Study of Alkaline Comet Assay at Various Tissues in SD Rats with Intragastric Administration of Procarbazine Hydrochloride and Ethyl Carbamate / 中国药房

OBJECTIVE： To evaluate the DNA damage response of procarbazine hydrochloride （PCZ） and ethyl carbamate （EC） to different tissues in rats by performing alkaline comet assay， to validate the feasibility of alkaline comet assay of various tissues. METHODS： Totally 30 SD rats were randomly divided into 6 groups according to body weight， with 5 rats in each group， such as negative control group （hyperpure water）， PCZ 75 mg/kg group， PCZ 150 mg/kg group， EC 400 mg/kg group， EC 800 mg/kg group， positive control group （N-ethyl-N-nitrosourea 40 mg/kg）. Those rats were given relevant medicine intragasttrically for 4 d； clinical symptoms of rats were observed and body weight was recorded during experiment. Within 3 h after last medication， the rats were sacrificed； liver， renal and lung weight were weighed； liver， kidney， lung and peripheral blood lymphocytes were collected. The single cell suspension was prepared to perform alkaline comet assay. After lysis， unwind， electrophoresis and dying， tail DNA％ and tail distance of samples were analyzed by Komet 6.0 software. RESULTS： Compared with negative control group， body weight， liver and renal weight of rats were decreased significantly in PCZ 75 mg/kg group， PCZ 150 mg/kg group and positive control group 4 d after medication （P＜0.05 or P＜0.01）. Body weight of rats were decreased significantly in EC 800    mg/kg 4 d after medication （P＜0.05 or P＜0.01）； there was no statistical significance （P＞0.05）. Compared with negative control group， tail DNA％ and tail distance in liver， kidney and peripheral blood lymphocytes were increased significantly in PCZ 75    mg/kg group， PCZ 150 mg/kg group and positive control group （P＜0.05 or P＜0.01）； PCZ showed more significant effects on liver and lung. Tail DNA％ and tail distance of liver， kidney and peripheral blood lymphocytes were increased significantly in EC 800 mg/kg group （P＜0.05 or P＜0.01）， and tail DNA％ and tail distance of renal tissue was increased significantly in EC 400   mg/kg group （P＜0.05）. CONCLUSIONS： PCZ induced stronger DNA damage； liver and lung are the major genotoxicity target of PCZ. EC-induced DNA damage is relatively weak， and kidney is the most sensitive organ for EC-induced genotoxicity.

Procarbazine and CCNU Chemotherapy for Recurrent Glioblastoma with MGMT Promoter Methylation

BACKGROUND: While procarbazine, CCNU (lomustine), and vincristine (PCV) has been an alternative chemotherapy option for malignant gliomas, it is worth investigating whether the combination of only procarbazine and CCNU is comparable because vincristine adds toxicity with uncertain benefit. The purpose of this study was to evaluate the feasibility of procarbazine and CCNU chemotherapy for recurrent glioblastoma multiforme (GBM) with O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation. METHODS: Eight patients with recurrent GBM following concurrent chemoradiotherapy and temozolomide (TMZ) adjuvant therapy were enrolled in this trial; they received no other chemotherapeutic agents or target therapy. They received CCNU (75 mg/m²) on day 1 and procarbazine (60 mg/m²) through days 11 and 24 every 4 weeks. The median cycle of CCNU and procarbazine was 3.5 (range: 2–6). RESULTS: One patient achieved stable disease. The median progression-free survival (PFS) with procarbazine and CCNU chemotherapy was eight weeks (range: 5–73), and the PFS rates were 25% and 12.5% at 16 and 30 weeks, respectively. The median overall survival (OS) from the initial diagnosis to death was 40 months, and the median OS from the administration of procarbazine and CCNU chemotherapy to death was 9.7 months (95% confidence interval: 6.7–12.7). Serious adverse events were found at six visits, and two cases were considered to be grade 3 toxicities. CONCLUSION: The efficacy of procarbazine and CCNU chemotherapy is not satisfactory. This study suggests the need to develop other treatment strategies for recurrent and TMZ-refractory GBM. Trial registry at ClinicalTrials.gov, NCT017337346.

El mecanismo de la electrooxidación de procarbacina y su descripción matemática / The procarbazine electrooxidation mechanism and its mathematical description

RESUMEN Al proceso de la electrooxidación de procarbacina fue atribuido el mecanismo, incluyendo dos etapas electroquímicas y las dos químicas. También, ha sido desarrollado y analizado un modelo matemático, capaz de describir el comportamiento del sistema. Por su intermedio, se dio la posibilidad de comparar el comportamiento de este sistema con el de los semejantes y análogos, como con el sistema de la electrosíntesis de monómeros.

