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Veterinary Medicine and Science Jan 2022Nimustine, similar to lomustine, is an alkylating agent from the nitrosourea family. There have been some reports regarding lomustine treatment for tumour-bearing cats....
BACKGROUND
Nimustine, similar to lomustine, is an alkylating agent from the nitrosourea family. There have been some reports regarding lomustine treatment for tumour-bearing cats. However, information regarding nimustine treatment for tumour-bearing cats is limited.
OBJECTIVES
To retrospectively evaluate adverse events and clinical outcomes in tumour-bearing cats receiving nimustine.
METHODS
Information regarding diagnosis, treatment condition, adverse events, and clinical outcomes was collected in tumour-bearing cats receiving nimustine through reviews of medical records.
RESULTS
Nine cats with lymphoma were treated with nimustine in the primary therapy (n = 2) and in the rescue therapy (n = 7). Median starting dose of nimustine was 25 mg/m (range: 20-30 mg/m ) with dosing interval of three weeks and 1-11 administrations. Adverse events were mild gastrointestinal toxicity (grade 1) including diarrhoea (n = 2) and vomiting (n = 2) and mild myelosuppression (grade 1 or 2) including thrombocytopenia (n = 3) and neutropenia (n = 1). No severe adverse events were observed. Progression-free survival durations among cats receiving nimustine in the primary therapy and in the rescue therapy were 274-688 days (median: 481 days) and 9-671 days (median: 102 days), respectively. Overall survival durations among cats receiving nimustine in the primary therapy and in the rescue therapy were 275-745 days (median: 510 days) and 14-671 days (median: 109 days), respectively.
CONCLUSIONS
Nimustine was well tolerated and showed clinical outcomes similar to lomustine in cats with lymphoma. These findings suggest that nimustine might be an alternative to lomustine in the treatment of feline lymphoma.
Topics: Animals; Cat Diseases; Cats; Lomustine; Lymphoma; Nimustine; Retrospective Studies; Treatment Outcome
PubMed: 34599792
DOI: 10.1002/vms3.652 -
Cancer Science Nov 2021Glioblastomas (GBM) often acquire resistance against temozolomide (TMZ) after continuous treatment and recur as TMZ-resistant GBM (TMZ-R-GBM). Lomustine (CCNU) and...
Glioblastomas (GBM) often acquire resistance against temozolomide (TMZ) after continuous treatment and recur as TMZ-resistant GBM (TMZ-R-GBM). Lomustine (CCNU) and nimustine (ACNU), which were previously used as standard therapeutic agents against GBM before TMZ, have occasionally been used for the salvage therapy of TMZ-R-GBM; however, their efficacy has not yet been thoroughly examined. Therefore, we investigated the antitumor effects of CCNU and ACNU against TMZ-R-GBM. As a model of TMZ-R-GBM, TMZ resistant clones of human GBM cell lines (U87, U251MG, and U343MG) were established (TMZ-R-cells) by the culture of each GBM cells under continuous TMZ treatment, and the antitumor effects of TMZ, CCNU, or ACNU against these cells were analyzed in vitro and in vivo. As a result, although growth arrest and apoptosis were triggered in all TMZ-R-cells after the administration of each drug, the antitumor effects of TMZ against TMZ-R-cells were significantly reduced compared to those of parental cells, whereas CCNU and ACNU demonstrated efficient antitumor effects on TMZ-R-cells as well as parental cells. It was also demonstrated that TMZ resistance of TMZ-R-cells was regulated at the initiation of DNA damage response. Furthermore, survival in mice was significantly prolonged by systemic treatment with CCNU or ACNU but not TMZ after implantation of TMZ-R-cells. These findings suggest that CCNU or ACNU may serve as a therapeutic agent in salvage treatment against TMZ-R-GBM.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; DNA Modification Methylases; DNA Repair Enzymes; Drug Resistance, Neoplasm; Female; Glioblastoma; Histones; Humans; Injections, Intraperitoneal; Lomustine; Methylation; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Recurrence, Local; Nimustine; Salvage Therapy; Temozolomide; Tumor Suppressor Proteins; Xenograft Model Antitumor Assays
PubMed: 34536314
DOI: 10.1111/cas.15141 -
Veterinary Medicine and Science Nov 2021A 7-year-old spayed female Scottish Fold cat presented with a 4-week history of anorexia, weight loss and vomiting. Abdominal ultrasonography revealed a jejunal mass and...
