Experimental Observation Of Neurotoxicity Of Several Antineoplastic Drugs That Are Administered Intracerebroventricularly

Intra-CSF administration of antineoplastic drugs is an effective method to prevention and cure dissemination of malignant tumor by CSF. The drugs that can be administered in this way are limited now. The neurotoxicity of drugs is the predominant problem to decide whether the drug can be used in this way, however, there were few reports about the neurotoxicity of antineoplastic drugs that are used in this way. Purpose: To make a preliminary assessment of neurotoxicity of a few antineoplastic drugs that are common used clinically through animal experiments, and provide experimental evidences for the clinical application in the future. Methods: We studied on the neurotoxicity of Methotrexate ( MTX ) , Methotrexate(VCR), Adriamycin(ADM), Carmustine(BCNU) , Cisplatin(C-DDP), Carboplatin(CBP), Topotecan(TPT) and Teniposide(VM-26) though intracerebroventricular injection to mice. Experimental groups of these drugs were divided into three groups of dosages (low, moderate and high) which could just make the final concentration of drugs in the CSF equal ,twice and 4 times to the half inhibiting concentration (IC50) while the animals of contral groups were administered physiologic saline of the same volume. Observed and recorded the changes of ethology such as ethology and motor dysfunction. Took the rotating rod tests of the mice in the 3rd day and 7th day to evaluate the balance abilities. Then took the water maze experiments to estimate the vacuity perceptibility from the 4th day. After the rotating rod tests of the mice in the 3rd day and 7th day, killed the mice and prepared the histological sections of brain tissues and observed the changes of pathology. Results: 1. All the mice that were administered of MTX,BCNU and TPT didn't show up epileptic attack and motor dysfunction , there were not any positive results of rotating rod tests, water maze experiments or pathology. 2. The mice that were administered of VCR showed up epileptic attack and motor dysfunction in different extent. The results of rotating rod tests indicated the decline in the balance abilities. The results of water maze experiments of animals in the moderate dosages group showed the damage of vacuity perceptibility. Were could see the neuronal degeneration, necrosis and hemangiectasia , congestion from the pathology of the high dosages group . 3. The animals that were administered of ADM received the similar results to the ones that were administered of ADM except for the mice in the low-dosages group didn't show up epileptic attack. 4. Epileptic attack didn't emerge in all the animals that were administered of DDP, the results of rotating rod tests indicated the decline in the balance abilities. There were motor dysfunction in the high dosages group. There were not any positive results of water maze experiments or pathology. 5. Epileptic attack emerged in all the mice that were administered of CBP, the results of water maze experiments of animals in the high dosages group showed the damage of vacuity perceptibility . There were not any other positive results. 6. There were motor dysfunction in the animals that were administered of VM-26 of high dosages. The results of rotating rod tests indicated the decline in the balance abilities, but the results of water maze experiments of animals showed no damage of vacuity perceptibility . We could see hemangiectasia and congestion from the pathology in the 3^rd days. Conlusions: 1.The neurotoxicity of the drugs that were administered through intra-CSF injecton was dosages dependent. 2. The mice that were administered of MTX in the high dosages didn't show any neurovirulent responses while the mice that were administered of VCR in the low dosages show obvious responses. It was the in conformity to the conlusions that were usually believed , and furthermore , it was an evidence of the reliability of the results to the experiments. 3. The mice that were administered of ADM,DDP and CBP in the low dosages showed neurovirulent responses , this results implied these drugs had abvious neurotoxicity, we suggested that they should not be used for the intra-CSF injecton. The mice that were administered of VM-26 in the high dosages showed neurovirulent responses but didn't in the low and moderate groups, which indicated that as long as a good control of dosages were maintained, VM-26 could be used in this way. 4. All the mice that were administered of BCNU and TPT didn't show neurovirulent responses, which implied that they could be chosen in this way, although whether they could be used in it was still to be studied.