SUMMARY A mechanism, including two electrochemical and two chemical stages, has been attributed to the procarbazine electrooxidation. Also, a mathematical model, capable to describe the system's behavior, has been developed. My its means, it was possible to compare the behavior of this system with that of the monomers' electrosynthesis.

Procarbazine, CCNU, and Vincristine Chemotherapy in Gliomatosis Cerebri

A 49-year-old female patient was admitted due to memory disturbances. Magnetic resonance (MR) imaging suggested gliomatosis cerebri (GC), which had spread to both insular lobes, both frontal and basal ganglia and the brain stem. A stereotactic biopsy was performed at the high signal intensity area of the T2-weighted MR image, and the revealed a diffuse astrocytoma. Radiation therapy was judged not to be an appropriate treatment for the patient because of her cognitive impairment. A combinatorial chemotherapy regiment consisting of Procarbazine, CCNU, and Vincristine (PCV) was agreed upon after discussion. The patient underwent six cycles of PCV chemotherapy (a full dose was applied until the 3rd cycle, and dose then was reduced to 75% for the remaining cycles). Although the patient exhibited side effects such as bone marrow suppression and gastrointestinal symptoms, these were managed by medication. Over the 28 months following initiation of treatment, the high signal area in the right frontal and temporal lobes in the T2-weighted MR image decreased, and the patient's cognitive function [global deterioration scale (GDS) 4 points, mini-mental state examination (MMSE) 25 point] also improved (GDS 1 points, MMSE 29 points). PCV chemotherapy can therefore be an alternative therapeutic option for patients with GC who cannot be treated with radiation therapy or other chemotherapies.

The Role of Chemotherapy in Anaplastic Astrocytoma Patients

OBJECTIVE: This retrospective study was performed to evaluate the role of chemotherapy in the management of patients with anaplastic astrocytoma (AA). METHODS: We compared the survival outcome among the 3 different treatment protocol groups in a single institution. A total of 86 patients (39 men and 47 women) with newly diagnosed AA after surgery were analyzed. Among them, 31 patients (36.0%) were treated with radiotherapy only (RT Group), 30 patients (34.9%) were treated with nimustine-cisplatin chemotherapy before RT (ACNU-CDDP group), and 25 patients (29.1%) were treated with procarbazine, lomustine and vincristine (PCV) chemotherapy after radiotherapy (PCV group). RESULTS: The median survival was 14.0, 30.0 and 72.0 months in RT, ACNU-CDDP, and PCV group, respectively and showed significant differences (RT vs. ACNU-CDDP; p=0.039, RT vs. PCV; 0.002, ACNU-CDDP vs. PCV; 0.045). PCV group showed less toxicity rate (5 patients; 20%) than ACNU-CDDP group (12 patients; 40%), while only 3 patients (9.6%) in RT group experienced grade 3 or 4 toxicities. CONCLUSION: An application of chemotherapy before or after radiotherapy is beneficial in prolonging the survival of patients with AA. Adjuvant PCV chemotherapy after radiotherapy is recommendable.

The Role of Chemotherapy in Anaplastic Astrocytoma Patients

OBJECTIVE: This retrospective study was performed to evaluate the role of chemotherapy in the management of patients with anaplastic astrocytoma (AA). METHODS: We compared the survival outcome among the 3 different treatment protocol groups in a single institution. A total of 86 patients (39 men and 47 women) with newly diagnosed AA after surgery were analyzed. Among them, 31 patients (36.0%) were treated with radiotherapy only (RT Group), 30 patients (34.9%) were treated with nimustine-cisplatin chemotherapy before RT (ACNU-CDDP group), and 25 patients (29.1%) were treated with procarbazine, lomustine and vincristine (PCV) chemotherapy after radiotherapy (PCV group). RESULTS: The median survival was 14.0, 30.0 and 72.0 months in RT, ACNU-CDDP, and PCV group, respectively and showed significant differences (RT vs. ACNU-CDDP; p=0.039, RT vs. PCV; 0.002, ACNU-CDDP vs. PCV; 0.045). PCV group showed less toxicity rate (5 patients; 20%) than ACNU-CDDP group (12 patients; 40%), while only 3 patients (9.6%) in RT group experienced grade 3 or 4 toxicities. CONCLUSION: An application of chemotherapy before or after radiotherapy is beneficial in prolonging the survival of patients with AA. Adjuvant PCV chemotherapy after radiotherapy is recommendable.