A 7-year-old spayed female Scottish Fold cat presented with a 4-week history of anorexia, weight loss and vomiting. Abdominal ultrasonography revealed a jejunal mass and a slightly enlarged jejunal lymph node. A fine-needle aspiration of the mass revealed many round cells with multiple small intracytoplasmic magenta granules. The mass was diagnosed as a large granular lymphocyte (LGL) lymphoma based on cytology. The LGL lymphoma was completely resected via open surgery. The histologic and cytologic evaluations showed no neoplastic findings in the jejunal lymph node, liver, spleen, kidney or bone marrow. The LGL lymphoma was localized to the jejunum. Postoperatively, the cat received chemotherapy with nimustine, L-asparaginase and prednisolone. The cat is currently receiving nimustine every 6 weeks, without adverse events, and treatment has been administrated a total of 18 times up until day 552. The cat is in a good condition, and the LGL lymphoma has not recurred. Nimustine should be considered one of the effective chemotherapeutic agents in the treatment of feline LGL lymphoma cases in the future.
Topics: Animals; Antineoplastic Agents; Cat Diseases; Cats; Female; Lymphocytes; Lymphoma; Neoplasm Recurrence, Local; Nimustine
PubMed: 34405564
DOI: 10.1002/vms3.612 -
Acta Neuropathologica Communications Mar 2017Among diffuse gliomas, oligodendrogliomas show relatively better prognosis, respond well to radiotherapy and chemotherapy, and seldom progress to very aggressive tumors....
Among diffuse gliomas, oligodendrogliomas show relatively better prognosis, respond well to radiotherapy and chemotherapy, and seldom progress to very aggressive tumors. To elucidate the genetic and epigenetic background for such behavior and tumor evolution during tumor relapse, we comparatively analyzed 12 pairs of primary and recurrent oligodendrogliomas with 1p/19q-codeletion. Initial treatment for these patients was mostly chemotherapy alone. Temozolomide was used for 3, and procarbazine, nimustine and vincristine (PAV chemotherapy) were used for 7 patients. World Health Organization histological grade at recurrence was mostly stable; it was increased in 2, the same in 9, and decreased in 1 cases. Whole-exome sequencing demonstrated that the rate of shared mutation between the primary and recurrent tumors was relatively low, ranging from 3.2-57.9% (average, 33.3%), indicating a branched evolutionary pattern. The trunk alterations that existed throughout the course were restricted to IDH1 mutation, 1p/19q-codeletion, and TERT promoter mutation, and mutation of the known candidate tumor suppressor genes CIC and FUBP1 were not consistently observed between primary and recurrent tumors. Multiple sampling from different regions within a tumor showed marked intratumoral heterogeneity. Notably, in general, the number of mutations was not significantly different after recurrence, remaining under 100, and no hypermutator phenotype was observed. FUBP1 mutation, loss of chr. 9p21, and TCF12 mutation were among a few recurrent de novo alterations that were found at recurrence, indicating that these events were clonally selected at recurrence but were not enough to enhance malignancy. Genome-wide methylation status, measured by Illumina 450 K arrays, was stable between recurrence and the primary tumor. In summary, although oligodendroglioma displays marked mutational heterogeneity, histological malignant transformation accompanying events such as considerable increase in mutation number and epigenetic profile change were not observed at recurrence, indicating that noticeable temporal and spatial genetic heterogeneity in oligodendrogliomas does not result in rapid tumor progression.
Topics: Adult; Aged; Biomarkers, Tumor; Brain Neoplasms; Cohort Studies; DNA Methylation; Epigenesis, Genetic; Female; Humans; Male; Middle Aged; Mutation; Neoplasm Grading; Neoplasm Recurrence, Local; Oligodendroglioma; Young Adult
PubMed: 28270234
DOI: 10.1186/s40478-017-0422-z -
Cancer Medicine Nov 2016Nimustine (ACNU) has antitumor activities in patients with malignant glioma. Hyperbaric oxygen (HBO) may enhance the efficacy of certain therapies that are hampered by...
