Evaluation of a multidrug chemotherapy protocol with mitoxantrone based maintenance (CHOP-MA) for the treatment of canine lymphoma

The purpose of this study was to evaluate the efficacy of adding mitoxantrone to a cyclophosphamide, doxorubicin, vincristine, l -asparaginase and prednisone containing protocol. Sixty-five dogs with multicentric lymphoma were evaluated for overall remission and survival times. Remission and survival time versus stage, substage, pretreatment hypercalcaemia and pretreatment steroid administration were also evaluated. Overall median remission for dogs with multicentric lymphoma was 302 days and overall median survival was 622 days. Of the dogs with multicentric lymphoma, 23 (35%) received all scheduled mitoxantrone doses. Only median survival versus substage was found to be significant (substage a median survival was 679 days and substage b median survival was 302 days, P = 0.025). Increasing the total combined dose of doxorubicin and mitoxantrone may improve remission times when compared with historical controls, and further studies are needed to determine how best to utilize mitoxantrone in multidrug chemotherapy protocols for canine multicentric lymphoma.     

Evaluation of intracavitary mitoxantrone and carboplatin for treatment of carcinomatosis,sarcomatosis and mesothelioma,with or without malignant effusions: A retrospective analysis of 12 cases (1997–2002)*

Carcinomatosis, sarcomatosis and mesothelioma, with or without malignant effusions, are difficult to treat and generally carry a poor prognosis. The purpose of this study was two‐fold; first, to determine the prognosis for dogs with carcinomatosis, sarcomatosis, or mesothelioma, with or without malignant effusions; second, to evaluate the safety and efficacy of treatment with intracavitary (IC) carboplatin and mitoxantrone in dogs with these syndromes. Nineteen dogs were evaluated. Seven were untreated and 12 were treated with IC chemotherapy (mitoxantrone and/or carboplatin), and multiple factors were analysed for significance with respect to survival time. The median survival time (MST) for untreated dogs was 25 days, whereas the MST for treated dogs was 332 days (Log Rank, P < 0.0001). Treatment with IC chemotherapy was well tolerated. This study suggests that IC chemotherapy with mitoxantrone and/or carboplatin is an effective treatment for dogs with carcinomatosis, sarcomatosis or mesothelioma, with or without malignant effusion.     

米托蒽醌通过活性氧诱导大鼠肝癌RH35细胞凋亡的研究

试验旨在探讨米托蒽醌（mitoxantrone,MTN）对大鼠肝癌RH35细胞毒性及其作用机制。以MTT法检测MTN的细胞毒性,显微镜观察细胞形态变化,流式细胞仪检测细胞凋亡率及细胞中活性氧（reactive oxygen species,ROS）的产生,Western blotting检测相关蛋白的表达。结果显示,MTN时间和剂量依赖性地抑制RH35细胞的生长;15 μmol/L MTN作用于细胞24、48 h后可使细胞皱缩、变圆,并出芽形成明显的凋亡小体,且其可时间依赖性地诱导凋亡细胞比率的增加及ROS的产生;ROS清除剂NAC可以极显著降低MTN诱导的RH35细胞的ROS的产生和凋亡率（P<0.01）;15 mmol/L NAC可以下调MTN诱导的caspase-3、Bax及CytC表达增加,上调MTN诱导的Bcl-2表达降低。结果提示,MTN通过增加细胞内ROS而诱导RH35细胞发生凋亡。     

Mitoxantrone Induced Apoptosis through ROS in Rat Hepatama RH35 Cell Line

The assay was aimed to study the cytotoxicity and mechanisms of mitoxantrone (MTN) in rat hepatama cell line RH35. MTT assay was performed to assess the cytotoxicity of MTN, and microscope was used to observe cellular morphologic changes. Apoptotic ratio and intracellular ROS generation were measured by flow cytometric analysis. The protein expression was examined by Western blotting analysis. The results showed that MTN inhibited RH35 cell growth in a time-and concentration-dependent manner. The morphologic changes were observed in the cells, including cell shrinkage, membrane blebbing and apoptotic bodies when treated with 15 μmol/L MTN for 24 and 48 h. And MTN also induced the increase of apoptotic ratio and generation of ROS in a time dependent manner. In addition, the intracellular ROS generation ratio and the apoptotic ratio of MTN treated group were extremely decreased by the ROS scavenger NAC (P<0.01). The pretreatment of RH35 cells with 15 mmol/L NAC thoroughly reversed the MTN-induced enhancement of caspase-3, Bax and CytC level and attenuation of Bcl-2 level. In conclusion, MTN induced apoptosis in RH35 cells through increasing the generation of ROS.     

Postoperative radiotherapy and mitoxantrone for anal sac adenocarcinoma in the dog: 15 cases (1991–2001)

The medical records of 15 dogs with anal sac adenocarcinoma (ASAC) treated with concurrent curative‐intent radiotherapy and mitoxantrone (MX) after surgical removal of the primary tumour were reviewed retrospectively. Radiation was prescribed at 15 daily fractions of 3.2 Gy for a total dose of 48 Gy. MX was given intravenously at a dosage of 5 mg m^?2 every 3 weeks for five treatment sessions. Twelve dogs received pelvic irradiation to include the regional lymph nodes (LNs) and three received radiation only to the perineum. At the time of diagnosis, four dogs were hypercalcaemic and seven dogs presented with regional LN metastasis. All the dogs with regional LN metastasis received pelvic irradiation, and in three cases, metastatic LNs were treated in the macroscopic disease setting. The median event‐free survival was 287 days, and the median overall survival was 956 days. Acute and chronic radiation complications were common and non‐life threatening, although chronic complications contributed to the decision to euthanize two dogs. The results observed in this retrospective analysis compare favourably with cases of ASAC in the literature related to treatment with surgery and/or chemotherapy.