy, the administration of ACNU by vein, will induce the patients to sufferer from the bone marrow suppression, nutritional status change, and abnormal nerve reaction. Therefore, the rational local application of ACNU was important but negatively effected last years, because of the lack on some significant researches.In this study, the evaluated indexes including the improved modified Neurological Severity Score (mNSS), body weight (offering some information about metabolism obliquely), hemogram (offering some information about myelosuppression) of white blood cell (WBC), red blood cell (RBC), and platelet (PLT) were assayed in the tested SD rats, in order to explore the correlation among these indexes and the ACNU doses after ACNU contacted to the rat local normal brain tissue, and to understand the maximum tolerated dose by it.MethodForty five of SD rats were randomly divided into5groups including A, B, C, D and E, in which there were10of rats except Group E with5rats. The different doses including2mg/kg,1mg/kg,0.5mg/kg,0.25mg/kg and Omg/kg of ACNU solution were respectively administrated in these groups. After being anesthetized, the parietal of the rat was opened to exposure the left cerebral hemisphere, and then the gelfoam (specification as2mm×2mm×2mm) dipped with the different dose of ACNU solution were respectively applied on the surface of the rat hemisphere, following cutting the dura and piamater. The wound was then surgically closed. The mNSS in every group was respectively evaluated at the6th hour,1st day,3rd day,7th day,10th day and14th day after administration of ACNU. Before surgery, each rat was weighed with the spring balance, and also did at postoperative1st day,3’d day,7th day,10th day and14th day. For each rat, the hemogram of WBC, RBC. PLT was assayed by the automatic blood cell automatic analyzer, following getting the whole blood from the tail tip of the rats, at the Oday,7th day, and14th day after administration of different doses of ACNU.Result(1) mNSS experimental results:①Group B showed the moderate nerve injury, while others exhibited the mild nerve functional obstacle, at the1st and3rd day after normal brain tissue exposured to ACNU. There was significant difference comparing2mg/kg or1mg/kg,0.5mg/kg dose ACNU solution respectively to Omg/kg-dose group, but no significant between GroupD and E.②Each group of experimental animals appeared the tendency as "mNSS gradually increasing, peaking at the1st day, then gradulually decreasing along the time-lapse up to stabilizing at the10th day after the normal brain tissue exposuring to ACNU".③At the same concentration, ACNU might damage rat normal brain tissue further along with the time-lapse, but peak only at the1st day after ACNU administration.④The mNSS in Groups C, D, and E were respectively was1.40±0.516,0.60±0.516, and0.40±0.548, closing to the normal score0, at14th day after contacting ACNU. However, the mNSS in Groups A and B showed as3.00±0.47、2.70±0.48at the same time.⑤There was statistcal difference about mNSS comparing Groups A or B, C1.40±0.516、0.60±0.516、0.40±0.548) respectively to Group E (2.07、1.27). but no significant difference between Group D (2.40±1.31) and E (P>0.05).(2) Weight measurement:At3rd day after ACNU administration, there was significant difference about the rat body weight comparing2mg/kg or1mg/kg,0.5mg/kg dose of ACNU solution respectively to Group E (Omg/kg dose), but no significant difference between Group D and E. The body weight in each group gradually decreased along with the time-lapse during the rat normal brain tissue contacting to ACNU. At the same dose ACNU, the rat body weight in Groups A, B and C showed the lowest151.50±9.14.166.00±6.15and177.00±6.32) at the7th day, while Groups D and E arrived the lowest body wight190.00±5.27and192.00±2.74) at the3rd day following the ACUN administration. Along with the time-lapse, the rat body weight gradually increased. The body weight in Groups A and B showed higher over the one before contacting with ACNU, at the14th day. While Groups C, D and E showed the body weight higher over the one before ACNU administration, at the10th day. The body weights of Groups A, B and C (187.25±19.38、194.92±16.42.200.50±15.03) showed the significant difference (P<0.05) comparing to Group E (211.33±19.78), but no statistical meaning between Groups D (207.08±17.18) and E。 (3) Hemogram assay:At the7th day following the ACNU administration, WBC and PLT in Group A(5.84±0.37、506.90±85.40) or B(6.34±0.13、577.70±47.55) showed the significant difference comparing to them (6.91±0.19、702.60±52.71) in Group E, bur the RBC exhibited the significant difference only between Groups A (8.81±0.18) and E (9.02±0.17). At the14th day after contacting ACNU, also there was a statistical meaning about rat WBC、PLT between Group A (6.24±0.27、573.10±60.31) and Group E (6.81±0.16、695.80±65.89)Conclusion1.≤0.25mg/kg of ACNU solution may be considered as a referenced safe dose, during evaluation of rat nerve function after ACNU exposed to normal rat brain tissue.2.≤0.25mg/kg of ACNU solution may be considered as a referenced safe dose point, during evaluation of rat nutritional state after ACNU exposed to normal rat brain tissue.3.≤1mg/kg of ACNU solution may be considered as the referenced safe dose. during evaluation of rat hematopoietic function state after ACNU exposed to normal rat brain tissue.4. Summarizing the results above,≤0.25mg/kg dose of ACNU solution still will be mainly considered as the referenced safe dose upon the rat mNSS and body weight in this study, although≤1mg/kg of ACNU showed only mild effection on rat hemogram. |
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