Nimustine (ACNU) has antitumor activities in patients with malignant glioma. Hyperbaric oxygen (HBO) may enhance the efficacy of certain therapies that are hampered by the hypoxic microenvironment. We examined the combined effects of ACNU and HBO in a GFP transgenic nude mice bearing human glioma model. Mice inoculated with human glioma cells SU3 were randomly divided into the four groups: (A) the control group, (B) the HBOT (HBO therapy) group, (C) the ACNU group, and (D) the HBOT+ACNU group. Tumor size was measured at the indicated time intervals with a caliper; mice were sacrificed 28 days after treatment, and immunohistochemistry staining and western blot analysis were carried out. By the end of the trial, the tumor weights of groups A, B, C, and D were (P < 0.05), 6.03 ± 1.47, 4.13 ± 1.82 (P < 0.05), 2.39 ± 0.25 (P < 0.05), and 1.43 ± 0.38 (P < 0.01), respectively. The expressions of TNF-α, MMP9, HIF-α, VEGF, NF-κB, and IL-1β were associated with the infiltration of inflammatory cells and the inhibition rate of tumor cells. Hyperbaric oxygen therapy (HBOT) could inhibit glioma cell proliferation and inflammatory cell infiltration, and exert a sensitizing effect on ACNU therapy partially through enhancing oxygen pressure (PO ) in tumor tissues and lower expression levels of HIF-1α, TNF-α, IL-1β, VEGF, MMP9, and NF-κB.
Topics: Animals; Antineoplastic Agents; Biomarkers; Body Weight; Cell Line, Tumor; Disease Models, Animal; Glioma; Humans; Hyperbaric Oxygenation; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Mice; Mice, Transgenic; Models, Biological; NF-kappa B; Nimustine; Signal Transduction; Tumor Burden; Tumor Necrosis Factor-alpha; Xenograft Model Antitumor Assays
PubMed: 27734611
DOI: 10.1002/cam4.851 -
Biological & Pharmaceutical Bulletin Apr 2001This report investigates the pharmacokinetics of nimustine (ACNU), cytosine arabinoside (Ara-C), and methotrexate (MTX) in cerebrospinal fluid (CSF) during CSF perfusion... (Clinical Trial)
Clinical Trial
This report investigates the pharmacokinetics of nimustine (ACNU), cytosine arabinoside (Ara-C), and methotrexate (MTX) in cerebrospinal fluid (CSF) during CSF perfusion chemotherapy. A 47-year-old Japanese man with spinal cord, cerebellum and brain stem dissemination of oligo-astrocytoma received nine courses of CSF perfusion chemotherapy with ACNU, Ara-C, and MTX. A CSF perfusion chemotherapy solution was perfused via an Ommaya reservoir in the ventricle, and was discharged by drainage though another Ommaya reservoir in the lumbar spinal canal. CSF samples via Ommaya reservoirs in the lumbar spinal canal were obtained during the fifth and eighth courses of treatment. The concentrations of ACNU and Ara-C in CSF were measured by HPLC, and the MTX concentrations by fluorescence polarization immunoassay. In the fifth course of treatment, a CSF injection chemotherapy solution, consisting of 5 mg of ACNU dissolved in 20 ml of artificial CSF, was injected over a few minutes using the Ommaya reservoir. Next, a CSF perfusion chemotherapy solution, consisting of 10 mg of Ara-C and 5 mg of MTX dissolved in 100 ml of artificial CSF, was perfused over 2 h. In the eighth course of treatment, a CSF perfusion chemotherapy solution, consisting of 5 mg of ACNU, 10 mg of Ara-C and 5 mg of MTX dissolved in 100 ml of artificial CSF, was perfused over 2 h. In both treatments, the highest concentrations of Ara-C and MTX in CSF were observed 1 or 2 h after the end of perfusion, with the values of each drug being similar. The CSF AUCs of Ara-C and MTX in each treatment were of similar values. Although the highest concentration of ACNU in CSF was observed in the fifth treatment 1 h after injection (an injection chemotherapy of ACNU plus a perfusion chemotherapy of Ara-C and MTX), the concentration of ACNU in CSF was undetectable in the eighth treatment (a perfusion chemotherapy of ACNU, Ara-C and MTX). We were successful in administering all anticancer drugs, and reaching a level of over 1.0 microg/ml concentration in CSF of the lumbar spinal canal, using an injection chemotherapy of ACNU plus a perfusion chemotherapy of Ara-C and MTX; this was done even though the drugs, in particular ACNU, underwent some perfusion-period dependent decomposition.
Topics: Adult; Antimetabolites, Antineoplastic; Antineoplastic Agents; Astrocytoma; Brain Neoplasms; Cytarabine; Humans; Male; Methotrexate; Nimustine; Perfusion
PubMed: 11305611
DOI: 10.1248/bpb.24.436 -
JFMS Open Reports 2021A 14-year 3-month-old spayed female mixed-breed cat presented with jaundice, anaemia and thrombocytopenia. Haemophagocytic syndrome associated with lymphoma was...
CASE SUMMARY
A 14-year 3-month-old spayed female mixed-breed cat presented with jaundice, anaemia and thrombocytopenia. Haemophagocytic syndrome associated with lymphoma was suspected after cytological examination of the spleen. Despite treatment with prednisolone, L-asparaginase and nimustine, the cat died 176 days after the initial presentation. Necropsy revealed splenomegaly and hepatomegaly, without lymphadenopathy. Histopathologically, neoplastic lymphoid cells infiltrated the hepatic sinusoid and splenic sinus. The neoplastic lymphoid cells showed marked hepatocytotropism and contained erythrocytes, which was also confirmed by electron microscopy. Immunohistochemically, neoplastic lymphoid cells were positive for CD3, TIA1 (GMP-17) and granzyme B, and negative for CD8, CD20, CD56, CD57, CD79a and Iba1. Based on these findings, the cat was diagnosed with hepatosplenic T-cell lymphoma (HS-TCL) with hepatocytotropism.
RELEVANCE AND NOVEL INFORMATION
This case shows cytotoxic immunophenotype of HS-TCL in a cat, which has not been demonstrated before. Severe hepatocytotropism and haemophagocytosis of the neoplastic cells were likely to be associated with jaundice and anaemia, respectively, and the poor outcome of the present case.
PubMed: 33959376
DOI: 10.1177/20551169211005914 -
Oncotarget Oct 2015The outcome of cancer therapy strongly depends on the complex network of cell signaling pathways, including transcription factor activation following drug exposure. Here...
The outcome of cancer therapy strongly depends on the complex network of cell signaling pathways, including transcription factor activation following drug exposure. Here we assessed whether and how the MAP kinase (MAPK) cascade and its downstream target, the transcription factor AP-1, influence the sensitivity of malignant glioma cells to the anticancer drugs temozolomide (TMZ) and nimustine (ACNU). Both drugs induce apoptosis in glioma cells at late times following treatment. Activation of the MAPK cascade precedes apoptosis, as shown by phosphorylation of Jun kinase (JNK) and c-Jun, a main component of AP-1. Pharmacological inhibition and siRNA mediated knockdown of JNK and c-Jun reduced the level of apoptosis in LN-229 glioma cells treated with TMZ or ACNU. Analyzing the underlying molecular mechanism, we identified the pro-apoptotic gene BIM as a critical target of AP-1, which is upregulated following TMZ and ACNU. Importantly, shRNA mediated downregulation of BIM in the malignant glioma cell lines LN-229 and U87MG led to an attenuated cleavage of caspase-9 and, consequently, reduced the level of apoptosis following TMZ and ACNU treatment. Overall, we identified JNK/c-Jun activation and BIM induction as a late pro-apoptotic response of glioma cells treated with alkylating anticancer drugs.
Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; Cell Line, Tumor; Cell Nucleus; Comet Assay; Dacarbazine; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; MAP Kinase Kinase 4; MAP Kinase Signaling System; Membrane Proteins; Nimustine; Phosphorylation; Protein Structure, Tertiary; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-jun; RNA, Small Interfering; Signal Transduction; Temozolomide; Up-Regulation
PubMed: 26418950
DOI: 10.18632/oncotarget.5274 -
Neuro-oncology Oct 2013The alkylating agent temozolomide (TMZ) is widely used for the treatment of gliomas. Although reports of treatment-related myelodysplastic syndrome (MDS), acute myeloid... (Clinical Trial)
Clinical Trial
BACKGROUND
The alkylating agent temozolomide (TMZ) is widely used for the treatment of gliomas. Although reports of treatment-related myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) associated with TMZ are accumulating, it remains unclear whether TMZ has the same leukemogenic potential as other alkylating agents.
METHODS
We performed a single-institution retrospective analysis using a database of 359 glioma patients given nimustine (ACNU)-based therapy, TMZ-based therapy, or combination therapy, who were followed up for a minimum of 2 months, between January 1990 and December 2009, at the National Cancer Center Hospital in Japan.
RESULTS
Of the 359 patients, 225 received ACNU alone or ACNU plus other chemotherapeutic drugs (ACNU-based group; median follow-up period, 31.4 mo), 63 patients received ACNU-based therapy followed by TMZ therapy (ACNU-TMZ group; median follow-up period, 19.1 mo), and 71 patients received TMZ alone or TMZ plus other chemotherapeutic drugs (TMZ-based group; median follow-up period, 16.9 mo). Three patients in the ACNU-based group developed MDS/AML (incidence rate: 2.9 cases per 1000 person-years), 2 patients in the ACNU-TMZ group developed MDS/AML (13.0 cases per 1000 person-years), and 1 patient in the TMZ-based group developed ALL (9.9 cases per 1000 person-years).
CONCLUSIONS
Despite the limitations of this study, published reports and our results suggest that TMZ induces secondary hematological malignancies, particularly ALL, and might shorten the latency period when used in combination with other chemotherapeutic agents.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Brain Neoplasms; Child; Child, Preschool; Dacarbazine; Female; Follow-Up Studies; Glioma; Hematologic Neoplasms; Humans; Infant; Infant, Newborn; Male; Middle Aged; Neoplasm Staging; Neoplasms, Second Primary; Prognosis; Retrospective Studies; Temozolomide; Young Adult
PubMed: 23519741
DOI: 10.1093/neuonc/not036 -
JCO Clinical Cancer Informatics Dec 2018A major adverse effect arising from nimustine hydrochloride (ACNU) therapy for brain tumors is myelosuppression. Because its timing and severity vary among individual...
PURPOSE
A major adverse effect arising from nimustine hydrochloride (ACNU) therapy for brain tumors is myelosuppression. Because its timing and severity vary among individual patients, the ACNU dose level has been adjusted in an empiric manner at individual medical facilities. To our knowledge, ours is the first study to develop a machine-learning approach to estimate myelosuppression through analysis of patient factors before treatment and attempts to clarify the relationship between myelosuppression and hematopoietic stem cells from daily clinical data. Adverse effect prediction will allow ACNU dose adjustment for patients predicted to have decreases in blood cell counts and will enable focused follow-up of patients undergoing chemoradiotherapy.
PATIENTS AND METHODS
Patients were newly pathologically diagnosed with WHO grade 2 or 3 tumors and were treated with ACNU-based chemoradiotherapy. For detailed analysis of the timing and intensity of adverse effects in patients, we developed a data-weighted support vector machine (SVM) based on adverse event criteria (nadir-weighted SVM [NwSVM]). To evaluate the estimation accuracy of blood cell count dynamics, the determination coefficient ( r) between real and estimated data was calculated by three regression methods: polynomial, SVM, and NwSVM.
RESULTS
Only the NwSVM-based regression enabled estimation of the dynamics of all blood cell types with high accuracy (mean r = 0.81). The mean timing of nadir arrival estimated using this regression was 35 days for platelets, 41 days for RBCs, 52 days for lymphocytes, 57 days for WBCs, and 62 days for neutrophils.
CONCLUSION
The NwSVM can be used to predict myelosuppression and clearly depicts nadir timing differences between platelets and other blood cells.
Topics: Adult; Antineoplastic Agents; Blood Platelets; Brain Neoplasms; Female; Follow-Up Studies; Humans; Leukopenia; Lymphocytes; Machine Learning; Male; Middle Aged; Models, Statistical; Myelopoiesis; Nimustine; Prognosis
PubMed: 30652567
DOI: 10.1200/CCI.17.00022